Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

33. Classification, Use, and Toxicity of Clinically Useful Chemotherapy and Molecular Targeted Therapy

Roland T. Skeel

I. CLASSES OF DRUGS

Chemotherapeutic agents are customarily divided into several classes. For two of the classes, the alkylating agents and the antimetabolites, the names indicate the mechanism of cytotoxic action of the drugs in their class. For the hormonal agents, the name designates the physiologic action of the drug, and for the natural products, the name reflects the source of the agents. The biologic response modifiers include agents that mimic, stimulate, enhance, inhibit, or otherwise alter the host responses to the cancer. Molecular targeted agents affect defined and putative abnormalities in the cancer cell and its environment. Drugs that do not fit easily into other categories are grouped together as miscellaneous agents. Data for individual agents are given in Section III of this chapter.

Within each class are several types of agents (Table 33.1). As with the criteria for separating into class, the types are also grouped according to the mechanism of action, biochemical structure or derivation, and physiologic action. In some instances, these groupings into classes and types are arbitrary, and some drugs seem to fit into either more than one category or none. However, the classification of chemotherapeutic agents in this fashion is helpful in several respects. For example, because the antimetabolites interfere with purine and pyrimidine metabolism and the formation of DNA and RNA, they are all at least cell cycle-specificandinsomeinstancesprimarilycellcyclephase-specific. The nitrosourea group of alkylating agents, on the other hand, contains drugs that are predominantly or entirely cell cycle-nonspecific. Such knowledge can be helpful in planning therapy for tumors when sufficient kinetic information permits a rational selection of agents and when drugs are selected for use in combination.

The classification scheme also mayhelp to predict cross-resistance between drugs. Tumors that are resistant to one of the nitrogen mustard types of alkylating agents thus would be likely to be resistant to another of that same type, but not necessarily to one of the other types of alkylating agents such as the nitrosoureas or the metal salts (e.g., cis-platin). The classification system does not help in predicting multidrug resistance, which may have several phenotypes.

A. Alkylating agents

1. General description. The alkylating agents are a diverse group of chemical compounds capable of forming molecular bonds with nucleic acids, proteins, and many molecules of low molecular weight. The compounds either are electrophiles or generate electrophiles in vivo to produce polarized molecules with positively charged regions. These polarized molecules then can interact with electron-rich regions of most cellular molecules. The cytotoxic effect of the alkylating agents appears to relate primarily to the interaction between the electrophiles and DNA. This interaction may result in substitution reactions, cross-linking reactions, or strand-breaking reactions. The net effect of the alkylating agent’s interaction with DNA is to alter the information coded in the DNA molecule. This alteration results in inhibition or inaccurate replication of DNA, with resultant mutation or cell death. One implication of the mutagenic capability of alkylating agents is the possibility that they are teratogenic and carcinogenic. Because they interact with preformed DNA, RNA, and protein, the alkylating agents are not phase-specific, and at least some are cell cycle–nonspecific.

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2. Types of alkylating agents

a. Nitrogen mustards. These compounds produce highly reactive carbonium ions that react with the electron-rich areas of susceptible molecules. They vary in reactivity from mechlorethamine, which is highly unstable in aqueous form, to cyclophosphamide, which must be biochemically activated in the liver. Bendamustine, a mechlorethamine derivative, contains a purinelike benzimidazole ring, and the exact mechanism of action of this unique agent is unknown.

b. Ethylenimine derivatives. Triethylenethiophosphoramide (thiotepa) is the only compound in this group that has much clinical use. Ethylenimine derivatives are capable of the same kinds of reactions as the nitrogen mustards.

c. Alkyl sulfonates. Busulfan is the only clinically active compound in this group. It appears to interact more with cellular thiol groups than with nucleic acids.

d. Triazines. Dacarbazine and its relative temozolomide are believed to act primarily as alkylators of DNA.

e. Nitrosoureas. The nitrosoureas undergo rapid, spontaneous activation in aqueous solution to form products capable of alkylation and carbamoylation. They are unique among the alkylating agents with respect to not being cross-resistant with other alkylating agents, being highly lipid soluble, and having delayed myelosuppressive effects (6 to 8 weeks).

f. Metal salts. Cisplatin, carboplatin, and oxaliplatin inhibit DNA synthesis probably through the formation of intrastrand crosslinks in DNA and formation of DNA adducts. They also react with DNA through chelation or binding to the cell membrane.

B. Antimetabolites

1. General description. The antimetabolites are a group of low-molecular-weight compounds that exert their effect by virtue of their structural or functional similarity to naturally occurring metabolites involved in nucleic acid synthesis. Because they are mistaken by the cell for normal metabolites, they either inhibit critical enzymes involved in nucleic acid synthesis or become incorporated into the nucleic acid and produce incorrect codes. Both mechanisms result in inhibition of DNA synthesis and ultimate cell death. Because of their primary effect on DNA synthesis, the antimetabolites are most active in cells that are actively growing and are largely cell cycle phase–specific.

2. Types of antimetabolites

a. Folic acid analogs. Methotrexate, the earliest member of this group and until recently, the only one in wide clinical use, inhibits the enzyme dihydrofolate reductase. This inhibition blocks the production of the reduced N-methylenetetra-hydrofolate, the coenzyme in the synthesis of thymidylic acid. Other metabolic processes in which there is one-carbon unit transfer are also affected but are probably of less importance in the cytotoxic action of methotrexate. Pemetrexed is a multitargeted pyrrolopyrimidine-based antifolate that, when polyglutamated, inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide form-yltransferase. Pralatrexate is a folate analogue that competitively inhibits dihydrofolate reductase. It is also an inhibitor for polyglutamylation by folylpolyglutamyl synthetase.

b. Pyrimidine analogs. These compounds inhibit critical enzymes necessary for nucleic acid synthesis and may become incorporated into DNA and RNA.

c. Purine analogs. The specific site of action for the purine analogs is less well defined than for most pyrimidine analogs, although it is well demonstrated that they interfere with normal purine interconversions and thus with DNA and RNA synthesis. Some of the analogs also are incorporated into the nucleic acids. The adenosine deaminase inhibitor pentostatin increases the intracellular concentration of de-oxyadenosine triphosphates in lymphoid cells and inhibits DNA synthesis, probably by blocking ribonucleotide reductase. Among the metabolic alterations is nicotinamide adenine dinucleotide depletion, which may result in cell death. Cladribine accumulates in cells as the triphosphate, is incorporated into DNA, and inhibits DNA repair enzymes and RNA synthesis. As with pentostatin, nicotinamide ad-enine dinucleotide levels are also depleted. Fludarabine is a purine analog that causes inhibition of DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis, though the primary mechanism is not known.

C. Natural products

1. General description. The natural products are grouped together not on the basis of activity but because they are derived from natural sources. The clinically useful drugs include plant products, fermentation products of various species of the soil fungus Streptomyces, and bacterial products.

2. Types of natural products

a. Mitotic inhibitors. Vincristine, vinblastine, and their semi-synthetic derivatives vindesine and vinorelbine are derived from the periwinkle plant (Catharanthus roseus), a species of myrtle. They appear to act primarily through their effect on microtubular protein with a resultant metaphase arrest and inhibition of mitosis. Ixabepilone is an analog of epothilone B (produced by the myxobacterium Sorangium cellulosum) that binds to β-tubulin subunits on microtubules, causes suppression of microtubule dynamics, and blocks the cell in mitosis, which leads to cell death.

b. Podophyllum derivatives. Etoposide and teniposide, semi-synthetic podophyllotoxins derived from the root of the Mayapple plant (Podophyllum peltatum), form a complex with topoisomerase II, an enzyme that is necessary for the completion of DNA replication. This interaction results in DNA strand breakage and arrest of cells in late S and early G2 phases of the cell cycle.

c. Camptothecins. These agents are analogs of camptothecin, a derivative of the Chinese tree Camptotheca accuminata. The primary target of the two clinically active agents, irinotecan and to potecan, is DNA topoisomerase I.

d. Antibiotics. The antitumor antibiotics are a group of related antimicrobial compounds produced by Streptomyces species in culture. Their cytotoxicity, which limits their antimicrobial usefulness, has proved to be of great value in treating a wide range of cancers. All of the clinically useful antibiotics affect the function and synthesis of nucleic acids.

(1) Dactinomycin, the anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin), and the anthracenedione mitoxantrone cause topoisomerase II–dependent DNA cleavage and intercalate with the DNA double helix.

(2) Bleomycins cause DNA strand scission. The resulting fragmentation is believed to underlie the drug’s cytotoxic activity.

(3) Mitomycin causes cross-links between complementary strands of DNA that impair replication.

e. Enzymes. Asparaginase, the one example of this type of agent, catalyzes the hydrolysis of asparagine to aspartic acid and ammonia and deprives selected malignant cells of an amino acid essential to their survival.

D. Hormones and hormone antagonists

1. General description. The hormones and hormone antagonists that are clinically active against cancer include steroid estrogens, progestins, androgens, corticoids and their synthetic derivatives, nonsteroidal synthetic compounds with steroid or steroid-antagonist activity, aromatase inhibitors, hypothalamic–pituitary analogs, and thyroid hormones. Each agent has diverse effects. Some effects are mediated directly at the cellular level by the drug binding to specific cytoplasmic receptors or by inhibition or stimulation of the production or action of the hormones. These agents may also act by stimulating or inhibiting natural autocrine and paracrine growth factors (e.g., epidermal growth factor, transforming growth factors [TGFs]-α and -β). The relative roles of the various actions of hormones and hormone antagonists are only partially understood and probably vary among tumor types. For selective estrogen receptor modulators such as tamoxifen, which, when bound to the estrogen receptor, ultimately controls the promoter region of genes that affect cell growth, there are a host of modulating factors including some 20 receptor-interacting proteins and 50 transcription-activating factors as well as many response elements. Other effects are mediated through indirect effects on the hypothalamus and its anterior pituitary–regulating hormones. The final common pathway in most circumstances appears to lead to the malignant cell, which retains some sensitivity to direct or indirect hormonal control of its growth. An exception to this mechanism is the effect of corticosteroids on leukemias and lymphomas, in which the steroids appear to have direct lytic effects on abnormal lymphoid cells that have high numbers of glucocorticoid receptors.

2. Types of hormones and hormone antagonists

a. Androgens may exert their antineoplastic effect by altering pituitary function or directly affecting the neoplastic cell.

b. Antiandrogens inhibit nuclear androgen binding.

c. Corticosteroids cause lysis of lymphoid tumors that are rich in specific cytoplasmic receptors and may have other indirect effects as well.

d. Estrogens suppress testosterone production (through the hypothalamus) in males and alter breast cancer cell response to prolactin.

e. Progestins appear to act directly at the level of the malignant cell receptor to promote differentiation.

f. Selective estrogen receptor modulators (acting as estrogen antagonists) compete with estrogen for binding on the cytosol estrogen receptor protein in cancer cells. The receptor/hormone complex ultimately controls the promoter region of genes that affect cell growth.

g. Aromatase inhibitors are nonsteroidal inhibitors of the aromatization of androgens to estrogens. Aminoglutethimide is relatively nonselective, having many biochemical sites of inhibition of steroidogenesis. Its use requires corticosteroid replacement. In contrast, the selective aromatase inhibitors such as anastrozole or letrozole primarily block the conversion of adrenally generated androstenedione to estrone by aromatase in peripheral tissues without inhibition of progesterone or corticosteroid synthesis.

h. Hypothalamic hormone analogs, such as the luteinizing hormone–releasing hormone agonists leuprolide or goserelin, can inhibit luteinizing hormone (LH) and follicle-stimulating hormone (FSH; after initial stimulation) and the production of testosterone or estrogen by the gonads.

i. Thyroid hormones inhibit the release of thyroid-stimulating hormone, thus inhibiting growth of well-differentiated thyroid tumors.

E. Molecularly targeted agents

1. General. This classification is a relatively recent one in oncology that has become possible because of maturation of knowledge about the molecular events that are responsible for the development of cancer. Understanding of the genetic changes in the cancer cell, the downstream molecular events that follow as a consequence, and the mechanisms by which these events regulate cell growth and death has led to a host of possibilities for the control of cancer growth.

2. Tyrosine kinase and multikinase inhibitors. The first clinical example of this was the signal transduction inhibitor imatinib mesylate, which inactivates the constitutively active fusion product tyrosine kinase arising from the Philadelphia chromosome (Ph) found in chronic myelogenous leukemia (CML), Bcr-Abl, as well as c-kit kinase, which is overexpressed in gastrointestinal stromal tumors. There are now a large number of small molecule inhibitors of intracellular kinase activity (receptor and nonreceptor molecules) in clinical use, with demonstrated clinical efficacy in breast cancer, colon cancer, renal cell carcinoma, lung cancer, pancreatic cancer, and hepatoma.

3. Monoclonal antibodies have emerged over the last 10 to 15 years as useful adjuncts to the medical oncologist’s armamentarium. These agents, which may be directed at growth factors or their receptors, are derived from murine antibodies, may have varying levels of humanization (chimerism), and may be unconjugated (alemtuzumab, bevacizumab, cetuximab, ofatumumab, rituximab, trastuzumab) or conjugated with radionuclides (ibritumomab tiuxetan, tositumomab) or another toxic moiety (gemtuzumab).

4. Other agents. Other agents affect nuclear activity, such as the binding of all-trans-retinoic acid with cytoplasmic proteins, which in turn interact with nuclear retinoic acid receptors (RARs) that affect expression of genes that control cell growth and differentiation; inhibit proteosomes, which mediate protein degradation and play an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis; or perturb other critical pathways.

F. Miscellaneous agents

These are listed in Table 33.1. Descriptions of specific agents are found in Section III.

II. CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND MOLECULAR TARGETED AGENTS

Section III of this chapter contains an alphabetically arranged compendium that contains a description of the chemotherapeutic, biologic, and molecular targeted agents that are recognized to be clinically useful. Each drug is listed by its generic name, with other common names or trade names included. A brief description is given of the probable mechanism of action, clinical uses, recommended doses and schedules, precautions, and side effects.

A. Recommended doses: CAUTION

Although every effort has been made to ensure that the drug dosages and schedules given here are accurate and in accord with published standards, readers are advised to check the product information sheet included in the package of each U.S. Food and Drug Administration (FDA)-approved drug. For drugs not yet approved for general use, active protocol guidelines and any current medical literature should be used to verify recommended dosages, contraindications, and precautions and to review potential toxicity.

B. Dose selection and designation

The doses are listed using body surface area (square meters) as the base for nearly all the agents included. Adult doses from the literature, which are expressed using a weight base, have been converted by multiplying the milligram-per-kilogram dose by 37 to give the milligram-per-square-meter dose. Doses using a weight base, which have been taken from the pediatric literature, have been converted using a factor of 25. Because many of the drugs are given in combination with other agents, doses most commonly used in popular combinations may also be indicated. These data should not be used as the sole source of information for any of the drugs but rather should be used as a guide to confirm and compare dose ranges and schedules and to identify potential problems. For some agents, the area under the curve (AUC) method of dose calculation seems to be most reliable for achieving the most accurate dosing and balance between efficacy and toxicity; when that is the standard, the AUC dose is used.

C. Drug toxicity: frequency designation

The designation of the frequency of toxic side effects is indicated as follows (probability of occurrence equals percentage of patients who may be expected to experience the toxic effect):

bull Universal (90% to 100%)

bull Common (15% to 90%)

bull Occasional (5% to 15%)

bull Uncommon (1% to 5%)

bull Rare (1%).

These designations are meant only to be guides, and the likelihood of a side effect in each patient depends on that patient’s physical status, including comorbidities, treatment history, dose, schedule, and route of drug administration, as well as other concurrent treatment.

D. Dose modification

1. Philosophy. The optimal dose and schedule of a drug are those that give maximum benefit with tolerable toxicity. Most classical chemotherapeutic agents (and some of the targeted agents) have a steep dose-response curve; therefore, if no toxicity is seen, as a rule, a higher dose (dose escalation) of most of the classical chemotherapeutic agents should be given to get the best possible therapeutic benefit. If toxicity is great, however, the patient’s life may be threatened or the patient may decide that the treatment is worse than the disease and refuse further therapy. How much toxicity the patient and the physician are willing to tolerate depends on the likelihood that more intensive treatment will make a major therapeutic difference (e.g., cure versus no cure) and on the patient’s physical and psychological tolerance for adverse effects.

The general grading scheme for all toxicity is as follows:

bull 0: None

bull 1: Mild

bull 2: Moderate

bull 3: Severe

bull 4: Life-threatening.

2. Guidelines

a. Nonhematologic toxicity

(1) Acute effects. Acute drug toxicity that is limited to 1 to 2 days and is not cumulative is not usually a cause of dose modification unless it is of grade 3 or 4, that is, severe or life-threatening. (For individual toxicities, see the Common Terminology Criteria for Adverse Events v4.0, available on the Internet at http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm.) Occasionally, repeating a dose that caused intractable nausea and vomiting, a temperature higher than 40°C (104°F), or an acute infusion reaction is warranted, but for most other grade 3 or 4 toxicities, the subsequent doses should be reduced by 25% to 50%, assuming that the toxicity is believed to be dose-related. If the acute drug effects (e.g., severe paresthesias or abnormalities of renal or liver function) last longer than 48 hours, the subsequent doses should be reduced by 35% to 50%.

A recurrence of the grade 3 or 4 side effects at the reduced doses would be an indication either to reduce by another 25% to 50% or to discontinue the drug altogether. Non–dose-related toxicity such as anaphylaxis is an indication to discontinue the offending drug. Lesser degrees of hypersensitivity can often be dealt with effectively by increasing the dose of protective agents (like dexamethasone or diphenhydramine), desensitization (e.g., carbo-platin), or slowing the rate of infusion (e.g., rituximab). For some biologic agents, such as trastuzumab, physiologic effects that look like immunologic hypersensitivity reactions are probably related to cytokine release, occur primarily on first or second infusions, and diminish with continued treatment.

(2) Chronic effects. Chronic or cumulative toxicity such as pulmonary function changes with bleomycin or decreased cardiac function with doxorubicin is nearly always an indication to discontinue the responsible agent. Chronic or cumulative neurotoxicity due to vincristine, cisplatin, paclitaxel, or other agents may require no dose change, reduction, or discontinuation, depending on the severity of the resultant neurologic dysfunction and the patient’s ability to tolerate it.

b. Hematologic toxicity. The degree of myelosuppression and attendant risk of infection and bleeding that are acceptable depend on the cancer, the duration of the myelosup-pression, the goals of therapy, and the general health of the patient. In addition, one must consider the relative benefit of less aggressive or more aggressive therapy. For example, with acute nonlymphocytic leukemia, remission is unlikely unless sufficient therapy is given to cause profound pancytopenia for at least 1 week. Because there is little benefit with lesser treatment, grade 4 leukopenia and thrombocytopenia are acceptable toxicities in this circumstance. Grade 4 myelosuppression is also acceptable when the goal is cure of a cancer that does not involve the marrow, such as testicular carcinoma. With breast cancer, on the other hand, responses are seen with less aggressive treatment, and prolonged pancytopenia may not be acceptable, particularly if chemotherapy is being used palliatively or in an adjuvant setting in which the proportion of patients expected to benefit from chemotherapy is relatively small and excessive toxicity would pose an unacceptable risk.

With these caveats in mind, the dose modification schemes shown in Tables 33.2 and 33.3 can serve as a guide to reasonable dose changes for drugs whose major toxicity is myelosuppression. Separate schemes are given for drugs with relatively short myelosuppression and for drugs such as the nitrosoureas that have more prolonged myelosuppression.

c. Dosing for the obese patient. In general, patients who are overweight (body mass index [BMI] 25–29.9) and those who are obese (BMI 30–34.9) should be treated with full doses of chemotherapy, based on the body surface area calculated from their actual weight. Whether this is true for those who are very obese (BMI 35–39.9) or extremely obese (BMI >40) is not clear, owing to a lack of sufficient data. Many clinicians would limit the dose, using a maximum weight based on a BMI of 35 (maximum treatment weight (kg) = 35 × [height (m)]2).

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III. DATA FOR CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC. AND MOLECULAR TARGETED AGENTS

Note: Although every effort has been made to ensure that the drug dosage and schedules herein are accurate and in accordance with published standards, users are advised to check the product information sheet included in the package of each FDA-approved drug and FDA-National Cancer Institute guidelines for drugs that are not yet approved for general use to verify recommended dosages, contraindications, and precautions.

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Agents that have not yet been approved by the FDA may be included because they either have shown preliminary efficacy in clinical trials or are currently being investigated and show promise of benefit. As their efficacy and toxicity are more firmly established, it is expected that some will be approved by the FDA for general use, whereas others will remain investigational or be dropped from further study.

DRUG PROFILES

ALDESLEUKIN

Other names. Interleukin-2 (IL-2), Proleukin.

Mechanism of action. Enhances mitogenesis of T-cells, natural killer (NK) cells, and lymphokine-activated killer (LAK) cells; augments cytotoxicity of NK and LAK cells; induces interferon subcutanously weekly.

Primary indications

1. Renal cell carcinoma

2. Melanoma.

Usual dosage and schedule. A wide range of doses and routes (intravenous [IV] or subcutaneous [SC]) have been used. In any of the schedules, therapy may be stopped prematurely for severe constitutional symptoms or for cardiovascular, renal, hepatic, neurologic, pulmonary, or hematologic toxicity.

1. 600,000 IU/kg (22 × 106 IU/m2) as a 15-minute IVinfusion every 8 hours for up to 14 doses on days 1 to 5. Repeat on days 15 to 19. Repeat cycle in 6 to 12 weeks if stable or responding disease. This schedule has the most experience and is generally the recommended regimen.

2. 18 × 106 IU/m2/24 hours as a continuous IV infusion (CIVI) daily for up to 5 days. Repeat in 4 weeks. Repeat cycle in 4 to 6 weeks if stable or responding disease.

3. 22 × 106 IU/m2 as a 15-minute infusion for 5 consecutive days for 2 successive weeks. Repeat every 3 to 6 weeks as tolerated. In some regimens, it is preceded by 3 days with a single dose of low-dose cyclophosphamide, 350 mg/m2 IV push.

Schedules 1 and 2 require hospitalization. Schedule 3 can be given in an outpatient setting but may require several hours of observation after treatment. Lower dose schedules and SC administration are generally not recommended.

Special precautions. Patients must be carefully monitored after treatment using any of the dosing regimens. Outpatient regimens require that patients have cardiovascular status observed for up to 5 hours, particularly after the first several doses. With higher doses, capillary leak syndrome resulting in hypotension, pulmonary edema, myocardial infarction, arrhythmias, azotemia, and alterations in mental status may occur. Administration of dopamine (1 to 5 μg/kg/min) to patients manifesting capillary leak syndrome, before the onset of hypotension, can help to maintain organ perfusion and thus preserve urine output. Weight and urine output should be carefully monitored. If organ perfusion and blood pressure are not sustained, increasing the dose of dopamine to 6 to 10 μg/kg/min or adding phenylephrine hydrochloride (1 to 5 μg/kg/min) to low-dose dopamine may be indicated. Administration of IV fluids, either colloids or crystalloids, is recommended for treatment of hypovolemia. Correction of hypovolemia may require large volumes of IV fluids, but caution is required because unrestrained fluid administration may exacerbate problems associated with edema formation or effusions.

Prolonged use of pressors, either in combination or as individual agents, at relatively high doses may be associated with cardiac rhythm disturbances. Intensive care and intubation may be required.

Toxicity. All are dose dependent.

1. Myelosuppression and other hematologic effects. Uncommon at lower doses; common but rarely serious at higher doses. Anemia requiring transfusion is common at higher doses. Thrombocytopenia is common at higher doses.

2. Nausea, vomiting, and other gastrointestinal effects:

a. Anorexia, nausea, vomiting, and diarrhea are common.

b. Transient liver function abnormalities, including hyperbilirubinemia and hypoalbuminemia and elevation of the prothrombin time (PT) and partial thromboplastin time, are common.

c. Colonic perforations are rare.

3. Mucocutaneous effects. Mucositis is occasional to common. Alopecia is uncommon. Pruritic erythematous rash is common.

4. Cardiovascular effects:

a. Arrhythmias are common and dose-related.

b. Hypotension is dose-related but is occasionally seen at the lower dose schedules.

c. Myocardial injury is seen primarily at the higher dose schedules.

d. Pulmonary edema from capillary leak syndrome is common with intensive dose regimens.

e. Weight gain is common from edema, particularly in more intensive dose regimens.

5. Neuropsychiatry effects:

a. Mental status changes are common, with dose-related severity.

b. Dizziness or light-headedness is common.

c. Blurry vision and other visual disturbances are occasional.

d. Seizures are uncommon to rare at lower dose regimens.

6. Renal function impairment. Common but reversible. More frequent laboratory abnormalities include creatinine elevation, hypomagnesemia, acidosis, hypocalcemia, hypophosphatemia, hypokalemia, hypouricemia, and hypoalbuminemia.

7. Fever. With or without chills, fever is common and may be severe.

8. Bacterial infection. Occasional. Probably related to chemotactic defect induced in granulocytes.

9. Myalgias and arthralgias. Occasional to common.

10. Malaise and fatigue. Common and dose-related.

Prophylaxis of acute toxicity

1. Acetaminophen 650 mg by mouth before therapy and every 6 hours for one or two doses for outpatient IL-2 dosing; every 6 hours for 3 doses for inpatient IL-2 regimens.

2. Cimetidine 800 mg by mouth, or other histamine H2-receptor antagonist before therapy and daily for duration of treatment.

3. Antiemetics: granisetron, ondansetron, or other 5HT3 antagonist; metoclopramide, and prochlorperazine may be used. Do not use dexamethasone.

4. Meperidine 25 to 50 mg IV when chills start after first dose. For subsequent doses, meperidine 50 mg by mouth 1.5 hours before chills are predicated to start, based on the first treatment.

5. Hydromorphone 0.5 to 1 mg IV may be substituted for meperidine in patients who tolerate meperidine poorly.

6. Diphenoxylate with atropine (Lomotil) 1 tablet up to six times daily for diarrhea.

7. Hydroxyzine 25 to 50 mg every 6 hours for itching.

ALEMTUZUMAB

Other names. Campath, Campath-1H

Mechanism of action. Alemtuzumab is a chimeric (murine and human) monoclonal antibody directed against the CD-52 antigen found on the surface of 95% of B- and T-lymphocytes. It is also expressed in other normal cells found in the peripheral blood and marrow, as well as some other somatic cells. Cellular cytotoxicity is mediated through complement-mediated lysis, antibody dependent cellular cytotoxicity, and induction of apoptosis.

Primary indications

1. B-cell chronic lymphocytic leukemia

2. Nonmalignant conditions and graft-versus-host disease.

Usual dosage and schedule (malignant conditions only).

1. Initiation: 3 mg as a 2-hour IV infusion daily.

2. Escalation: When infusion related toxicities are lower than grade 2, the dose is escalated to 10 mg as a 2-hour IV infusion daily. When the 10-mg dose is tolerated, maintenance therapy is initiated.

3. Maintenance: 30 mg as a 2-hour IVinfusion three times a week—on alternate days—for 12 weeks.

Infusion-related events (see subsequent discussions) are ameliorated by pretreatment with antihistamines, acetaminophen, and antiemetics, as well as incremental dose escalation.

Special precautions. Must not be administered as IV push or bolus dose. Single doses of greater than 30 mg and cumulative doses of greater than 90 mg/week should not be given. If therapy is interrupted for 7 or more days, the dose initiation and escalation scheme is required to avert toxicity. Alemtuzumab is contraindicated in patients who have active systemic infections, underlying immunodeficiency, or known type I hypersensitivity or anaphylactic reactions to the drug or any of its components. Reactivation of hepatitis B or other viruses is a risk.

Toxicity

1. Myelosuppression and other hematologic effects. Lymphopenia is universal. Neutropenia, anemia, and thrombocytopenia are common and often severe (grade 3) or greater. Opportunistic and other infections, including pneumonia and sepsis, are seen in 10% to 15% of patients. Autoimmune hemolytic anemia and thrombocytopenia are uncommon (1% to 2%). Pancytopenia and marrow hypoplasia are uncommon but may require permanent discontinuation of therapy. Because of the high incidence of opportunistic infections, prophylaxis against Pneumocystis jiroveci pneumonia and herpes virus infections during and at least 2 months after completion of treatment is recommended.*

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common; diarrhea, abdominal pain, and dyspepsia are occasional.

3. Mucocutaneous effects. Rash, urticaria, pruritis, and increased sweating are common. Stomatitis is occasional.

4. Infusion-relatedevents. Rigors, fever, nausea and vomiting, and rash— including urticaria—are common. Shortness of breath, hypotension, bronchospasm, headache, pruritis, and diarrhea are occasional. Angioedema is uncommon.

* For Pneumocystis jiroveci pneumonia prophylaxis: trimethoprim-sulfamethoxazole double strength, 1 tablet by mouth twice a day (on Monday, Wednesday, and Friday). If allergic, use dapsone 100 mg on Monday, Wednesday, and Friday. For herpes zoster prophylaxis, famciclovir 250 mg by mouth twice a day or valacyclovir 500 mg by mouth three times a day.

5. Miscellaneous effects:

a. Respiratory: Dyspnea, cough, and bronchitis are common. Pneumonia, pharyngitis, bronchospasm, and rhinitis are occasional.

b. Cardiovascular: Hypotension is common; hypertension occasional. Tachycardia and supraventricular tachycardia are occasional, but usually not severe. Syncope is uncommon.

c. Hypersensitivity reactions to alemtuzumab may occur (2%) and result in hypersensitivity to other monoclonal antibodies.

d. Neuropsychiatric: Insomnia, depression, and somnolence are occasional. Headache, dysthesias, dizziness, and tremor are occasional.

e. Infections: Reactivation of hepatitis B and other viruses is uncommon to rare.

ALITRETINOIN

Other names. 9-cis-retinoic acid, Panretin Gel.

Mechanism of action. Binds to cytoplasmic retinoic acid-binding proteins and then is transported to the nucleus where it interacts with nuclear RARs. These then affect expression of the genes that control cell growth and differentiation.

Primary indication. AIDS-related cutaneous Kaposi sarcoma.

Usual dosage and schedule. Apply sufficient gel (0.1%) to cover lesion with a generous coating 2 to 4 times daily, according to individual lesion tolerance. Allow to dry for 3 to 5 minutes before covering with clothing.

Special precautions. Women are advised to avoid becoming pregnant because of potential fetal risk. Minimize exposure to ultraviolet rays from sun or sun lamps.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. None

3. Mucocutaneous effects. Skin reactions with erythema, scaling, irritation, redness, rash, or other dermatitis are common. Pruritis, exfoliative dermatitis, or other erosive or draining skin lesions are occasional.

4. Miscellaneous effects:

a. Neurologic complaints of burning or pain are common.

b. Edema is occasional.

ALTRETAMINE

Other names. Hexamethylmelamine, Hexalen, HXM.

Mechanism of action. Unknown. Although it structurally resembles the known alkylating agent triethylenemelamine, it has some antimetabolite characteristics.

Primary indication. Carcinoma of the ovary that is persistent or recurrent after first-line therapy.

Usual dosage and schedule

1. 260 mg/m2 by mouth daily in three or four divided doses after meals and at bedtime for 14 or 21 days every 4 weeks when used as a single agent.

2. 150 to 200 mg/m2 by mouth daily in three or four divided doses for 2 out of 3 or 4 weeks when used in combination.

Special precautions. Concurrent altretamine and antidepressants of the monoamine oxidase inhibitor class may cause severe orthostatic hypotension. Cimetidine may increase toxicity.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and thrombocytopenia are uncommon, though lesser degrees are common. Anemia is common.

2. Nausea, vomiting, and other gastrointestinal effects. Mild to moderate nausea, vomiting, and other gastrointestinal effects occur in about 30% of patients and are rarely severe. Diarrhea is occasional. Tolerance may develop.

3. Mucocutaneous effects. Alopecia, skin rash, and pruritus are rare.

4. Miscellaneous effects:

a. Peripheral sensoryneuropathies are common and maybe ameliorated by pyridoxine, but tumor response may be compromised.

b. Central nervous system (CNS) effects, including agitation, confusion, hallucinations, depression, and parkinsonian-like symptoms are uncommon with recommended intermittent schedule.

c. Decreasedrenalfunctionis occasional.

d. Increased alkaline phosphatase level is occasional.

AMIFOSTINE

Other name. Ethyol.

Mechanism of action. The prodrug amifostine is dephosphorylated to an active lree thiol metabolite that can reduce the toxic effects of cisplatin. The differential activity between normal and cancer tissue is thought to be related to higher capillary alkaline phosphatase activity and better vascularity of normal tissue. Pretreatment reduces cumulative renal toxicity from cisplatin.

Primary indications

1. For reduction of cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced cancer.

2. For reduction of moderate to severe xerostomia from radiation of the head and neck where the radiation port includes a substantial portion of the parotid glands.

Usual dosage and schedule

1. For reduction of cumulative renal toxicity with chemotherapy: 910 mg/m2 IV over 15 minutes once daily, starting 30 minutes before chemotherapy.

2. For reduction of xerostomia from radiation of the head and neck: 200 mg/m2 administered once daily as a 3-minute IV infusion, starting 15 to 30 minutes prior to standard fraction radiation therapy (1.8 to 2.0 Gy).

Special precautions. To minimize hypotension during the infusion, patients should be adequately hydrated prior to the amifostine infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion and thereafter as clinically indicated. Interrupt the infusion if the decrease in systolic pressure is more than 20% to 25% of the baseline systolic pressure.

Toxicity

1. Myelosuppression and other hematologic effects. Not increased by amifostine.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common and may be severe.

3. Mucocutaneous effects. Rarely, serious cutaneous reactions have been associated with amifostine administration. They have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and exfoliative dermatitis.

4. Miscellaneous effects:

a. Transient hypotension during the infusion is common. Loss of consciousness may occur, but is usually easily reversed.

b. Flushing and feeling of warmth are occasional.

c. Chilling and feeling of coldness are occasional.

d. Dizziness, somnolence, hiccups, and sneezing are occasional.

e. Allergic reactions are rare but have included anaphylactic reactions.

f. Hypocalcemia is rare.

g. Seizures are rare.

AMINOGLUTETHIMIDE

Other names. Cytadren.

Mechanism of action. Inhibits aromatization and cytochrome P-450 hydroxylating enzymes, thereby blocking the conversion of androgens to estrogens and the biosynthesis of all steroid hormones. This drug causes, in effect, a reversible chemical adrenalectomy.

Primary indications. Adrenocortical carcinoma and ectopic Cushing syndrome.

Usual dosage and schedule. 1000 mg by mouth daily in four divided doses.

Special precautions. Hydrocortisone must be given concomitantly to prevent adrenal insufficiency. Suggested dose is 100 mg by mouth daily in divided doses for 2 weeks, then 40 mg by mouth daily in divided doses.

Toxicity

1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are rare; if they occur, they resolve rapidly when the drug is stopped.

2. Nausea, vomiting, and other gastrointestinal effects. Occasionaland usually mild.

3. Mucocutaneous effects. A morbilliform rash is commonly seen during the first week of treatment, but it usually disappears within 1 week.

4. Hormonaleffects:

a. Adrenal insufficiency is common without replacement hydro-cortisone in patients with normal adrenal glands.

b. Hypothyroidism is uncommon.

c. Masculinization is possible.

5. Neurologic effects:

a. Lethargy is common. Although usually mild and transient, it is occasionally severe.

b. Vertigo, nystagmus, and ataxia are occasional.

c. Headache is uncommon.

6. Miscellaneous effects:

a. Facial flushingisuncommon.

b. Periorbitaledemais uncommon.

c. Cholestatic jaundice is rare.

d. Fever is uncommon.

ANAGRELIDE

Other names. Imidazo(2,1-b)quinazolin-2-one, Agrylin.

Mechanism of action. Mechanism for thrombocytopenia unknown but may be due to impaired megakaryocyte function. Inhibitor of platelet aggregation but not at usual therapeutic doses.

Primary indication. Uncontrolled thrombocytosis in chronic myeloprolifer-ative disorders, such as essential thrombocythemia, chronic granulocytic leukemia, and polycythemia rubra vera.

Usual dosage and schedule

1. 0.5 mg by mouth four times a day or 1 mg by mouth twice a day. Increase by 0.5 mg/d every 5 to 7 days if no response. Maximum daily dose is 10 mg/day. Maximum single dose is 2.5 mg. Higher doses cause postural hypotension.

2. Alternate dosing schedules:

a. Elderly: 0.5 mg by mouth daily, increase by 0.5 mg each week.

b. Abnormal renal or hepatic function: 0.5 mg by mouth twice a day.

Special precautions. Contraindicated in patients who are pregnant and in patients with severe hepatic impairment. Use with caution in patients with heart disease. Tachycardia and forceful heartbeat may be exacerbated by caffeine; consumption of caffeine should be avoided for 1 hour before and 1 hour after anagrelide is taken. Use other drugs that inhibit platelet aggregation (such as nonsteroidal anti-inflammatory drugs [NSAIDs]) with caution. Monitor platelet count every few days during the first week, then weekly until the maintenance dose is reached.

Toxicity

1. Myelosuppression and other hematologic effects. Leukopenia is rare. Anemia is common but mild. Thrombocytopenic hemorrhage is uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are occasional. Diarrhea, gas, and abdominal pain are common; pancreatitis is rare. Lactase supplementation eliminates diarrhea (anagrelide formulated with lactose). Hepatic enzyme elevation is rare, but caution is recommended when there is evidence of hepatic dysfunction.

3. Mucocutaneous. Rash, including urticaria, is occasional (8%). Hy-perpigmentation is rare. Sun sensitivity is possible.

4. Miscellaneous effects:

a. Cardiovascular: Palpitations, forceful heartbeat, and tachycardia are common. Congestive heart failure is uncommon, but fluid retention or edema is common. Tachyarrhythmias (including atrial fibrillation and premature atrial beats) are occasional. Angina, cardiomyopathy, or other severe cardiovascular effects are rare, although there are somewhat more frequent (8%) episodes of chest pain. Drinking alcoholic beverages may cause flushing. Higher than recommended single doses cause postural hypotension. Cardiovascular effects appear to result from vasodilation, positive inotropy, and decreased renal blood flow.

b. Neurologic: Headaches are common and occasionallyare severe; they usually diminish in about 2 weeks. Weakness (asthenia) is common. Dizziness is occasional.

c. Pulmonary: Infiltrates are rare but areareason to stop anagrelide and treat with steroids.

ANASTROZOLE

Other name. Arimidex.

Mechanism of action. Decreases estrogen biosynthesis by selective inhibition of aromatase (estrogen synthetase).

Primary indications

1. Carcinoma of the breast as adjuvant treatment in postmenopausal women with positive hormone receptors.

2. Carcinoma of the breast that is advanced or metastatic as first therapy in postmenopausal women with positive or unknown hormone receptors.

3. Carcinoma of the breast that is advanced or metastatic as second therapy in postmenopausal women with progression following initial response to tamoxifen.

Usual dosage and schedule. 1 mg by mouth daily.

Special precautions. Potential hazard to fetus if given during pregnancy. In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events occurred with anastrozole use compared to tamoxifen use. Consider obtaining bone mineral density testing prior to initiation of anastrozole and treating as clinically indicated.

Toxicity

1. Myelosuppression and other hematologic effects. No dose-related myelosuppression. Thromboembolic events are uncommon (3%).

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, diarrhea, and constipation are occasional. Vomiting is uncommon.

3. Mucocutaneous effects. Rash is occasional. Hot flushes are common (35%). Vaginal dryness and leukorrhea are uncommon.

4. Miscellaneous effects:

a. Asthenia is common. Headache and dizziness are occasional.

b. Musculoskeletalpainis occasional.Arthralgiais occasional.

c. Peripheral edema and weight gain are occasional (lower than with megestrol).

d. Dyspnea and cough are occasional.

e. Cataracts are occasional (6%).

f. Decreased bone mineral density with osteoporosis is occasional (11%), and there is increased risk for fractures (10%).

g. Vaginal bleeding is uncommon, and endometrial cancer is rare (0.2%).

ARSENIC TRIOXIDE

Other names. Trisenox.

Mechanism of action. Although the mechanism is incompletely understood, effects of arsenic trioxide include morphologic changes and DNA fragmentation characteristic of apoptosis and alteration of the fusion protein PML-RAR alpha.

Primary indication. Acute promyelocytic leukemia that is refractory to retinoid and anthracycline therapy and has t(15;17) translocation or PML-RAR alpha gene expression.

Usual dosage and schedule

1. Induction: 0.15 mg/kg IV daily until marrow remission. Maximum of 60 doses.

2. Consolidation: 0.15 mg/kgIVdailyfor 25 doses overaperiod ofup to 5 weeks. Consolidation is started 3 to 6 weeks after completion of induction therapy.

Special precautions. Tachycardia and prolonged QT interval are common. This may lead to complete arteriovenous (AV) block with fatal ventricular arrhythmia. Electrolyte (including magnesium) abnormalities should be corrected prior to initiation of therapy, and patients with prolonged QT intervals should have measures taken to reduce this prolongation prior to treatment with arsenic trioxide. A QT value greater than 500 msec during therapy is an indication to suspend arsenic trioxide treatment and to initiate measures to correct other risk factors that may be contributing to the prolongation of the QT.

Acute promyelocytic leukemic differentiation syndrome, similar to that seen with retinoic acid, may be seen and is potentially fatal. This syndrome consists of fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions with or without leukocytosis. High-dose corticosteroids (e.g. dexamethasone 10 mg twice a day) should be started at the first signs of this syndrome and continued until it has subsided.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia, thrombocytopenia, and neutropenia are occasional. Leukocytosis is common. Disseminated intravascular coagulation is occasional and may be severe. Infections and neutropenic fever are occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, diarrhea, and abdominal pain are common (>50%). Gastrointestinal bleeding, with or without diarrhea, is occasional (8%). Constipation, anorexia, and other abdominal distress are occasional.

3. Mucocutaneous effects. Sore throat is common (40%). Dermatitis, pruritis, and ecchymosis are also common. More severe mu-cocutanous reactions including local exfoliation, urticaria, and oral blistering are occasional to uncommon. Epistaxis is common (25%). Eye irritation and injection are occasional.

4. Miscellaneous effects:

a. Cardiovascular: Tachycardia and prolonged QT interval are common. This may lead to complete AV block with fatal ventricular arrhythmia.

b. Acute promyelocytic leukemic differentiation syndrome, similar to that seen with retinoic acid, may be seen. This consists of fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions with or without leukocytosis. This syndrome may be fatal.

c. General and administration site: Headache and insomnia are common. Edema and pleural effusion are common (though not commonly serious), and general weight gain is occasional. Drug hypersensitivity is uncommon. Injection site edema, erythema, and pain are occasional.

d. Metabolic: Hypokalemia, hypomagnesemia, and hyperglycemia are common (45% to 50%). Hyperkalemia is occasional to common (18%), as are elevated transaminases, hypocalcemia, and hypoglycemia.

e. Pulmonary: Cough and dyspnea are common (>50%). Pleural effusion, hypoxia, wheezing, and asymptomatic ascultatory findings are occasional to common (8% to 20%).

f. Renal: Renal failure is occasional.

ASPARAGINASE

Other names. L-Asparaginase, Elspar, Kidrolase, pegaspargase, Oncaspar.

Mechanism of action. Hydrolysis of serum asparagine occurs, which deprives leukemia cells of the required amino acid and inhibits protein synthesis. Normal cells are spared because they generally have the ability to synthesize their own asparagine. Pegaspargase is a chemically modified formulation of asparaginase in which the L-asparaginase is covalently conjugated with monomethoxypolyethylene glycol (PEG). This modification increases its half-life in the plasma by a factor of 4 to about 5.7 days and reduces its recognition by the immune system, which allows the drug to be used in patients previously hypersensitive to native L-asparaginase.

Primary indication. Acute lymphocytic leukemia, primarily for induction therapy.

Usual dosage and schedule. All schedules are used in combination with other drugs. The schedules listed are only a few of many acceptable dosing schedules.

1. L-asparaginase 6000 IU/m2 SC on days 5, 8, 11, 15, and 22 of the treatment period.

2. L-asparaginase 10,000 IUIV dailyfor 10 successive days beginning on day 17 of the treatment period.

3. Pegaspargase 2500 IU/m2 intramuscularly (IM; or IV) once every 14 days, either for first-line acute lymphocytic leukemia or in patients who have developed hypersensitivity to native forms of as-paraginase. For IM use, limit volume at single injection site to 2 mL. For IV administration, give over 1 to 2 hours in saline or normal saline with 5% dextrose.

Special precautions. Asparaginase is contraindicated in patients with pancreatitis or a history of pancreatitis. Asparaginase is contraindicated in patients who have had significant hemorrhagic events associated with prior L-asparaginase therapy. Pegaspargase is also contraindicated in patients who have had previous serious allergic reactions, such as generalized urticaria, bronchospasm, laryngeal edema, hypotension, or other unacceptable adverse reactions to prior pegaspargase.

Be prepared to treat anaphylaxis at each administration of the drug. Epinephrine, antihistamines, corticosteroids, and life-support equipment should be readily available. Giving concurrently with or immediately before vincristine may increase vincristine toxicity. The IM route is preferred for pegaspargase because of a lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and renal disorders compared to the IV route of administration.

Toxicity

1. Myelosuppression and other hematologic effects. Occasional myelosup-pression. CNS thrombosis and other coagulopathies are uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Occasionalandusually mild (see subsequent discussion for liver and pancreas effects).

3. Mucocutaneous effects. No toxicity occurs except as a sign of hyper-sensitivity.

4. Anaphylaxis. Mild to severe hypersensitivityreactions, including ana-phylaxis, occur in 20% to 30% of patients. Such reaction is less likely to occur during the first few days of treatment. It is particularly common with intermittent schedules or repeat cycles. If the patient develops hypersensitivity to the Escherichia coli-derived enzyme (Elspar), Erwinia-derived asparaginase may be safely substituted because the two enzyme preparations are not cross-reactive. Note that hypersensitivity may also develop to Erwinia-derived asparaginase, and continued preparedness to treat anaphylaxis must be maintained.

If given via the IM route, asparaginase should be given in an extremity so that a tourniquet can be applied to slow the systemic release of asparaginase should anaphylaxis occur.

Approximately 30% of patients previously sensitive to L-aspara-ginase will have a hypersensitivity reaction to pegaspargase, while only 10% of those who were not hypersensitive to the native form will have a hypersensitivity reaction to the PEG-modified drug.

5. Miscellaneous effects:

a. Mild fever and malaise are common and occasionally progress to severe chills and malignant hyperthermia.

b. Hepatotoxicity is common and occasionally severe. Abnormalities observed include elevations of serum glutamic-oxaloacetic transaminase (SGOT), alkaline phosphatase, and bilirubin; depressed levels of hepatic-derived clotting factors and albumin; and hepatocellular fatty metamorphosis.

c. Renal failure is rare.

d. Pancreatic endocrine and exocrine dysfunction, often with manifestations of pancreatitis, occasionally occurs. Nonketotic hyperglycemia is uncommon.

e. CNS effects (depression, somnolence, fatigue, confusion, agitation, hallucinations, or coma) are seen occasionally. They are usually reversible following discontinuation of the drug.

AZACITIDINE

Other name. Vidaza.

Mechanism of action. Pyrimidine analog that inhibits methyltransferase, causing hypomethylation of DNA and thus, it is believed, results in cellular differentiation or apoptosis. May restore normal function of genes that are critical for the control of cellular differentiation and proliferation. Nonproliferating cells are relatively insensitive to azacitidine.

Primary indication. Myelodysplastic syndromes (MDSs).

Usual dosage and schedule. 75 mg/m2 SC or IV daily for 7 days, repeated every 4 weeks. Dose may be increased to 100 mg/m2 if no toxicity other than nausea and vomiting. Therapy may be continued as long as the patient has improved from the drug.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common. Febrile neutropenia is four times as common as in patients receiving supportive care. Petechiae or ecchymosis are occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea or constipation are common. Abdominal pain is occasional.

3. Mucocutaneous effects. Pharyngitis and stomatitis are occasional. Skin rash and urticaria are occasional. Injection site pain is common.

4. Neurotoxicity. Insomnia is common. Lethargy, dizziness, or confusional state are occasional.

5. Miscellaneous effects:

a. Cardiorespiratory: Cough and dyspnea are common. Pulmonary edema is uncommon. Edema is occasional. Tachycardia or other more serious cardiac disorders are uncommon.

b. Fever is common.

c. Fatigueandweaknessarecommon.

d. Arthralgias andbackpain are occasional.

e. Hypokalemia is occasional.

BENDAMUSTINE

Other names. Treanda, bendamustine hydrochloride.

Mechanism of action. Bendamustine is an alkylating agent that is a bifunctional mechlorethamine derivative containing a purinelike benzimidazole ring. It forms interstrand DNA crosslinks that lead to cell death in both resting and dividing cells, though the exact mechanism of cell death is not clear.

Primary indications

1. Chronic lymphocytic leukemia

2. Indolent B-cell non-Hodgkin lymphoma.

Usual dosage and schedule

1. Chronic lymphocytic leukemia: 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6 cycles.

2. Non-Hodgkin lymphoma: 120 mg/m2 IV over 30 minutes on days 1 and 2 of a 21-day cycle, up to 8 cycles.

Initiation of successive cycles of therapy is usually delayed until there is an absolute neutrophil count (ANC) of at least 1 × 109/L and a platelet count of at least 75 × 109/L. Dose reductions of 50% to 75% should be initiated for grade 3 to 4 hematologic or nonhematologic toxicity.

Special precautions. Infusion reactions consisting of fever, chills, pruritis, and rash are common. Severe anaphylactic or anaphylactoid reactions, particularly in the second or subsequent cycles of therapy, may rarely occur. Antihistamines (e.g., diphenhydramine and cimetidine) and corti-costeroids are commonly used to minimize the severity of infusion reactions. Tumor lysis syndrome has been observed, particularly in the first cycle of therapy. Toxic epidermal necrolysis has rarely occurred when bendamustine was given with rituximab. Stevens-Johnson syndrome has rarely occurred when bendamustine was administered concomitantly with allopurinol. The relationship of these severe reactions to bendamustine is not known. If severe skin reactions occur, bendamustine should be withheld or discontinued. Do not give if known hypersensitivity to bendamustine or mannitol. Bendamustine can cause fetal harm and must not be administered to pregnant women.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression is common and is universal in the higher dosage ranges. Grade 3 to 4 leukopenia (both neutrophils and lymphocytes) is common. Grade 3 to 4 anemia and thrombocytopenia are occasional. Infections overall are occasional. Pneumonia and neutropenic sepsis are uncommon but may be fatal.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are occasional to common and dose-dependent, but rarely severe. Anorexia, dyspepsia, gastroesophageal reflux, upper abdominal pain, and distention are occasional.

3. Mucocutaneous effects. Skin rash and pruritis are occasional, including toxic skin reactions and bullous exanthema.

4. Immunologic effects and infusion reactions. Infusion reactions consisting of fever, chills, pruritis, and rash are common. Severe ana-phylactic or anaphylactoid reactions, particularly in the second or subsequent cycles of therapy, are rare. Preventive measures, including antihistamines and corticosteroids, should be given if grade 1 or 2 infusion reactions were experienced in a prior cycle. Bendamustine should generally not be repeated if patients have had a prior grade 3 or 4 infusion reaction.

5. Miscellaneous effects:

a. Fever (occasionally with chills) and fatigue are common; weakness and weight loss are occasional.

b. Tumor lysis syndrome, including hyperuricemia, may occur, primarily with the first cycle of therapy, and lead to acute renal failure. With concomitant allopurinol, watch closely for severe skin reactions.

c. Hypokalemia is only occasional, but may be severe.

d. Cough, dyspnea, throat pain, wheezing, and nasal congestion are occasional to common.

e. Hypotension is occasional.

BEVACIZUMAB

Other name. Avastin.

Mechanism of action. Binds vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors on the surface of endothelial cells. This in turn impairs endothelial cell proliferation and new blood vessel formation, impeding tumor growth and metastasis.

Primary indications

1. Breast, colon, kidney, rectum, and nonsquamous non–small-cell lung cancers, usually with other agents.

2. Glioblastoma, alone or with other agents.

Usual dosage and schedule

1. 5 to 10 mg/kg IV once every 2 weeks

2. 15 mg/kg IV once every 3 weeks.

Special precautions. Gastrointestinal perforation occurs in up to 4% of patients and may have a fatal outcome. Impaired wound healing may rarely lead to anastomotic dehiscence. Bevacizumab should not be initiated for at least 28 days following major surgery. The interval between termination of bevacizumab and subsequent surgery should take into account the accumulation ratio of 2.8 (with dosing every 2 weeks) and the half-life of approximately 20 days. Blood pressure monitoring is recommended every 2 to 3 weeks because of the risk of hypertension. Reversible posterior leu-koencephalopathy syndrome (RPLS) has been reported rarely; if it occurs, therapy must be discontinued immediately and treatment for hypertension initiated if it is present. Urinary protein should be evaluated prior to each treatment with a urine dipstick, and if 2 + or greater, the patient should undergo further assessment to rule out severe proteinuria, such as with a urine protein-creatinine (UPC) ratio. Hold therapy if UPC is greater than 3.5.

Toxicity

1. Myelosuppression and other hematologic effects. Leukopenia is common but associated primarily with the cytotoxic agents used together with bevacizumab. Thrombocytopenia is uncommon. Minor bleeding, such as epistaxis, is common; severe hemorrhage is not common, except for hemoptysis in patients with squamous cell carcinomas of the lung. Serious, and in some cases fatal, hemoptysis has occurred in non–small-cell lung cancer, with the highest risk appearing in patients with squamous cell histology; other severe or fatal hemorrhage, including CNS bleeding, has occurred. Thromboembolic events are occasional and may be severe.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and constipation are common. Diarrhea is common, particularly when used with fluorouracil and irinotecan chemotherapy. Abdominal pain is common. Gastrointestinal hemorrhage is occasional.

3. Mucocutaneous effects. Dry skin, skin discoloration, stomatitis, and exfoliative dermatitis are occasional to common. Alopecia, skin ulcers, and nail changes are uncommon.

4. Immunologic effects and infusion reactions. Infusion reactions with hypertension, wheezing, stridor, desaturation, chest pain, headaches, and diaphoresis are uncommon. Severe reactions are rare (0.2%).

5. Miscellaneous effects:

a. Fatigue, weakness, and headache are common.

b. Cardiovascular and respiratory: Hypertension is common and occasionally is severe (>200/110 mm Hg). Blood pressure greater than 160/100 or rise of greater than 30 mm Hg requires holding therapy, at least temporarily. Hypotension is occasional. Dyspnea is occasional. Congestive heart failure is uncommon, but risk with anthracyclines is increased (14%). Venous thromboembolic events are increased by about 15% compared with chemotherapy not containing bevacizumab.

c. Neurologic: Dizziness is common. RPLS has been reported rarely (0.1%); if it occurs, therapy must be discontinued immediately and treatment for hypertension initiated if it is present.

d. Metabolic: Proteinuria is common, but severe proteinuria (> 3.5 g/24 h) is uncommon and rarely leads to nephrotic syndrome (1%), but requires holding bevacizumab and rechecking prior to next cycle.

BEXAROTENE (capsules)

Other name. Targretin.

Mechanism of action. A member of the subclass of retinoids (rexinoid) that selectively activates retinoid X receptors (RXRs). These receptors are distinct from RARs, but also act as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. The exact mechanism in cutaneous T-cell lymphoma (CTCL) is unknown.

Primary indication. Cutaneous manifestations of CTCL in patients refractory to at least one prior systemic therapy.

Usual dosage and schedule. 300 mg/m2/day to start as a single oral daily dose taken with a meal. Dosage is adjusted downward by 100 mg/m2/day decrements for toxicity, or upward to 400 mg/m2/day if there has been no response and good tolerability after 8 weeks of treatment. Treatment may be continued for up to 2 years.

Special precautions. Avoid use in pregnant women because of marked teratogenic potential.

Toxicity

1. Myelosuppression and other hematologic effects. Mild to moderate leukopenia is occasional to common with a time of onset of 4 to 8 weeks. Severe or worse leukopenia is occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Mild nausea, abdominal pain, and diarrhea are occasional. Vomiting and anorexia are uncommon. Inflammatory bowel disease and pancreatitis (associated with hypertriglyceridemia) are rare.

3. Mucocutaneous effects. Skin reactions are occasional to common. They include redness, dryness, and pruritus of the skin and mucous membranes; possible vesicle formation; exfoliative dermatitis; cheilitis; and conjunctivitis. There also may be increased skin photosensitivity (e.g., to sun) and the nails may become brittle. Alopecia is uncommon.

4. Miscellaneous effects:

a. Cataracts and corneal ulcerations or opacities are uncommon.

b. Systemic: Arthralgias, bone pain, muscle aches are occasional. Fever, chills, and headache (flu syndrome) are occasional.

c. Hypertriglyceridemia (80%) and hypercholesterolemia (35% to 40%) are common. Hypertriglyceridemia is usually more severe. These are reversible with discontinuation of therapy and may be reduced by antilipemic therapy.

d. Neurologic: Headache is common. Lethargy, fatigue, contusion, and mental depression are uncommon; pseudotumor cerebri is rare.

e. Hepatotoxicitywithincreasedlactatedehydrogenase(LDH), SGOT, serum glutamic-pyruvic transaminase (SGPT), gamma-glutamyl transpeptidase (GGTP), and alkaline phosphatase is occasional.

f. Hypothyroidism is common, with decreased T4 and thyroid-stimulating hormone (TSH).

g. Peripheral edema is occasional.

h. Hypernatremia is rare.

BEXAROTENE (gel)

Other name. Targretin Gel (1%).

Mechanism of action. A member of the subclass of retinoids (rexinoid) that selectively activates RXRs. These receptors are di stinct from RARs, but also act as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. The exact mechanism in CTCL is unknown.

Primary indication. Cutaneous manifestations of CTCL in patients who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

Usual dosage and schedule. The gel is applied once every other day for the first week. The frequency is then increased at weekly intervals as tolerated to once daily, twice daily, and up to four times daily, according to individual lesion tolerance. Treatment frequency should be reduced or treatment suspended for severe local irritation.

Special precautions. Avoid use in pregnant women because of marked teratogenic potential.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Notexpected.

3. Mucocutaneous effects. Skin reactions are occasional to common. They include pain, redness, dryness, and pruritus of the skin; possible vesicle formation; exfoliative dermatitis. There also may be increased skin photosensitivity (e.g., to sun).

4. Miscellaneous effects:

a. Hypertriglyceridemia is occasional.

b. Neurologic: Headache and paresthesias are occasional.

c. Peripheral edema is occasional.

BICALUTAMIDE

Other name. Casodex.

Mechanism of action. A nonsteroidal antiandrogen that is a competitive inhibitor of androgens at the cellular androgen receptor in target tissues, such as the prostate.

Primary indication. Carcinoma of the prostate.

Usual dosage and schedule. 50 mg daily in combination with luteinizing hormone-releasing hormone (LHRH) analog.

Special precautions. Rare cases of severe liver injury have been reported. Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment.

Toxicity

1. Myelosuppression and other hematologic effects. No myelosuppression. May interact with warfarin and increase International Normalized Ratio (INR).

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, diarrhea, flatulence, and constipation are occasional; vomiting is uncommon.

3. Mucocutaneous effects. Mild skin rash is occasional.

4. Miscellaneous effects:

a. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot flashes, impotence, and loss of libido, are common but reversible after cessation of therapy.

b. Elevated liver function tests are uncommon, but severe hepatic failure has been observed only rarely.

c. Dyspnea and cough are seen occasionally.

d. Adverse cardiovascular events are similar to those seen with orchiectomy.

e. Dizziness or vertigo is occasional.

BLEOMYCIN

Other name. Blenoxane.

Mechanism of action. Bleomycin binds to DNA, causes single- and double-strand scission, and inhibits further DNA, RNA, and protein synthesis.

Primary indications

bull Testis, head and neck, penis, cervix, vulva, anus, and skin carcinomas

bull Hodgkin and non-Hodgkin lymphomas

bull Pleural effusions—used as sclerosing agent.

Usual dosage and schedule

1. 10to 20 units/m2 IVor IM once or twiceaweek, or

2. 30 units IVpush weeklyfor 9 to 12 weeks in combination with other drugs for cancer of the testis.

3. 60 units in 50 mL of normal saline instilled intrapleurally.

Special precautions

1. In patients with lymphoma, a test dose of one or two units should be given IM prior to the first dose of bleomycin because of the possibility of anaphylactoid, acute pulmonary, or severe hyperpyretic responses. If no acute reaction occurs within 4 hours, regular dosing may begin.

2. Reduce dose for renal failure.

f0725-01

3. The cumulative lifetime dose should not exceed 400 units because of the dose-related incidence of severe pulmonary fibrosis. Smaller limits may be appropriate for older patients or those with pre-existing pulmonary disease. Frequent evaluation of pulmonary status, including symptoms of cough or dyspnea, rales, infiltrates on chest x-ray film, and pulmonary function studies are recommended to avert serious pulmonary sequelae.

4. Glass containers are recommended for continuous infusion to minimize drug instability.

5. High fraction ofinspired oxygen (such as might be used during surgery) should be avoided as it exacerbates lung injury, sometimes acutely.

Toxicity

1. Myelosuppression and other hematologic effects. Significant depression of counts is uncommon. This factor permits bleomycin to be used in full doses with myelosuppressive drugs.

2. Nausea, vomiting, and other gastrointestinal effects. Occasionaland self-limiting.

3. Mucocutaneous effects. Alopecia, stomatitis, erythema, edema, thickening of nail bed, and hyperpigmentation and desquamation of skin are common.

4. Pulmonaryeffects:

a. Acute anaphylactoid or pulmonary edema–like response is occasional in patients with lymphoma (see special precautions discussed previously).

b. Dose-related pneumonitis with cough, dyspnea, rales, and infiltrates, progressing to pulmonary fibrosis.

5. Fever. Common. Occasionally, severe hyperpyrexia, diaphoresis, dehydration, and hypotension have occurred and resulted in renal failure and death. Antipyretics help control fever.

6. Miscellaneous effects:

a. Lethargy, headache, and joint swelling are rare.

b. IM or SQ injection may cause pain at injection site.

BORTEZOMIB

Other name. Velcade.

Mechanism of action. A reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, which mediates ubiquitinated protein degradation and plays an essential role in intracellular protein regulation, and consequent cellular signal transduction pathways and cellular homeostasis. Disruption of these homeostatic mechanisms can lead to cell death. Bortezomib is metabolized by liver enzymes.

Primary indications

1. Multiple myeloma

2. Mantle cell lymphoma.

Usual dosage and schedule

1. Multiple myeloma: 1.3 mg/m2 IV bolus twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32), often together with oral melphalan and oral prednisone (days 1 to 4 every 6 weeks) for four 6-week treatment cycles. Then once weekly (days 1, 8, 22, and 29) together with oral melphalan and oral prednisone (days 1 to 4 every 6 weeks) for five more 6-week treatment cycles. The intensity may be modified by giving the twice weekly component for one cycle only followed by eight cycles of the weekly schedule, or by using the weekly schedule for all nine cycles. Similar schedule used in combination with other agents.

2. Mantle cell lymphoma: 1.3 mg/m2 IV bolus twice weekly (days 1, 4, 8, and 11 every 3 weeks) for up to eight cycles. Frequency may be reduced to weekly for 3 out of 4 weeks for maintenance.

3. Reduce each dose to 0.7 mg/m2 in the first cycle for patients with moderate or severe liver function impairment (bilirubin > 1.5 upper limit of normal [ULN]). Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.

Special precautions. Cardiogenic shock, congestive heart failure, and respiratory insufficiency have rarely been observed. Anaphylaxis has also been observed. Patients with hepatic impairment should be monitored closely, as bortezomib is metabolized by liver enzymes. Consider acyclovir 400 mg twice a day for herpes zoster prophylaxis.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common; neutropenia is only occasionally severe (grade 3 or 4). Thrombocytopenia is severe in 30% of patients. Disseminated intravascular coagulation has been observed (rare to uncommon).

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, diarrhea, and constipation are common. Dehydration is a concern because of vomiting and diarrhea and may be seen occasionally.

3. Mucocutaneous effects. Rash is common (20%).

4. Neurotoxicity. Peripheral neuropathy is common and occasionally (7%) severe. This is frequently manifest by paresthesias and dyses-thesias. Headache is common.

5. Immunologic effects and infusion reactions. Hypersensitivity reactions have been seen, including anaphylactic reactions and immune complex mediated hypersensitivity (rare). Tumor lysis syndrome may be seen in patients with a high tumor burden. The incidence of herpes zoster is increased compared with controls and is occasional.

6. Miscellaneous effects:

a. Fatigue and weakness are common.

b. Arthralgias, muscle cramps, and back pain are occasional.

c. Fever is common.

d. Cardiovascular: Hypotension is occasional, is seen throughout therapy, and may or may not be orthostatic. Peripheral edema is common. Other cardiovascular events during treatment have included severe congestive heart failure, AV block, angina, atrial fibrillation, and flutter—these are probably uncommon to rare as a consequence of the drug.

e. Infiltrative pulmonary disease is rare, but maybe severe or fatal.

f. Hepatitis and pancreatitis have been observed and are probably rare.

BUSULFAN

Other names. Myleran, Busulfex.

Mechanism of action. Bifunctional alkylating agent. Its effect may be greater on cellular thiol groups than on nucleic acids.

Primary indications

1. Standard doses: CML

2. High doses with stem cell rescue: Acute leukemia, lymphoma, chronic granulocytic leukemia.

Usual dosage and schedule

1. 3 to 4 mg/m2 by mouth daily for remission induction in adults until the leukocyte count is 50% of the original level, then 1 to 2 mg/m2 by mouth daily. Busulfan may be given continuously or intermittently for maintenance.

2. High doses with stem cell rescue—consult specific protocols. Not recommended outside of research setting. High-dose therapy requires pretreatment with phenytoin.

Special precautions. Obtain complete blood count weekly while patient is on therapy. If leukocyte count falls rapidly to less than 15,000/μL, discontinue therapy until nadir is reached and rising counts indicate a need for further treatment.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting. A fall in the leukocyte count may not begin for 2 weeks after starting therapy, and it is likely to continue for 2 weeks after therapy has been stopped. Recovery of marrow function may be delayed for 3 to 6 weeks after the drug has been discontinued. High-dose therapy requires stem cell rescue (e.g., bone marrow transplantation).

2. Nausea, vomiting, and other gastrointestinal effects. Rare at standard doses.

3. Mucocutaneous effects. Hyperpigmentation occurs occasionally, particularly in skin creases.

4. Miscellaneouseffects

a. Pulmonary effects: Interstitial pulmonary fibrosis is rare and is an indication to discontinue drug. Corticosteroids may improve symptoms and minimize permanent lung damage.

b. Metabolic effects: Adrenal insufficiency syndrome is rare. Hy-peruricemia may occur when the leukemia cell count is rapidly reduced. Ovarian suppression and amenorrhea are common.

c. Secondary neoplasia is possible.

d. Fatal hepatic veno-occlusive disease with high-dose therapy is occasional.

e. Seizures after high-dose therapy are occasional.

CABAZITAXEL

Other name. Jevtana.

Mechanism of action. Microtubule inhibitor that binds to tubulin, which leads to the stabilization of microtubules and the inhibition of mitotic and interphase cellular functions.

Primary indication. Carcinoma of the prostate, metastatic, previously treated with a docetaxel-containing regimen.

Usual dosage and schedule. 25 mg/m2 IV over 1 hour every 3 weeks in combination with prednisone 10 mg daily. Reduce dose to 20 mg/m2 if the patient experiences prolonged grade 3 or higher neutropenia, febrile neutropenia, or severe or persistent diarrhea.

Special precautions. Hypersensitivity reactions can occur, and therefore patients should be premedicated with corticosteroids and histamine H1 and H2 antagonists. Should not be given to patients with hepatic impairment. Patients age 65 and older are more likely to experience adverse effects from cabazitaxel treatment. Because cabazitaxel is metabolized primarily through CYP3A, coadministration with strong CYP3A inhibitors should be avoided.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia, anemia, and thrombocytopenia are common. Grade 3 to 4 febrile neutropenia is occasional but may be fatal.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, anorexia, diarrhea, and constipation are common, but infrequently (2% to 6%) severe.

3. Mucocutaneous effects. Alopecia is occasional.

4. Immunologic effects and infusion reactions. Hypersensitivity reactions are uncommon but may occur within a few minutes following initiation of therapy; they may be associated with rash, erythema, hypotension, and bronchospasm.

5. Miscellaneous effects:

a. Fatigue and weakness are common. Fever is occasional.

b. Renal failure is uncommon, but may be fatal (rare). Hematuria is occasional.

c. Peripheral edema is occasional.

d. Cardiac arrythmias and hypotension are uncommon.

e. Back pain and arthralgias are occasional.

f. Peripheral neuropathy and headache are occasional.

g. Dyspnea and cough are occasional.

CAPECITABINE

Other name. Xeloda.

Mechanism of action. An orally administered prodrug that is converted to fluorouracil intracellularly. When this is converted to the active nucleotide, 5-fluoro-2-deoxyuridine monophosphate, it inhibits the enzyme thymidylate synthetase and blocks DNA synthesis. The triphosphate may also be mistakenly incorporated into RNA, which interferes with RNA processing and protein synthesis.

Primary indications

1. Metastatic breast cancer that is resistant to anthracycline- and paclitaxel-containing chemotherapy regimens. May also be used in patients in whom anthracyclines are contraindicated.

2. Colorectal (adjuvant or metastatic), small bowel, stomach, pancreas, and biliary carcinomas.

Usual dosage and schedule. Generally taken with water, twice daily (about 12 hours between doses) within 30 minutes after a meal. Dose reductions are commonly required by reducing the daily dose, the number of consecutive daily treatments, or both.

1. 1000 to 1250 mg/m2 orally twice daily for 2 weeks as a single agent, followed by a 1-week rest, given as 3-week cycles.

2. 850 to 1250 mg/m2 orally twice daily for 2 weeks when used in combination with other drugs, followed by a 1-week rest, given as 3-week cycles.

3. 800 mg/m2 orally twice daily 5 days per week during radiotherapy as a radiosensitizer.

Special precautions. Increase in PT and INR may be seen in patients previously stable on oral anticoagulants. Monitor PT/INR more frequently when patient is on capecitabine. Patients with moderate renal impairment (CCr30–50 mL/min) require a 25% dosage reduction: Diarrhea may be severe and require fluid and electrolyte replacement. Incidence and severity may be worse in patients 80 years of age or older. Therapy may need to be interrupted and subsequent doses decreased for severe or repeated toxicity. Phenytoin levels should be monitored, as elevated levels may occur.

Toxicity

1. Myelosuppression and other hematologic effects. Common, but when used as a single agent, these usually are mild to moderate with anemia predominating. Neutropenia is common when used in combination and may be associated with neutropenic fever.

2. Nausea, vomiting, and other gastrointestinal effects. Both nausea (45%) and vomiting (35%) are common, but usually not severe. Diarrhea is common (55%); in up to 15% of patients, it is severe to life-threatening. Gastrointestinal motility disorders, including ileus, may be seen, and necrotizing enterocolitis has been reported. Abdominal pain is occasional to common. Anorexia is occasional to common (26%). Hyperbilirubinemia is common (48%) but only occasionally severe or life-threatening.

3. Mucocutaneous effects. Hand-foot syndrome is common (54%) and may be severe. Dermatitis is also common (27%), as is stomatitis, but it is uncommon that these are severe. Eye irritation and increased lacrimation are occasional.

4. Miscellaneous effects:

a. Fatigueiscommon.

b. Paresthesias are occasional.

c. Fever is occasional.

d. Headache or dizziness is occasional.

e. Cardiotoxicity is possible as with any fluorinated pyrimidine.

CARBOPLATIN

Other names. Paraplatin, CBDCA.

Mechanism of action. Covalent binding to DNA.

Primary indications. Ovarian, endometrial, breast, bladder, and lung cancers, and other cancers in which cisplatin is active.

Usual dosage and schedule. AUC dosing (Calvert formula) is generally preferred.

1. Target AUC is commonly 4 to 6, depending on previous treatment and other drugs to be used. Administration dose (mg) = (target AUC) × ([creatinine clearance] + 25). Administration dose is given by IV infusion over 15 to 60 minutes and repeated every 4 weeks.

2. Higher doses up to 1600 mg/m2 divided over several days have been used followed by stem cell rescue (e.g., bone marrow transplantation).

Special precautions. Much less renal toxicity than cisplatin, so there is no need for a vigorous hydration schedule or forced diuresis. If AUC dosing is not used, reduce dose to 250 mg/m2 for creatinine clearance of 41 to 59 mL/minute, reduce to 200 mg/m2 for clearance of 16 to 40 ml/minute.

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin administration. Infusion reactions generally develop after several months of drug tolerance. Epinephrine, corticosteroids, antihistamines, and fluid administration for hypotension have been employed to alleviate symptoms. Skin testing for hypersensitivity (see Table 26.2) may be helpful.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia, granulo-cytopenia, and thrombocytopenia are common and dose-limiting. Red blood cell transfusions or epoetin may be required. Thrombocytopenia may be delayed (days 18 to 28).

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but vomiting (65%) is not as frequent or as severe as with cisplatin and can be controlled with combination antiemetic regimens. Liver function abnormalities are common. Gastrointestinal pain is occasional.

3. Mucocutaneous effects. Alopecia is uncommon. Mucositis is rare.

4. Immunologic effects and infusion reactions. Infusion reactions are occasional but may be severe. These may include rash, urticaria, pruritus, and rarely bronchospasm and hypotension. Desensitization protocols may allow continued therapy with carboplatin, but should be carried out under close observation (see Special precautions).

5. Miscellaneous effects:

a. Peripheral neuropathies or central neurotoxicity are uncommon.

b. Cardiovascular (cardiac failure, embolism, cerebrovascular accidents) complications are uncommon.

c. Hemolytic uremic syndrome is rare.

d. Renal tubular abnormalities: Elevation in serum creatinine or blood urea nitrogen occurs occasionally. More common is electrolyte loss with decreases in serum sodium, potassium, calcium, and magnesium.

CARMUSTINE

Other names. BCNU, BiCNU, Gliadel wafer (surgically implantable, biodegradable polymer wafer that releases impregnated carmustine from the hydrophobic matrix after implantation).

Mechanism of action. Alkylation and carbamoylation by carmustine metabolites interfere with the synthesis and function of DNA, RNA, and proteins. Carmustine is lipid soluble and easily enters the brain.

Primary indications

1. Systemic therapy:

a. Brain tumors

b. Hodgkin and non-Hodgkin lymphomas

c. Melanoma.

2. Implantable carmustine-impregnated wafer: glioblastoma multiforme.

Usual dosage and schedule

1. Systemic therapy:

a. 200 to 240 mg/m2 IV as a 30- to 45-minute infusion every 6 to 8 weeks. Dose often is divided and given over 2 to 3 days. Some recommend limiting the cumulative dose to 1000 mg/m2 to limit pulmonary and renal toxicity.

b. Higher doses of up to 600 mg/m2 have been used with stem cell rescue (e.g., bone marrow or peripheral blood stem cell transplantation).

2. Implantable carmustine-impregnated wafer: Up to eight wafers, each containing 7.7 mg of carmustine, are applied to the resection cavity surface after removal of the tumor.

Special precautions (systemic therapy). Because of delayed myelosuppression (3 to 6 weeks), do not administer drug more often than every 6 weeks. Await a return of normal platelet and granulocyte counts before repeating therapy. Amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension.

Toxicity

1. Systemic therapy:

a. Myelosuppression and other hematologic effects. Delayed and often biphasic, with the nadir at 3 to 6 weeks; it may be cumulative with successive doses. Recovery may be protracted for several months. High-dose therapy requires stem cell rescue.

b. Nausea, vomiting, and other gastro intestinal effects. Begins 2 hours after therapy and lasts 4 to 6 hours; it is common.

c. Mucocutaneouseffects:

(1) Facial flushing and a burning sensation at the IV site may be due to alcohol used to reconstitute the drug; this is common with rapid injection.

(2) Hyperpigmentation of skin after accidental contact is common.

d. Miscellaneouseffects:

(1) Hepatotoxicity is uncommon but can be severe.

(2) Pulmonary fibrosis is uncommon at low doses, but its frequency increases at doses higher than 1000 mg/m2.

(3) Secondary neoplasia is possible.

(4) Renal toxicityis uncommon at doses ofless than 1000 mg/m2.

(5) With high-dose therapy, encephalopathy, hepatotoxicity, and pulmonary toxicity are common and dose-limiting. Hepatic veno-occlusive disease also occurs (occasional).

2. Implantable carmustine-impregnated wafer. Limited toxicity beyond that expected from craniotomy is seen. Serious intracranial infection was seen in 4% of patients, compared with 1% of placebotreated patients. Brain edema not responsive to steroids may also be seen in a similar percentage of patients. Abnormal wound healing may occur. Remnants of the wafer may be seen for many months after implantation.

CETUXIMAB

Other names. Epidermal growth factor receptor (EGFR) antibody, C225, Erbitux.

Mechanism of action. EGFR antibody that blocks the ligand-binding site and inhibits proliferation of cells. It is thought potentially most useful in those tumors that overexpress EGFR, but correlation with percent of positive cells or intensity of EGFR expression is weak.

Primary indications

1. Carcinoma of head and neck, in combination with radiation therapy or after failure of platinum-based therapy.

2. Colon cancer when KRAS is wild type, after failure of irinotecan-and oxaliplatin-based regimens. Often in combination with irinotecan or other cytotoxic regimens.

3. Lung cancer if EGFR amplification.

Usual dosage and schedule. 400 mg/m2 IV loading dose administered over 2 hours on day 1. Then 250 mg/m2 IV maintenance doses administered over 1 hour weekly thereafter. May be administered in combination with other agents.

Special precautions. Sersious infusion reactions, some fatal, may occur (3% of patients). A 1-hour observation period is recommended following a cetuximab infusion. Cardiopulmonary arrest or sudden death has occurred in 2% of patients receiving cetuximab in combination with radiation therapy. Severe hypomagnesemia is seen in 10% to 15% of patients, and all patients should have magnesium levels monitored throughout the persistence of cetuximab (8 weeks).

All patients with metastatic colorectal cancer who might be candidates for cetuximab should have their tumor tested for KRAS and BRAF mutations. If KRAS mutation in codon 12 or 13 or BRAF V600E mutation is detected, cetuximab should not be given, as the patient is unlikely to benefit.

Toxicity

1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, diarrhea, and constipation are occasional. Abdominal pain is common.

3. Mucocutaneous effects. Acnelike rash is common (76%). Stomatitis is occasional when used alone, but universal when used in combination with radiation therapy. Severe radiation dermatitis may be seen when used concurrently with radiation therapy.

4. Miscellaneous effects:

a. Asthenia is common; headache and back pain are occasional.

b. Weight loss, peripheral edema, and dehydration are occasional.

c. Infusion reactions with allergic or hypersensitivity reactions, fever, chills, or dyspnea are occasional to common (~20%) but may be severe.

d. Human antichimeric antibodies (HACAs) are uncommon.

e. Electrolyte depletion, particularly hypomagnesemia, occurs commonly. Hypomagnesemia is occasionally severe.

CHLORAMBUCIL

Other name. Leukeran.

Mechanism of action. Classic alkylating agent, with primary effect on preformed DNA.

Primary indications

1. Chronic lymphocytic leukemia

2. Low-grade non-Hodgkin lymphoma.

Usual dosage and schedule

1. 3 to 4 mg/m2 by mouth daily until a response is seen or cytopenias occur; then, if necessary, maintain with 1 to 2 mg/m2 by mouth daily.

2. 30 mg/m2 by mouth once every 2 weeks (with or without prednisone 80 mg/m2 by mouth on days 1 to 5).

Special precautions. Increased toxicity may occur with prior barbiturate use.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting and may be prolonged.

2. Nausea, vomiting, and other gastrointestinal effects. May be seen with higher doses but are uncommon.

3. Mucocutaneous effects. Rash is uncommon.

4. Miscellaneous effects:

a. Liver function abnormalities are rare.

b. Secondary neoplasia is possible.

c. Amenorrhea and azoospermia are common.

d. Drug fever is uncommon.

e. Pulmonary fibrosisis rare.

f. CNS effects including seizure and coma maybe seen at very high doses (>100 mg/m2).

CISPLATIN

Other names. cis-Diamminedichloroplatinum (II), DDP, CDDP, Platinol.

Mechanism of action. Similar to alkylating agents with respect to binding and cross-linking strands of DNA.

Primary indications. Usually used in combination with other cytotoxic drugs.

1. Testis, ovary, endometrial, cervical, bladder, head and neck, gastrointestinal, and lung carcinomas

2. Soft-tissue and bone sarcomas

3. Non-Hodgkin lymphoma.

Usual dosage and schedule

1. 40 to 120 mg/m2 IV on day 1 as infusion every 3 weeks

2. 15 to 20 mg/m2 IV on days 1 to 5 as infusion every 3 to 4 weeks.

Special precautions. Do not administer if serum creatinine level is more than 1.5 mg/dL. Irreversible renal tubular damage may occur if vigorous diuresis is not maintained, particularly with higher doses (>40 mg/m2) and with additional concurrent nephrotoxic drugs, such as the amino-glycosides. At higher doses, diuresis with mannitol with or without furo-semide plus vigorous hydration is mandatory.

1. An acceptable method for hydration in patients without cardiovascular impairment for cisplatin doses up to 80 mg/m2 is as follows:

a. Have patient void and begin infusion of 5% dextrose in half-normal saline with potassium chloride (KCl) 20 mEq/liter and magnesium sulfate (MgSO4) 1 g/liter (8 mEq/liter); run at 500 mL/hour for 1.5 to 2.0 L.

b. After 1 hour of infusion, give 12.5 gm of mannitol by IV push.

c. Immediately thereafter, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 hour through the sidearm of the IV, while continuing the hydration.

d. Give additional mannitol (12.5 to 50.0 gm) by IV push if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given.

2. For doses more than 80 mg/m2 a more vigorous hydration is recommended:

a. Have patient void and begin infusion of 5% dextrose in half-normal saline with KCl 20 mEq/liter and MgSO4 1 gm/liter (8 mEq/ liter); run at 500 mL/hour for 2.5 to 3.0 L.

b. After 1 hour of infusion, give 25 g of mannitol by IV push.

c. Continue hydration.

d. After 2 hours of hydration, if urinary output is at least 250 mL/hour, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 to 2 hours (1 mg/m2/minute) through the side-arm of the IV, while continuing the hydration.

e. Give additional mannitol (12.5 to 50 g by IV push) if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given.

3. For patients with known or suspected cardiovascular impairment (ejection fraction 45%), a less vigorous rate of hydration may be used, provided the dose of cisplatin is limited (e.g., 60 mg/m2). An alternative is to give carboplatin.

Toxicity

1. Myelosuppression and other hematologic effects. Mild to moderate, depending on the dose. Relative lack of myelosuppression and other hematologic effects allows cisplatin to be used in full doses with more myelosuppressive drugs. Anemia is common and may have a hemolytic component. Anemia often is amenable to epoetin therapy.

2. Nausea, vomiting, and other gastrointestinal effects. Severe and often intractable vomiting regularly begins within 1 hour of starting cisplatin and lasts 8 to 12 hours. Prolonged nausea, vomiting, and other gastrointestinal effects occur occasionally. Nausea, vomiting, and other gastrointestinal effects may be minimized by the use of a combination antiemetic regimen (see Chapter 26).

3. Mucocutaneous effects. None.

4. Renal tubular damage. Acute reversible and occasionally irreversible nephrotoxicity may occur, particularly if adequate attention is not given to achieving sufficient hydration and diuresis. Nephrotoxic antibiotics increase risk of acute renal failure.

5. Ototoxicity. High-tone hearing loss is common, but significant hearing loss at vocal frequencies occurs only occasionally. Tinnitus is uncommon.

6. Severe electrolyte abnormalities. Marked hyponatremia, hypomag-nesemia, hypocalcemia, and hypokalemia may be seen up to several days after treatment.

7. Anaphylaxis. May occur after several doses. Responds to epinephrine, antihistamines, and corticosteroids.

8. Miscellaneous effects:

a. Peripheral neuropathies are clinically significant; signs and symptoms are common at cumulative doses more than 300 mg/m2.

b. Hyperuricemia is uncommon and parallels renal failure.

c. Autonomic dysfunction with symptomatic postural hypotension is occasional.

CLADRIBINE

Other names. 2-Chlorodeoxyadenosine, Leustatin.

Mechanism of action. Deoxyadenosine analog with high cellular specificity for lymphoid cells. Resistant to effect of adenosine deaminase. Accumulates in cells as triphosphate, is incorporated into DNA, and inhibits DNA repair enzymes and RNA synthesis. Also results in nicotinamide adenine dinucleotide depletion. Effect is independent of cell division.

Primary indications. Hairy-cell leukemia, chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and possibly other lymphoid neoplasms.

Usual dosage and schedule

1. 0.09 mg/kg (3.33 mg/m2) IV daily as a continuous 7-dayinfusion

2. 0.14 mg/kg (5.2 mg/m2) IV as a 2-hour infusion daily for 5 days

3. 0.14 mg/kg (5.2 mg/m2) SC dailyfor 5 days

4. 0.12 mg/kg IV daily × 3 together with cyclophosphamide 250 mg/ m2 IV daily × 3 every 28 days up to 6 cycles (for chronic lymphocytic leukemia [CLL] with TP53 [17p13] gene deletion).

Special precautions. Give allopurinol, 300 mg daily, as prophylaxis against hyperuricemia. Opportunistic infections occur occasionally and should be watched for closely.

Toxicity

1. Myelosuppression and other hematologic effects. Moderate granulocyte suppression is common. Marrow suppression with leukopenia and thrombocytopenia may be prolonged for over a year. Serious infection is common. Profound suppression of cluster of differentiation (CD) 4 and CD8 counts is common and often prolonged for over 1 year. Opportunistic infections, including herpes, fungus, and pneumocystis infection, may occur and should be monitored. Some routinely use prophylaxis against one or more of these infections, including acyclovir 400 mg twice a day and trimethoprim-sulfamethoxazole one double-strength tablet twice daily on 2 or 3 days a week. Autoimmune hemolytic anemia and immune thrombocytopenic purpura occur occasionally; pure red cell aplasia rarely.

2. Nausea, vomiting, and other gastrointestinal effects. Mild nausea with decrease in appetite is common, but no vomiting is expected. Mild reversible increase in liver function tests may be seen.

3. Mucocutaneous effects. Rash is common. Injection site reactions are occasional.

4. Miscellaneous effects:

a. Fever, possibly due to release of pyrogens from tumor cells, is common.

b. Fatigue is common. Headache, dizziness, insomnia, myalgia, and arthralgia are occasional.

c. Edema and tachycardia are occasional.

d. Cough, shortness of breath, and abnormal breath sounds are occasional.

CLOFARABINE

Other name. Clolar.

Mechanism of action. Clofarabine is a nucleoside analog (an adenine derivative) that is a potent inhibitor of ribonucleotide reductase. It also inhibits DNA polymerases and DNA synthesis. Increases intracellular arabinosylcytosine triphosphate (ara-CTP) when used with cytarabine.

Primary indications

1. Acute lymphoblastic leukemia (ALL) in children (age 1 to 21 years) who have relapsed or are refractory to other therapy

2. Acute lymphoblastic or acute myeloid leukemia (AML) in adults.

Usual dosage and schedule

1. 52 mg/m2 IV over 2 hours daily for 5 consecutive days. May be repeated in 2 to 6 weeks.

2. 40 mg/m2 IV over 1 hour (days 2 to 6), followed in 4 hours by cytara-bine 1 g/m2 IV as a 2-hour infusion (days 1 to 5) in adults with AML.

3. 30 mg/m2 IV over 1 hour daily for 5 days in older adults with AML and unfavorable prognostic factors. For reinduction (day 29) or consolidation (on recovery of counts), dose reduced to 20 mg/m2 IV daily for 5 days (6 cycles maximum).

Special precautions. Capillary leak syndrome or systemic inflammatory response syndrome have been observed with clofarabine administration.

Toxicity

1. Myelosuppression and other hematologic effects. Pancytopeniais common. Febrile neutropenia and documented infections are common.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, diarrhea, and abdominal pain are common. Elevation of transaminases is common and may be severe (grade 3 to 4); jaundice is occasional. Anorexia is common.

3. Mucocutaneous effects. Nonspecific dermatitis and pruritis are common. Palmar-plantar erythrodysesthesia is occasional.

4. Miscellaneous effects:

a. Arthralgia and back pain are occasional.

b. Creatinine elevations are uncommon to occasional.

c. Fatigue is common. Lethargyis occasional.

d. Flushing and hypotension are occasional to common.

CORTICOSTEROIDS

Other names. Prednisone, dexamethasone (Decadron), and others.

Mechanism of action. Unknown but apparently related to the presence of glucocorticoid receptors in tumor cells. Mediated in part by bcl-2 gene and promotion of apoptotic cell death.

Primary indications

1. Acute and chronic lymphocytic leukemia

2. Hodgkin and non-Hodgkin lymphomas

3. Multiple myeloma

4. Carcinoma of the breast

5. Cerebral edema or spinal cord injury (compression)

6. Nausea and vomiting from chemotherapy.

Usual dosage and schedule

1. Prednisone: dose varies with neoplasm and combination. Typical regimen, except for acute lymphocytic leukemia, is as follows:

a. 40 mg/m2 by mouth days 1 to 14 every 4 weeks, or

b. 100 mg/m2 by mouth days 1 to 5 every 4 weeks.

2. Prednisone: for acute lymphocytic leukemia, 40 to 50 mg/m2 by mouth daily for 28 days.

3. Dexamethasone: for cerebral edema or spinal cord injury, 10 mg IV push, then 16 to 32 mg by mouth daily in four divided doses. As signs and symptoms are controlled, gradually reduce to lowest effective dose.

Special precautions. Monitor for hyperglycemia.

Toxicity

1. Myelosuppression and other hematologic effects. No myelosuppression but may exacerbate hypercoagulability when given together with thalidomide or lenolidamide.

2. Nausea, vomiting, and other gastrointestinal effects. No acute nausea and vomiting. Epigastric pain, extreme hunger, and occasional peptic ulceration with bleeding may occur even with short courses. Antacids or inhibitors of acid secretion are recommended as prophylaxis.

3. Mucocutaneous effects. Acne; increased risk for oral, rectal, and vaginal yeast infections. Thinning of skin and striae develop with continuous use.

4. Suppression ofadrenal-pituitary axis. May lead to adrenal insufficiency when corticosteroids are withdrawn. This problem is not common with intermittent schedules.

5. Metabolic effects. Potassium depletion, sodium and fluid retention, diabetes, increased appetite, loss of muscle mass, myopathy, weight gain, osteoporosis, and development of Cushingoid features. Their frequency depends on dose and duration of therapy.

6. Miscellaneous effects:

a. CNS effects, including euphoria, depression, and sleeplessness, are common and may progress to dementia or frank psychosis.

b. Increased susceptibility to infection is common.

c. Subcapsular cataracts in patients are uncommon but have been seen even when used for prophylaxis and treatment of drug-induced emesis.

CYCLOPHOSPHAMIDE

Other names. CTX, Cytoxan, Neosar.

Mechanism of action. Metabolism of cyclophosphamide by hepatic microsomal enzymes produces active alkylating metabolites. Cyclophosphamide’s primary effect is probably on DNA.

Primary indications

1. Breast, lung, ovary, testis, and bladder carcinomas

2. Bone and soft-tissue sarcomas

3. Hodgkin and non-Hodgkin lymphomas

4. Acute and chronic lymphocytic leukemias

5. Waldenstrom macroglobulinemia

6. Neuroblastoma and Wilms tumor of childhood

7. Gestational trophoblastic neoplasms

8. Multiple myeloma.

Usual dosage and schedule

1. 1000 to 1500 mg/m2 IV every 3 to 4 weeks, or

2. 400 mg/m2 by mouth days 1 to 5 every 3 to 4 weeks, or

3. 60 to 120 mg/m2 by mouth daily.

4. High-dose regimens (4 to 7 g/m2 divided over 4 days) are investigational and should only be used with some kind of stem cell rescue (e.g., bone marrow transplantation) and mesna bladder protection.

Special precautions. Give dose in the morning, maintain ample fluid intake, and have patient empty bladder several times daily to diminish the likelihood of cystitis.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting. Platelets are relatively spared. Nadir is reached approximately 10 to 14 days after IV dose with recovery by day 21.

2. Nausea, vomiting, and other gastrointestinal effects. Frequent with large IV doses; less common after oral doses. Symptoms begin several hours after treatment and are usually over by the next day.

3. Mucocutaneous effects. Reversible alopecia is common, usually starting after 2 to 3 weeks. Skin and nails may become darker. Mucositis is uncommon.

4. Bladder damage. Hemorrhagic or nonhemorrhagic cystitis may occur in 5% to 10% of patients treated. It is usually reversible with discontinuation of the drug, but it may persist and lead to fibrosis or death. Frequency is diminished by ample fluid intake and morning administration of the drug. Mesna will protect from this effect.

5. Miscellaneous effects:

a. Immunosuppressioniscommon.

b. Amenorrhea and azoospermia are common.

c. Inhibition of antidiuretic hormone is only of significance with very large doses.

d. Interstitialpulmonaryfibrosis is rare.

e. Secondary neoplasia is possible.

f. Acute and potentially fatal cardiotoxicity occurs with high-dose therapy. Abnormalities include pericardial effusion, congestive heart failure, decreased voltage on electrocardiogram (ECG), and fibrin microthrombi in cardiac capillaries with endothelial injury and hemorrhagic necrosis.

CYTARABINE

Other names. Cytosine arabinoside, ara-C, Cytosar-U, DepoCyt (cytarabine, liposomal for intrathecal use only).

Mechanism of action. A pyrimidine analog antimetabolite that, when phosphorylated to ara-CTP, is a competitive inhibitor of DNA polymerase.

Primary indications

1. Acute nonlymphocytic leukemia

2. Meningeal lymphoma or leukemia.

Usual dosage and schedule

1. Induction: 100 to 200 mg/m2 IV daily as a continuous infusion for 5 to 7 days (in combination with other drugs).

2. Maintenance: 100 mg/m2 SC every 12 hours for 4or5 days every 4 weeks (with other drugs).

3. Intrathecally:

a. 40 to 50 mg/m2 of cytarabine, unencapsulated, every 4 days in preservative-free buffered isotonic diluent.

b. 50 mg of cytarabine, liposomal, repeated in 14 to 28 days.

4. High dose:

a. Induction: 2 to 3 g/m2 IV over 1 to 2 hours every 12 hours for up to 12 doses.

b. Consolidation: 3 g/m2 IV over 3 hours every 12 hours on days 1, 3, and 5.

Special precautions. None for standard doses. High dose, give in 1- to 3-hour infusion. Longer infusion enhances toxicity. CNS toxicity is increased in patients with a decreased creatinine clearance. Cytarabine (liposomal [DepoCyt]) should be used only intrathecally.

Toxicity (standard dose only).

1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and thrombocytopenia occur, with nadir at 7 to 10 days after treatment has ended and with recovery during the following 2 weeks, depending on the degree of suppression. Megaloblastosis is common.

2. Nausea, vomiting, and other gastrointestinal effects. Common, particularly if the drug is given as a push or rapid infusion.

3. Mucocutaneous effects. Stomatitis is seen occasionally.

4. Miscellaneous effects:

a. Flulike syndrome with fever, arthralgia, and sometimes a rash is occasional.

b. Transient mild hepatic dysfunction is occasional.

Toxicity (high dose).

1. Myelosuppression and other hematologic effects. Universal.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common.

3. Mucocutaneous effects. Occasional to common mucositis. Kerato-conjunctivitis is common; glucocorticoid eye drops may ameliorate or prevent this effect in some patients.

4. Neurotoxicity. Cerebellar toxicity is common, particularly in the elderly, but is usually mild and reversible. However, on occasion it has been severe and permanent or fatal.

5. Hepatic toxicity with cholestaticjaundice. Uncommon.

DACARBAZINE

Other names. Imidazole carboxamide, DIC, DTIC-Dome.

Mechanism of action. Uncertain but probably interacts with preformed macromolecules by alkylation. Inhibits DNA, RNA, and protein synthesis.

Primary indications

1. Melanoma

2. Soft-tissue sarcomas

3. Hodgkin lymphoma.

Usual dosage and schedule

1. 150 to 250 mg/m2 IV push or rapid infusion on days 1 to 5 every 3 to 4 weeks, or

2. 400 to 500 mg/m2 IV push or rapid infusion on days 1 and 2 every 3 to 4 weeks, or

3. 200 mg/m2 IV daily as a continuous 96-hour infusion.

Special precautions

1. Administer cautiously to avoid extravasation as tissue damage may occur.

2. Venous pain along the injection site may be reduced by diluting dacarbazine in 100 to 200 mL of 5% dextrose in water and infusing over 30 minutes rather than injecting rapidly. Ice application may also reduce pain.

Toxicity

1. Myelosuppression and other hematologic effects. Mild to moderate. This factor allows dacarbazine to be used in full doses with other myelosuppressive drugs.

2. Nausea, vomiting, and other gastrointestinal effects. Common and severe but decrease in intensity with each subsequent daily dose. Onset is within 1 to 3 hours, with duration up to 12 hours.

3. Mucocutaneous effects. Moderately severe tissue damage if extravasation occurs. Alopecia is uncommon. Erythematous or urticarial rash is uncommon.

4. Miscellaneous effects:

a. Flulike syndrome with fever, myalgia, and malaise lasting several days is uncommon.

b. Hepatictoxicityisuncommon.

DACTINOMYCIN

Other names. Actinomycin D, ACT-D, Cosmegen.

Mechanism of action. Binds to DNA and inhibits DNA-dependent RNA synthesis. Inhibition of topoisomerase II.

Primary indications

1. Gestational trophoblastic neoplasms

2. Wilms tumor, childhood rhabdomyosarcoma, and Ewing sarcoma.

Usual dosage and schedule

1. Children: 0.40 to 0.45 mg/m2 (upto a maximum of 0.5 mg) IV daily for 5 days every 3 to 5 weeks

2. Adults:

a. 0.40 to 0.45 mg/m2 IV on days 1 to 5 every 2 to 3 weeks

b. 0.5 mg IV daily for 5 days every 3 to 5 weeks

c. 0.5 mg IV daily for 2 days every 2 weeks (in combination therapy).

Special precautions

1. Administer by slow IV push through the sidearm of a running IV infusion, being careful to avoid extravasation, which causes severe soft-tissue damage.

2. If given at or about the time of infection with chickenpox or herpes zoster, a severe generalized disease may occur that sometimes results in death.

Toxicity

1. Myelosuppression and other hematologic effects. Cytopenias may be dose-limiting and severe. They begin within the first week of treatment, but the nadir may not be reached for 21 days.

2. Nausea, vomiting, and other gastrointestinal effects. Severevomiting often occurs during the first few hours after drug administration and lasts up to 24 hours.

3. Mucocutaneous effects. Erythema, hyperpigmentation, and desquamation of the skin with potentiation by previous or concurrent radiotherapy are common. Oropharyngeal mucositis is potentiated by previous or concurrent radiotherapy. Alopecia is common. Moderately severe tissue damage occurs with extravasation.

4. Miscellaneous effects:

a. Mentaldepressionisrare.

b. Hepatic veno-occlusive disease, worse with higher doses and shorter schedules (e.g., single dose of 2.5 mg versus 5 days at 0.5 mg/day).

DARBEPOETIN

Other names. Aranesp, darbepoetin alfa.

Mechanism of action. Darbepoetin is an erythropoiesis-stimulating protein, closely related to erythropoietin, that is produced in Chinese hamster ovary cells by recombinant DNA technology. It has the same biologic activity as endogenous erythropoietin, inducing erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells.

Primary indications

1. Anemia from concomitant chemotherapy in patients with nonmyeloid malignancies, when cure is not the anticipated outcome

2. Anemia from low-risk MDS

3. Anemia associated with chronic renal failure.

Usual dosage and schedule

1. Patients with anemia during chemotherapy, if the hemoglobin is less than 10 or with low-risk MDS:

a. 500 µg by SC injection every 3 weeks (schedule used in MDS), or

b. 2.25 µg/kg/weekbySCinjection.

2. Adult patients with chronic renal failure: Starting dose of 0.45 µg/kg/week by IV or SC injection. Dose adjustments of 2% to 40% upward or downward are recommended to keep the hemoglobin below 12.

Special precautions. There is a greater risk for death, serious cardiovascular events, and stroke when erythropoiesis-stimulating agents (ESAs) are administered to target hemoglobin levels of 13 g/dL and above in chronic renal failure. ESAs shorten survival or increase tumor progression in some studies, and to decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion. Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program (www.esa-apprise.com) to prescribe and/or dispense ESAs to patients with cancer. Contraindicated in patients with uncontrolled hypertension or known hypersensitivity to albumin or mammalian cell-derived products. Potential for serious allergic or anaphylactic reaction. Rare cases of pure red cell aplasia have been reported.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression is not seen, except for rare cases of pure red cell aplasia. Thromboembolic complications are uncommon but serious cardiovascular events and stroke may be seen.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrhea is occasional.

3. Mucocutaneous effects. Uncommon rashes or urticaria. Pruritis is occasional.

4. Miscellaneous effects:

a. Cardiovascular: Hypertension may occasionally occur in association with a significant increase in hematocrit; the risk is greatest in patients with pre-existing hypertension. Chest pain is uncommon and myocardial infarction is uncommon to rare; edema is occasional.

b. Neurologic: Seizures, stroke, and transient ischemic attacks are all rare.

c. Influenza-like syndrome is rare to uncommon. Fever alone is occasional.

DASATINIB

Other name. Sprycel.

Mechanism of action. Inhibition of multiple receptor tyrosine kinases (RTKs), including Bcr-Abl and the SRC family. Believed to bind to multiple conformations of the ABL kinase.

Primary indications

1. CML, chronicphase, newly diagnosed

2. CML in the chronic, accelerated, or blast phase (myeloid or lymphoid) with resistance or intolerance to prior therapy including imatinib

3. ALL that is Ph+ and refractory to prior therapy

4. ALL that is Ph+. newly diagnosed, in combination with chemotherapy (investigational).

Usual dosage and schedule

1. Chronic-phase CML 100 mg by mouth daily. Doses are adjusted up or down in 20 mg increments as needed.

2. Accelerated-phase CML, blast-phase CML, or Ph+ ALL: 140 mg by mouth daily.

Special precautions. Should not be administered to patients who have or are at risk for prolonged QT interval.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common in all patients. Bleeding is common and occasionally is severe, but is seen primarily in the accelerated or blastic phases. Use with caution in patients requiring platelet inhibitors or anticoagulants. Febrile neutropenia is uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are occasional but rarely severe. Diarrhea is common, but severe diarrhea uncommon. Abdominal pain is common. Constipation is occasional.

3. Mucocutaneous effects. Stomatitis is occasional. Various skin maladies are occasional.

4. Miscellaneous effects:

a. Cardiovascular: Fluid retention is common and occasionally severe. Pleural effusions are occasional. Pericardial effusions are uncommon. Severe pulmonary edema is rare. Prolonged cardiac ventricular repolarization (QT prolongation) is uncommon and rarely severe.

b. Respiratory: Dyspnea, cough, and upper respiratory infections are common.

c. Neurologic: Peripheral neuropathy is occasional. Headache is common.

d. Musculoskeletal pain and myalagia are occasional to common.

e. Fever is uncommon; fatigue is common.

f. Hypophosphatemia is occasional. Hypokalemia and hypocalcemia are uncommon. Abnormal transaminases or elevated bili-rubin are rare.

DAUNORUBICIN

Other names. Daunomycin, rubidomycin, DNR, Cerubidine.

Mechanism of action. DNA strand breakage mediated by anthracycline effects on topoisomerase II; DNA intercalation; DNA polymerase inhibition.

Primary indications. AML, ALL.

Usual dosage and schedule

1. 60 to 90 mg/m2 IV push on days 1, 2, and 3 in combination with other drugs as induction therapy AML. Second cycle may be given at same or lower dose if blasts are not gone by day 15.

2. 45 to 60 mg/m2 IV push in various schedules in combination with other drugs as induction therapy in ALL.

Special precautions

1. Administer over several minutes into the sidearm of a running IV infusion, taking precautions to avoid extravasation. Severe local tissue damage may progress to skin ulceration, and necrosis may occur with subcutaneous extravasation.

2. Do not give if patient has significantly impaired cardiac function (ejection fraction 45%), angina pectoris, cardiac arrhythmia, or recent myocardial infarction.

3. Do not exceed cumulative dosage of 550 mg/m2 (400 mg/m2 if given previous radiation therapy that has encompassed the heart).

4. Reduce dose if patient has impaired liver or renal function.

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Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting pancytopenia with nadir at 1 to 2 weeks.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting occur on the day of administration in 50% of patients.

3. Mucocutaneous effects. Alopecia is common, but stomatitis is rare. Severe local tissue damage may progress to skin ulceration, and necrosis may occur with subcutaneous extravasation.

4. Cardiac effects. Potentially irreversible congestive heart failure may occur owing to cardiomyopathy. The incidence is highly dependent on the lifetime cumulative dose, which should not exceed 550 mg/m2(400 mg/m2 if patient was given previous radiotherapy that encompassed the heart). Discontinue drug if there is clinical congestive heart failure or if the ejection fraction falls on the radionuclide angiogram to:

a. Less than 45%, or

b. Less than 50% if the total decrease is 10% or more (e.g., falls from 59% to 49%).

If repeat ejection fraction determination shows return of function, drug may be cautiously restarted, but ejection fraction should be measured before each dose. Transient ECG changes are common and are not usually serious.

5. Miscellaneous effects:

a. Red urine caused by the drug and its metabolites is common.

b. Chemical phlebitis and phlebothrombosis of veins used for injection is common.

DAUNORUBICIN, LIPOSOMAL

Other name. DaunoXome.

Mechanism of action. Daunorubicin, liposomal, which is designed to be protected from removal by the reticuloendothelial system, has a prolonged circulation time compared with the unprotected drug. The agent penetrates tumor tissue and releases the active ingredient daunorubicin.

Primary indication. Kaposi sarcoma, advanced, HIV-associated.

Usual dosage and schedule. 40 mg/m2 IV over 60 minutes every 2 weeks.

Special precautions

1. Must be diluted to a concentration of 1 mg/mL with 5% dextrose for injection. Liposomal daunorubicin should be considered an irritant, and care should be taken to avoid extravasation.

2. Do not give if the patient has significantlyimpaired cardiac function.

3. Do not exceed a lifetime cumulative dose of 550 mg/m2 (400 mg/m2 if the patient was given prior chest radiotherapy). Patients with HIV may experience a decrease in left ventricular ejection fraction and congestive heart failure at lower doses than those without.

4. Reduce or hold dose in patients with impairment of liver function. A 25% dose reduction is recommended if the serum bilirubin is 1.2 to 3 mg/dL. One half the normal dose is recommended in patients with serum bilirubin concentration greater than 3 mg/dL.

Toxicity. Effects that are a result of the liposomal daunorubicin have been somewhat difficult to determine with certainty, because most patients have been on several other agents that can result in other drugs that may cause marrow or other toxicity.

1. Myelosuppression and other hematologic effects. Common and dose-related. May be severe.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common.

3. Mucocutaneous effects. Alopecia is occasional. Stomatitis is occasional.

4. Immunologic effects and infusion reactions. Acute infusion-associated reactions with back pain, flushing, and tightness in the chest and throat, alone or in combination, occur occasionally. They usually occur with the first infusion and are not likely to occur later if the first infusion is given without a reaction. Generally occur during first 5 minutes of the infusion and subside with interruption of the infusion. Some patients tolerate restarting at a lower rate of infusion. Most patients are able to continue therapy.

5. Miscellaneous effects:

a. Cardiac events, including cardiomyopathy or congestive heart failure, may occur and are dose dependent.

b. Fatigue, fever, and headache are common.

c. Pain at the injection site is likely after extravasation.

d. Neuropathyis occasional.

DECITABINE

Other name. Dacogen.

Mechanism of action. Pyrimidine analog that inhibits methyltransferase, causing hypomethylation of DNA and thus, it is believed, results in cellular differentiation or apoptosis. May restore normal function of genes that are critical for the control of cellular differentiation and proliferation.

Primary indications

1. MDSs

2. AML in the elderly.

Usual dosage and schedule

1. MDS:

a. 20 mg/m2 IV over 1 hour daily for 5 days every 4 weeks

b. 15 mg/m2 CIVI over 3 hours, repeated every 8 hours for 3 days. This cycle is repeated every 6 weeks for a minimum offour cycles (older schedule). Therapy may be continued as long as the patient is improved from the drug.

2. AML: 20 mg/m2 IV on days 1 to 10 of a 4-week cycle for induction. May be repeated if persistent AML. 20 mg/m2 daily for 3 to 5 days for maintenance.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common. Febrile neutropenia is five times as common as in patients receiving supportive care.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea or constipation occurs in about one-third of patients. Abdominal pain may be associated.

3. Mucocutaneous effects. Stomatitis is occasional. Skin rash and alopecia are occasional. Urticaria is uncommon.

4. Neurotoxicity. Insomnia is common. Lethargy or confusional state are occasional.

5. Miscellaneous effects:

a. Cardiovascular: Pulmonary edema is uncommon. Peripheral edema is occasional.

b. Blurred vision is uncommon.

c. Fever is common; infections are occasional.

d. Arthralgias and backpain are occasional.

e. Hypomagnesemia, hypokalemia, hyperglycemia, hyponatremia, and hypoalbuminemia occur in 20% to 25% of patients.

f. Abnormal liver function tests are occasional.

DEGARELIX

Other name. Firmagon.

Mechanism of action. Gonadotropin-releasing hormone receptor antagonist that causes a decrease in LH and FSH and subsequently testosterone.

Primary indication. Carcinoma of the prostate.

Usual dosage and schedule. 240 mg as two 120-mg SC injections in the abdominal region, followed by a single injection of 80 mg every 28 days.

Special precautions. May prolong QT interval, as does other androgen depletion.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, diarrhea, and constipation are uncommon.

3. Mucocutaneous effects. Injection site erythema, swelling, and induration are common.

4. Miscellaneous effects:

a. Weight increase, fatigue, chills, and asthenia are occasional to uncommon.

b. Hot flushes are common.

c. Hypertensionisoccasional.

d. Musculoskeletal: Occasional arthralgias.

e. Increase in transaminases is occasional.

f. Dizziness, headache, and insomnia are uncommon.

g. Erectile dysfunction, gynecomastia, and testicular atrophy are reported, but the frequency above baseline is not established.

DENILEUKIN DIFTITOX

Other name. Ontak.

Mechanism of action. Denileukin diftitox is produced by genetically fusing protein from the diphtheria toxin to IL-2. This stable, fusion protein targets cells with receptors for IL-2 on their surfaces, including malignant cells and some normal lymphocytes, resulting in cell death. Efficacy in patients without the CD25 receptor is not known.

Primary indication. Persistent or recurrent CTCL that expresses the CD25 component of IL-2 receptor. (Confirm that the patient’s malignant cells express CD25 prior to treatment.)

Usual dosage and schedule. 9 or 18 µg/kg/day (350 to 700 mg/m2/day) IV over 30 to 60 minutes for 5 consecutive days every 21 days for eight cycles.

Special precautions. Acute hypersensitivity reactions occur commonly. Loss of visual acuity, usually with loss of color vision, usually resulting in permanent visual impairment.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia and lymphopenia are common. Thrombocytopenia is occasional. Thrombotic events are occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common. Dehydration as a consequence is occasional.

3. Mucocutaneous effects. Rashes, including generalized macropapular, petechial, vesicular bullous, urticarial, and eczematous, may be seen, with both acute and delayed onset.

4. Immunologic effects and infusion reactions. Mild infusion reactions are common. Severe acute infusion reactions occur occasionally (8%), including hypotension, back pain, dyspnea, vasodilation, rash, chest pain or tightness, and tachycardia. Syncope is uncommon; anaphylaxis is rare. Fever is common. Neutralizing antibodies develop in most patients by three cycles of treatment.

5. Miscellaneous effects:

a. Cardiovascular effects, including hypotension, vasodilation, fluid retention, and tachycardia, are occasional.

b. Respiratory reactions of dyspnea, increase in cough, and pharyngitis are occasional.

c. Capillary leak syndrome is common and is often delayed.

d. Metabolic changes that include hypoalbuminemia, transami-nase increase, and hypocalcemia are common.

e. Arterial and venous thromboses are uncommon.

f. Flulike symptoms with chills, fever, headache, and weakness are common. Myalgias and arthralgias are occasional.

g. Visual changes, including loss of visual acuity, which may be persistent, are uncommon.

DEXRAZOXANE

Other names. Zinecard, ICRF-187.

Mechanism of action. Probably by means of conversion of dexrazoxane intracellularly to a chelating agent that interferes with iron-mediated free radical generation, which is thought to be responsible, in part, for anthra-cycline-related cardiomyopathy. Appears to protect against myocardial toxicity without impairment of tumor response.

Primary indication. Prophylaxis of cardiomyopathy in patients who have received a cumulative dose of doxorubicin of 300 mg/m2 or greater and who are believed would benefit from continued therapy with this drug.

Usual dosage and schedule. 10 mg of dexrazoxane for every 1 mg of doxorubicin (e.g, 600 mg/m2 of dexrazoxane for 60 mg/m2 of doxorubicin). Repeat whenever doxorubicin is to be repeated. Administered as a slow injection or rapid infusion over 15 to 30 minutes.

Special precautions. None.

Toxicity. Most side effects encountered with dexrazoxane administration are likely to be from the concurrent chemotherapy regimen.

1. Myelosuppression and other hematologic effects. Nadir granulocyte and platelet counts lower than with chemotherapy alone, but duration not prolonged.

2. Nausea, vomiting, and other gastrointestinal effects. No increase observed.

3. Mucocutaneous effects. No increase observed.

4. Miscellaneous effects:

a. Pain at the injection site is occasional.

b. Hepatictoxicityispossible.

DOCETAXEL

Other name. Taxotere.

Mechanism of action. Enhanced formation and stabilization of microtu-bules. Antineoplastic effect may result from nonfunctional tubules or altered tubulin–microtubule equilibrium. Mitotic arrest is seen and is associated with accumulated polymerized microtubules.

Primary indications. Carcinomas of the breast, stomach, head and neck, lung, ovary, and prostate.

Usual dosage and schedule. 75 mg/m2 as a 1-hour infusion every 3 weeks, alone or in combination with other agents. Dose from 60 to 100 mg/m2 may be used depending on tolerance. Dexamethasone, 8 mg by mouth twice a day for 3 days starting 1 day before docetaxel, should be given before each course of docetaxel to limit the frequency and severity of hypersensitivity reactions and to reduce the severity of fluid retention.

Special precautions. Severe hypersensitivity reactions with flushing and hypotension with or without dyspnea occur in about 1% of patients (even when premedication is used). Should be used with caution in patients with bilirubin above ULN or other abnormal liver function tests (>1.5 ULN), because of more profound neutropenia.

Toxicity

1. Myelosuppression and other hematologic effects. Severe (grade 4) neutropenia is common and dose-related. Many patients have neutropenic fever.

2. Nausea, vomiting, and other gastrointestinal effects. Common, but brief; severe episodes are uncommon.

3. Mucocutaneous effects. Mild mucositis is common; severe mucositis is uncommon. Alopecia is common. Mild to moderate cutaneous reactions such as maculopapular eruptions are common; severe reactions that may be associated with desquamation or bullous eruptions occur only occasionally if systemic prophylaxis is used. Mild to moderate nail changes are common, but severe oncholysis is uncommon.

4. Immunologic effects and infusion reactions. Mild to moderate hypersensitivity reactions with flushing, hypotension (or rarely hypertension) with or without dyspnea and drug fever are occasional with use of the prophylactic regimen recommended. Severe hypersensitivity reactions are uncommon.

5. Miscellaneous effects:

a. Fluid retention syndrome is common and cumulative (more commonly after four courses); can be reduced to occasional frequency (6%) by prophylactic steroids; may limit continuing therapy. May be associated with both pleural and pericardial effusions.

b. Neurologic: Mild and reversible dysesthesias or paresthesias are common; more severe sensory neuropathies are uncommon.

c. Hepatic: Reversible increases in transaminase, alkaline phosphatase, and bilirubin

d. Local reactions: Reversible peripheral phlebitis

e. Mild diarrhea is common; severe diarrhea is rare.

f. Fatigue, weakness (asthenia), and myalgia are common; arthralgia is occasional.

DOXORUBICIN

Other names. ADR, Adriamycin, Rubex, hydroxyldaunorubicin.

Mechanism of action. DNA strand breakage mediated by anthracycline effects on topoisomerase II; DNA intercalation; DNA polymerase inhibition.

Primary indications

1. Breast, bladder, liver, lung, prostate, stomach, and thyroid carcinomas

2. Bone and soft-tissue sarcomas

3. Hodgkin and non-Hodgkin lymphomas

4. Multiple myeloma

5. Wilms tumor, neuroblastoma, and rhabdomyosarcoma of childhood.

Usual dosage and schedule

1. 60 to 75 mg/m2 IV every 3 weeks (or as 72- to 96-hour continuous infusion)

2. 30 mg/m2 IV on days 1 and 8 every 4 weeks (in combination with other drugs)

3. 9 mg/m2 IV daily for 4 days as a continuous infusion (in myeloma)

4. 15 to 20mg/m2IV weekly

5. 50 to 60 mg instilled into the bladder weekly for 4 weeks, then every 4 weeks for six cycles.

Special precautions

1. Administer over several minutes into the sidearm of a running IV infusion (except when given as a continuous infusion), taking care to avoid extravasation.

2. Do not give if patient has significantly impaired cardiac function (ejection fraction 45%), angina pectoris, cardiac arrhythmia, or recent myocardial infarction.

3. Do not exceedalifetime cumulative dose of550 mg/m2 (450 mg/m2 if patient was given prior chest radiotherapy or concomitant cyclophosphamide) unless there are known risk modifiers, such as continuous infusion, weekly dosing, or cardioprotective dexrazoxane, and serial measurements of cardiac ejection fraction show minimal change and adequate function.

4. Reduce or hold dose if patient has impaired liver function.

a. For serum bilirubin of 1.2 to 3.0 mg/dL, give halfthe normal dose.

b. For serum bilirubin of more than 3.0 mg/dL, give one-fourth the normal dose.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting for most patients. Nadir white blood cell (WBC) and platelet counts occur at 10 to 14 days; recovery by day 21.

2. Nausea, vomiting, and other gastrointestinale ffects. Mild to moderate in about half of patients.

3. Mucocutaneous effects. Stomatitis that is dose-dependent. Alopecia beginning 2 to 5 weeks from start of therapy with recovery following completion of therapy is common. Recall of skin reaction due to prior radiotherapy is common. Severe local tissue damage possibly progressing to skin ulceration and necrosis if subcutaneous extravasation occurs is common. Hyperpigmentation of skin overlying veins used for drug injection in which chemical phlebitis has occurred is common.

4. Cardiac effects. Potentially irreversible congestive heart failure may occur owing to cardiomyopathy. The incidence is highly dependent on the lifetime cumulative dose, which should not exceed 550 mg/m2. This limit is lower (450 mg/m2) if patient has received prior chest radiotherapy or is taking cyclophosphamide concomitantly. Weekly schedule and 96-hour infusions are less cardiotoxic and higher cumulative doses may be tolerable. Congestive heart failure may be predicted by serial measurement of left ventricular function or endomyocardial biopsy. Discontinue drug if there is clinical congestive heart failure or if the ejection fraction falls on the radionuclide angiogram to:

a. Less than 45%, or

b. Less than 50% if the total decrease is 10% or more (e.g., falls from 59% to 49%).

If repeat ejection fraction determination shows return of function, drug may be cautiously restarted, but ejection fraction determination should be done before each dose. Transient ECG changes are common and are not usually serious.

5. Miscellaneous effects:

a. Red urine caused by drug and its metabolites is common.

b. Chemical phlebitis and phlebosclerosis of veins used for injection are common, particularly if a vein is used repeatedly.

c. Fever, chills, and urticaria are uncommon.

DOXORUBICIN, LIPOSOMAL

Other name. Doxil.

Mechanism of action. Liposomal doxorubicin, which is designed to be protected from removal by the reticuloendothelial system, has a prolonged circulation time compared with unprotected drug. The agent penetrates tumor tissue and releases the active ingredient doxorubicin.

Primary indications

1. Kaposi sarcoma, advanced, HIV-associated

2. Ovarian and breast carcinomas

3. Multiple myeloma.

Usual dosage and schedule

1. 20 mg/m2 IVinfusion at a rate of 1mg/min for the first dose, then over 30 minutes for subsequent doses every 3 weeks for Kaposi sarcoma.

2. 40 to 50 mg/m2 IV infusion at a rate of 1 mg/min for the first dose, then over 1 hour every 4 weeks for ovarian or breast carcinoma when used as a single agent

3. 40 mg/m2 IV infusion at a rate of 1 mg/min for the first dose, then over 1 hour every 4 weeks for multiple myeloma, together with vin-cristine and dexamethasone

4. 30 mg/m2 IVinfusion on day 1 or 4in combination with bortezomib in relapsed and refractory multiple myeloma.

Special precautions. Must be diluted in 250 mL of 5% dextrose for injection. Liposomal doxorubicin is not a vesicant but should be considered an irritant. Initial doses should be given at a rate of 1 mg/min to avoid infusion reactions.

Toxicity. Effects that are a result of the liposomal doxorubicin have been somewhat difficult to determine with certainty because most patients have been on several other agents that can result in marrow or other toxicity.

1. Myelosuppression and other hematologic effects. Common and dose-related. May be severe.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common at the higher doses. Constipation is occasional. Diarrhea is occasional. Anorexia is occasional.

3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia is common at the higher doses and is occasionally severe. Stomatitis is common. Alopecia is occasional. Rash is occasional to common.

4. Immunologic effects and infusion reactions. Acute infusion-associated reactions with flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest and throat, or hypotension, alone or in combination, have occurred in approximately 7% of patients treated with liposomal doxorubicin. They usually occur with the first infusion and are not likely to occur later if the first infusion is given without a reaction. Most resolve over the course of several hours to a day.

5. Miscellaneous effects:

a. Cardiac events, including cardiomyopathy or congestive heart failure, occur in 5% to 10% of patients treated. This is dose-dependent and not really adequately tested with liposomal doxorubicin.

b. Astheniais occasional.

c. Fever is occasional.

d. Pain at the injection site is likely after extravasation.

EPIRUBICIN

Other names. Ellence, 4’epi-doxorubicin, EPI.

Mechanism of action. DNA-strand breakage, mediated by anthracycline effects on topoisomerase II.

Primary indications

1. Carcinomas of the breast, esophagus, and stomach

2. Hodgkin and non-Hodgkin lymphoma.

Usual dosage and schedule

1. 100 mg/m2 IV through the sidearm of a freely flowing IV infusion, repeated every 3 weeks administered, or

2. 60 mg/m2 IV on days 1 and 8 repeated every 3 weeks.

Special precautions

1. Take care to avoid extravasation.

2. Do not exceed a lifetime cumulative dose of 900 mg/m2. (Use a lesser dose for patients with prior chest radiotherapy or prior an-thracycline or anthracenedione therapy. 720 mg/m2 was the maximum cumulative dose in adjuvant studies.)

3. Reduce or hold dose if patient has impaired liver function.

a. For serum bilirubin of 1.2 to 3.0 mg/dL, give half the normal dose.

b. For serum bilirubin of more than 3.0 mg/dL, give one-fourth the normal dose.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia with recovery by day 21.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting are common. Diarrhea and abdominal pain are occasional.

3. Mucocutaneous effects:

a. Stomatitis that is dose-dependent.

b. Alopecia beginning approximately 10 days after the first treatment with regrowth when cessation of drug treatment occurs is common but not universal (25% to 50%).

c. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed.

d. Severe local-tissue damage possiblyprogressing to skin ulceration and necrosis if subcutaneous extravasation occurs is common.

4. Cardiac effects. Potentially irreversible congestive heart failure may occur owing to cardiomyopathy. The incidence depends on the lifetime dose, which should not exceed 900 mg/m2. This limit is lower if the patient has received prior chest radiotherapy or prior anthra-cycline or anthracenedione therapy. Congestive heart failure may be predicted by serial measurement of left ventricular function or endomyocardial biopsy. Transient ECG changes are similar in type and frequency to those observed after doxorubicin.

5. Miscellaneous effects:

a. Red-orange urine for 24 hours after injection owing to drugs and its metabolites is common.

b. Urticaria and anaphylaxis have been reported in patients treated with epirubicin; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.

c. SecondaryAMLandMDSarerare.

EPOETIN

Other names. Recombinant human erythropoietin (rHuEPO), EPO, epoetin-alfa, Epogen, Procrit.

Mechanism of action. Epoetin-alfa is a recombinant glycoprotein that contains 165 amino acids in a sequence identical to that of endogenous human erythropoietin. It has the same biologic activity, inducing erythro-poiesis by stimulating the division and differentiation of committed erythroid progenitor cells.

Primary indications

1. Anemia from concomitant chemotherapy in patients with nonmy-eloid malignancies, when cure is not the anticipated outcome

2. Anemia from low-risk MDS

3. Anemia associated with chronic renal failure

4. Anemia associated with zidovudine therapyin HIV-infected patients.

Usual dosage and schedule (in malignancy). 40,000 units SC once weekly. If there is no response after 4 to 8 weeks, the dose may be increased to 60,000 units SC once weekly. If no response to this dose, it should be discontinued.

Special precautions. There is a greater risk for death, serious cardiovascular events, and stroke when ESAs are administered to target hemoglobin levels of 13 g/dL and above in chronic renal failure. ESAs shorten survival or cause increase of tumor progression in some studies, and to decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion. Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program (www.esa-apprise.com) to prescribe and/ or dispense ESAs to patients with cancer. Contraindicated in patients with uncontrolled hypertension or known hypersensitivity to albumin or mammalian cell–derived products. Potential for serious allergic or anaphylactic reaction. Rare cases of pure red cell aplasia have been reported. Iron supplementation is beneficial if there is any question of body iron stores.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression is not seen, except for rare cases of pure red cell aplasia. Thromboembolic complications are uncommon but serious cardiovascular events and stroke may be seen.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrheais occasional.

3. Mucocutaneous effects. Rare rashes or hives.

4. Miscellaneous effects:

a. Edema is occasional.

b. A rise in blood pressure occurs in about 25% of patients. Hypertension may rarely occur in association with a significant increase in hematocrit; the risk is greatest in patients with preexisting hypertension.

c. Chest pain is uncommon.

d. Edema is occasional.

e. Seizures are rare.

f. Influenzalike syndrome is rare to uncommon. Fever alone is occasional.

ERIBULIN MESYLATE

Other name. Halaven.

Mechanism of action. Eribulin is a nontaxane microtubule dynamics inhibitor that is a synthetic analog of halichondrin B, a product isolated from the marine sponge Halichondria okadai.

Primary indication. Carcinoma of the breast, metastatic, in patients who have previously received an anthracycline and a taxane (either adjuvant or metastatic) and at least two chemotherapeutic regimens for metastatic disease.

Usual dosage and schedule. 1.4 mg/m2 IV over 2 to 5 minutes days 1 and 8 of a 21-day cycle.

Special precautions. Reduce dose by 20% to 50% in patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment or moderate renal impairment. Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia is common and often (57%) grade 3 or higher but febrile neutropenia is uncommon (4%). Anemia is common but not usually severe.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and anorexia are common, but vomiting is only occasional. Constipation is common. Diarrhea is occasional.

3. Mucocutaneous effects. Alopecia is common. Stomatitis or mucosal inflammation is occasional. Rash is occasional. Increased lacrimation is occasional.

4. Miscellaneous effects:

a. Asthenia and fatigue are common and occasionally severe; insomnia and depression are occasional.

b. Peripheral neuropathy is common and occasionally high grade (8%).

c. Headache is common; dizziness is occasional.

d. Myalgias and bone pain are occasional; muscle spasms and weakness are occasional.

e. Weight loss is common; peripheral edema is occasional.

f. Cough and dyspnea are occasional.

g. Hypokalemia is occasional.

ERLOTINIB

Other name. Tarceva.

Mechanism of action. Inhibits intracellular phosphorylation of the tyrosine kinase associated with EGFR.

Primary indications

1. Non–small-cell lung cancer:

a. Locally advanced after failure of one prior regimen

b. Maintenance treatment after four cycles of platinum-based chemotherapy.

2. Pancreatic cancer (with gemcitabine).

Usual dosage and schedule. Give at least 1 hour before or 2 hours after food.

1. 150 mg by mouth daily for lung cancer

2. 100 mg daily for pancreatic cancer.

Special precautions. May be associated with interstitial lung disease–like events, manifest by unexplained dyspnea, cough, and fever. If this occurs, erlotinib therapy should be discontinued and management of the pulmonary condition instituted. Gastrointestinal perforation; bullous, blistering, and exfoliative skin conditions, suggestive of toxic epidermal necrolysis; and ocular disorders including corneal perforation or ulceration have been reported.

CYP3A4 inhibitors such as ketoconazole increase erlotinib AUC while inducers such as rifampicin decrease erlotinib AUC, resulting in potential increase in toxicity or reduction in efficacy respectively. Monitor closely for INR elevation in patients taking concomitant warfarin. Give with extreme caution if liver impairment (bilirubin >3 × ULN); monitor those with less liver impairment closely.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression is not an effect of erlotinib. Deep venous thrombosis is uncommon. Unexpected INR elevation may occur in patients taking warfarin. Microangiopathic hemolytic anemia with thrombocytopenia is rare.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, dyspepsia, nausea, vomiting, diarrhea (second most common reason for dose interruption), constipation, and abdominal pain are common. Transaminase elevations are common and occasionally associated with increased bilirubin, but they are rarely life-threatening.

3. Mucocutaneous effects. Rash is common (75%) and the most common reason for dose interruption; stomatitis is occasional to common (17%). Keratoconjunctivitis is occasional.

4. Miscellaneous effects:

a. Systemic: Fatigue, weight loss, and edema are common; fever is common, occasionally with rigors.

b. Bonepainandmyalgiaarecommon.

c. Dyspnea is common; cough is occasional.

d. Anxiety, depression, headache, and neuropathy are occasional

e. Myocardial ischemia or infarction is uncommon

f. Cerebrovascular accidents are uncommon.

ETOPOSIDE

Other names. Epipodophyllotoxin, VP-16, VP-16-213, VePesid, Etopophos (etoposide phosphate).

Mechanism of action. Interaction with topoisomerase II produces single-strand breaks in DNA. Arrests cells in late S phase or G2 phase.

Primary indications

1. Small cell anaplastic and non–small-cell lung carcinomas

2. Stomach carcinoma

3. Germ cell cancers

4. Lymphomas

5. Acute leukemia

6. Neuroblastoma.

Usual dosage and schedule

1. 120 mg/m2 IV on days 1 to 3 every 3 weeks

2. 50 to 100 mg/m2 IV on days 1 to 5 every 2 to 4 weeks

3. 50 mg/m2 by mouth (rounded to nearest 50 mg) on days 1 to 5 every 3 weeks

4. 125 to 140 mg/m2 IV on days 1, 3, and 5 every 3 to 5 weeks

5. High-dose therapy (750 to 2400 mg/m2) is investigational and should only be used with progenitor cell rescue (e.g., bone marrow or peripheral blood stem cell transplantation).

Special precautions

1. Administer etoposide as a 30- to 60-minute infusion to avoid severe hypotension. Monitor blood pressure during infusion. Etoposide phosphate may be administered as a 5-minute bolus infusion.

2. Take care to avoid extravasation.

3. Etoposide must be diluted in 20 to 50 volumes (100 to 250 mL) of isotonic saline before use. Etoposide phosphate vials (100 mg) may be reconstituted in 5 to 10 mL (water, saline, or dextrose) to a concentration of 10 or 20 mg/mL.

4. Decrease dose by 50% for bilirubin levels of 1.5 to 3 mg/dL; decrease by 75% for bilirubin levels of 3 to 5 mg/dL; discontinue drug if bilirubin level is more than 5 mg/dL.

5. Decrease dose by 25% for creatinine clearance rate of less than 30 mL/min.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and less severe thrombocytopenia have a nadir at 16 days with recovery by days 20 to 22.

2. Nausea, vomiting, and other gastrointestinal effects. Usually mild to moderate nausea and vomiting in about one-third of patients receiving standard doses; common with high-dose therapy. Anorexia is common. Diarrhea is uncommon.

3. Mucocutaneous effects:

a. Alopecia is common.

b. Stomatitis is uncommon with standard doses; common with high-dose therapy.

c. Painful rash may occur with high-dose therapy.

d. Chemical phlebitis is occasional.

4. Miscellaneous effects:

a. Hepatotoxicity is rare.

b. Peripheral neurotoxicity is rare.

c. Allergic reaction is rare.

d. Hemorrhagic cystitis may occur with high-dose therapy.

EVEROLIMUS

Other name. Afinitor.

Mechanism of action. Everolimus, after complexing with an intracellular protein, FKBP-12, is an inhibitor of the mammalian target of rapamycin (mTOR), a serine threonine kinase, the pathway of which is dysregulated in several human cancers. It also inhibits the expression of hypoxia-inducible factor-1 and the expression of VEGF. Mechanism is similar, if not identical, to temsirolimus.

Primary indication. Advanced renal cell carcinoma.

Usual dosage and schedule

1. 10 mg by mouth once daily

2. Reduce dose to 5 mg by mouth once daily for patients with Child-Pugh class B hepatic impairment or as needed to manage adverse drug reactions.

3. If strong inducers of CYP3A4 are required, increase daily dose in 5 mg increments to a maximum of 20 mg once daily.

Special precautions. Coadministration of everolimus with strong or moderate inhibitors of CYP3A4 or the multidrug efflux pump P-glycoprotein, such as ketoconazole, increases the AUC of everolimus by up to 15-fold and should be avoided. CYP3A4 inducers may decrease everolimus AUC, and increased doses may be required.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia and lymphopenia are common and occasionally severe. Thrombocytopenia and neutropenia occur only occasionally and are rarely grade 3 or 4. Hemorrhage is uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrhea, nausea, and vomiting are common but rarely severe. Abdominal pain is occasional.

3. Mucocutaneous effects. Mucositis is common (44%), but grade 3 or 4 ulceration is uncommon. Rash is common; pruritis and dry skin are occasional. Hand-foot syndrome is uncommon, as are nail disorders and acneiform dermatitis.

4. Miscellaneous effects:

a. Noninfectious pneumonitis (a class effect of rapamycin derivatives) is occasional, but grade 3 or 4 reaction is uncommon.

b. Infections, particularly with opportunistic infections, are common and may occasionally be severe.

c. Metabolic changes: Elevations in lipids, glucose, creatinine, transaminases, and decreased phosphate are common. Except for glucose elevation, which is occasional, severe (grade 3 or 4) abnormalities of the other changes are uncommon to rare.

d. Asthenia, fatigue, peripheral edema, fever, headache, cough, and dyspnea are common (15% to 30%), but severe episodes are uncommon to rare. Decreased weight is occasional.

e. Cardiovascular: Hypertension, tachycardia, and chest pain are uncommon, and congestive heart failure is rare.

f. Nervous system: Insomnia, dizziness, and paresthesias are occasional to uncommon.

g. Acute renal failure is rare.

EXEMESTANE

Other name. Aromasin.

Mechanism of action. Exemestane is an irreversible, steroidal aromatase inactivator that decreases estrogen biosynthesis by selective inhibition of aromatase (estrogen synthetase) in peripheral tissues.

Primary indications

1. Carcinoma of the breast in postmenopausal women that has progressed following tamoxifen therapy

2. Carcinoma of the breast as adjuvant treatment in postmenopausal women with estrogen-receptor–positive breast cancer.

Usual dosage and schedule. 25 mg by mouth once daily after meal.

Special precautions. Potential hazard to fetus if given during pregnancy.

Toxicity

1. Myelosuppression and other hematologic effects. No dose-related effect. Thromboembolic events are uncommon to rare.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, constipation, and diarrhea are uncommon to occasional.

3. Mucocutaneous effects. Rash is uncommon.

4. Miscellaneous effects:

a. Fatigue is occasional.

b. Musculoskeletal pain (arthralgia or bone) is occasional to common.

c. Headache is occasional.

d. Peripheral edema and weight gain are occasional (lower than with megestrol).

e. Dyspnea and cough are uncommon to occasional.

f. Hot flushes are occasional.

g. Decreased bone mineral densitywith osteoporosis is occasional and there is increased risk for fractures.

h. Hypertension is occasional.

FILGRASTIM

Other names. Granulocyte colony-stimulating factor (G-CSF), Neupogen.

Mechanism of action. Promotes growth and differentiation of myeloid progenitor cells. May improve survival and function of granulocytes.

Primary indications

1. Prophylaxis of granulocytopenia secondary to intensive chemotherapy with febrile neutropenia rate of greater than 20% or in patients with previous episode of febrile neutropenia.

2. Treatment of granulocytopenia secondary to chemotherapy.

3. Granulocytopenia from primary marrow disorders, such as idio-pathic neutropenia and aplastic anemia, and MDS.

4. Granulocytopenia associated with AIDS and its therapy.

Usual dosage and schedule

1. Adjunct to chemotherapy: commonly 200 to 400 μg/m2 (5 to 10 μg/kg) SC daily, starting no sooner than 24 hours and no later than 4 days after the last dose of chemotherapy, for 10 to 20 days until the neutrophil count exceeds 10,000/μL after the expected nadir. Because of cost factors, vial size, and comparability of effect with “ballpark” doses, some physicians choose to treat patients weighing less than 75 kg with 300 μg daily and patients weighing more than 75 kg with 480 μg daily.

2. Other purposes: 40 to 500 μg/m2 SC, IM, or IV daily. Dose and duration are dependent on the purpose of administration.

Special precautions. Use with caution in disorders of myeloid stem cells, as it may promote growth of leukemic cells.

Toxicity

1. Myelosuppression and other hematologic effects. None (leukocytosis).

2. Nausea, vomiting, and other gastrointestinal effects. Rare.

3. Mucocutaneous effects. Exacerbation of pre-existing dermatologic conditions are occasional; pyoderma gangrenosum is rare.

4. Miscellaneous effects:

a. Bone pain, musculoskeletal symptoms such as cramps, and back or leg pain are common but are usually mild and short-lived.

b. Splenomegaly occurs with prolonged use.

c. Exacerbation of pre-existing inflammatory or autoimmune disorders is rare.

d. Mild elevation ofLDH and alkaline phosphatase.

FLAVOPIRIDOL

Other name. Alvocidib.

Mechanism of action. Cyclin-dependent kinase inhibitor that induces apop-tosis. Also induces apoptosis independent of p53.

Primary indication. CLL with high-risk genetic features, including del(17p13.1) and del(11q22.3), that has previously been treated.

Usual dosage and schedule. 30 mg/m2 by 30-minute IV bolus infusion followed by 30 mg/m2 as a CIVI for dose 1. The CIVI dose could be escalated to 50 mg/m2 if dose 1 was tolerated well without tumor lysis syndrome. Treatments are repeated days 1, 8, and 15 every 28 days.

Special precautions. Tumor lysis syndrome occurs commonly during the first and second cycles of treatment. Rasburicase, 2 hours before the first and second doses of flavopiridol, should be considered and plans made for urgent dialysis if needed. Treatment requires prophylactic dexamethasone 20 mg IV on each treatment day to modify the cytokine release syndrome, allopurinol daily, and valcyclovir 100 mg daily for the duration of the treatment. Prophylactic pegfilgrastim should be given on day 16 of each cycle, and ciprofloxacin 500 mg twice a day for the duration of the flavopiridol therapy. Pneumocystis pneumonia prophylaxis is frequently used.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia is universal and commonly grade 3 to 4. Anemia and thrombocytopenia are common and only occasionally severe.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting are common and only occasionally severe. Diarrhea is universal and commonly severe. Anorexia is common.

3. Mucocutaneous effects. Not reported.

4. Immunologic effects and infusion reactions. Cytokine release syndrome is common; clinical tumor lysis syndrome is common (20% to 25%) and may be severe.

5. Miscellaneous effects:

a. Infection is common and severe in about 25% of patients.

b. Fatigue is universal.

c. Anxiety and depression are occasional.

d. Transaminase elevations are universal and commonly are grade 3 to 4. Bilirubin elevations are common, but grade 3 to 4 is uncommon.

FLUDARABINE

Other names. FAMP, Fludara, Oforta.

Mechanism of action. A purine analog that causes inhibition of DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis.

Primary indications

1. CLL(B-cell)

2. Macroglobulinemia

3. Indolent lymphomas

4. Acute leukemia (in combination).

Usual dosage and schedule

1. 25 mg/m2 IV as a 30-minute infusion daily for 5 days (Fludara). Other dose schedules, usually less intensive, have been used, often in combinations with other drugs. Repeat every 4 weeks.

2. 40 mg/m2 by mouth daily for 5 days. Repeat every 4 weeks (Oforta).

Special precautions. If there is the potential for tumor lysis syndrome, administer allopurinol and ensure good hydration and close clinical monitoring. Transfusion-associated graft-versus-host disease may be seen. Therefore, prior irradiation of blood products for transfusion in patients at risk is recommended. Fatal cases of autoimmune hemolytic anemia have been reported, and patients should be closely monitored for hemolysis, particularly if there is a prior history of autoimmune hemolysis or immune thrombocytopenia related to the chronic lymphocytic leukemia. Not recommended for use in combination with pentostatin because of high incidence of pulmonary toxicity. Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2 should have a 20% dose reduction of fludarabine). It should not be given to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

Toxicity

1. Myelosuppression and other hematologic effects. Granulocytopenia and thrombocytopenia are common but appear to become less common in patients whose disease is responding. May progress to trilineage marrow hypoplasia. Infection, particularly pneumonia, is common during early courses and uncommon after the sixth course. Autoimmune hemolytic anemia and immune thrombocytopenia have been observed (probably rare).

2. Nausea, vomiting, and other gastrointestinal effects. Nauseais occasional to common but not usually severe. Diarrhea is occasional.

3. Mucocutaneous effects. Occasional mucositis and rash; no alopecia.

4. Neurotoxicity. Uncommon at usual dosage. Somnolence or fatigue, paresthesias, and twitching of extremities may be seen. Severe neurologic symptoms, including visual disturbances, have been common at higher doses than those recommended.

5. Immune suppression. Common. Usually seen as a depression in CD4 and CD8 lymphocyte counts. Opportunistic infections may result, and many recommend Pneumocystis pneumonia prophylaxis with trimethoprim-sulfamethoxazole until the CD4 lymphopenia resolves.

6. Miscellaneous effects:

a. Abnormal liver or renal function is rare.

b. Cough, dyspnea, are upper respiratoryinfections are occasional.

c. Fever, infection, diaphoresis, are headache are occasional.

d. Allergic pneumonitis is occasional to uncommon.

e. Edema is occasional.

f. Tumor lysis syndrome is uncommon.

FLUOROURACIL

Other names. 5-FU, Adrucil, Efudex, Fluoroplex, 5-fluorouracil.

Mechanism of action. A pyrimidine antimetabolite that, when converted to the active nucleotide, inhibits the enzyme thymidylate synthetase and thereby blocks DNA synthesis.

Primary indications

1. Breast, colorectal, anal, stomach, pancreas, esophagus, liver, head and neck, and bladder carcinomas

2. Actinic keratosis; basal and squamous cell carcinomas of skin (topically).

Usual dosage and schedule

1. Systemic options (alternatives). Other schedules when in combinations.

a. 500 mg/m2 IV on days 1 to 5 every 4 weeks

b. 450 to 600 mg/m2 IV weekly

c. 200 to 400 mg/m2 daily as a CIVI

d. 1000 mg/m2 daily for 4 days as a CIVI every 3 to 4 weeks

e. Leucovorin 20 mg/m2 IVis followedbyfluorouracil 425 mg/m2 IV. The combination is given daily for 5 days. Courses are repeated every 4 weeks.

2. Intracavitary: 500 to 1000 mg for pericardial effusion; 2000 to 3000 mg for pleural or peritoneal effusions

3. Topically: Apply solution or cream twice daily. Use only5% strength for carcinomas.

Special precautions

1. Reduce the dose in patients with compromised liver function.

2. Precipitation may occur if leucovorin and fluorouracil are mixed in the same bag.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting with a nadir at 10 to 14 days after the last dose and recovery by 21 days.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting may occur but are not usually severe. Diarrhea is common with higher doses, continuous infusion, or when used in combination with leucovorin and irinotecan. Esophagitis and proctitis may also occur.

3. Mucocutaneous effects:

a. Stomatitis is an early sign of severe toxicity. It progresses from soreness and erythema to frank ulceration, which becomes hemorrhagic in a small number of patients.

b. Partial alopecia is uncommon.

c. Hyperpigmentation of skin over face, hands, and the veins used for infusion is occasional.

d. Maculopapular rash is uncommon.

e. Sun exposure tends to increase skin reactions.

f. Hand-foot syndrome with painful, erythematous desquamation and fissures of palms and soles is common with continuous infusion and occasional with other schedules or combinations.

4. Miscellaneous effects:

a. Neurotoxicity, including headache, minor visual disturbances, and cerebellar ataxia, is rare.

b. Increased lacrimation is uncommon.

c. Cardiac toxicity, including arrhythmias, angina, ischemia, and sudden death, is rare. May be more common with continuous infusion and previous history of coronary artery disease.

FLUTAMIDE

Other name. Eulexin.

Mechanism of action. Competitive inhibitor of androgens at the cellular androgen receptor in prostate cancer cells.

Primary indication. Carcinoma of the prostate, most often in combination with LHRH agonists.

Usual dosage and schedule. 250 mg by mouth every 8 hours.

Special precautions. Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose serum transaminase values exceed twice the ULN.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting are uncommon to occasional. Diarrhea, flatulence, and mild abdominal pain are occasional.

3. Mucocutaneous effects. Mild skin rash is occasional.

4. Miscellaneous effects:

a. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot flashes, impotence, and loss of libido, are common but reversible after cessation of therapy.

b. Elevated liver function tests are uncommon; liver failure is rare but may be preceded by flulike symptoms or right upper quadrant pain and tenderness.

c. Hypertensionisoccasional.

d. Adverse cardiovascular events are similar to those seen with orchiectomy.

FULVESTRANT

Other name. Faslodex.

Mechanism of action. An estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner. It downregulates the estrogen receptor protein in human breast cancer cells. In vitro, there is reversible inhibition in the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines.

Primary indications

1. Hormone receptor–positive metastatic breast cancer in postmeno-pausal women with disease progression following antiestrogen therapy. (There are no efficacy data for premenopausal women with advanced breast cancer.)

2. Hormone receptor–positive metastatic breast cancer in postmeno-pausal women with disease progression following therapy with a third generation aromatase inhibitor.

Usual dosage and schedule

1. 500 mg IM over 1 to 2 minutes as two concurrent 5-mL injections (50 mg/mL) into each buttock, repeated once monthly after loading on days 1, 15, and 29.

2. Reduce dose to 250 mg in patients with moderate hepatic impairment (Child-Pugh class B), using the same schedule as previously discussed.

Special precautions. Safety has not been evaluated in patients with severe hepatic impairment.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia is rare.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseais common; vomiting, constipation, diarrhea, and anorexia are occasional.

3. Mucocutaneous effects. Rash and increased sweating are occasional.

4. Miscellaneous effects:

a. For the body as a whole, headache, back pain, abdominal pain, injection site pain, and pelvic pain are occasional. Occasional patients also experience a flulike syndrome or fever.

b. Vasodilation and edema are occasional.

c. Dizziness, insomnia, paresthesias, depression, and anxiety are uncommon to occasional.

d. Pharyngitis, dyspnea, and increased cough are occasional.

GEFITINIB

Other names. Iressa, ZD1839.

Mechanism of action. Selectively inhibits tyrosine kinase activity of the EGFR. EGFR tyrosine kinase inhibition by gefitinib impairs epidermal growth factor–stimulated autophosphorylation and thus blocks growth signals within the cell.

Primary indication. Carcinoma of the lung as monotherapy for the continued treatment of patients with locally advanced or metastatic non–small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from its use.

Usual dosage and schedule. 250 mg daily (may require interruption for diarrhea or skin reactions).

Special precautions. Diarrhea may be dose-limiting and require discontinuation of the drug.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon, except for anemia, which is occasional and not dose-related.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common. Diarrhea may be dose-limiting. Anorexia, constipation, and abdominal pain are also common but usually not severe.

3. Mucocutaneous effects. Acnelike or folliculitis-type rash is common, usually appearing by day 14; frequency and severity are dose-related. May be associated with dry skin and itching. Rash usually does not worsen with continued treatment and resolves within a week of discontinuation of the drug. Dry mouth and conjunctivitis are occasional.

4. Miscellaneous effects:

a. Dyspnea is occasional to common.

b. Astheniais common.

c. Headache is occasional.

d. Somnolence is occasional.

e. Elevated hepatic transaminases are occasional butmaybe severe (grade 3 or 4).

GEMCITABINE

Other name. Gemzar.

Mechanism of action. After being metabolized intracellularly to the active diphosphate and triphosphate nucleotides, gemcitabine, a cytidine analog, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.

Primary indications

1. Carcinoma of the pancreas, locally advanced or metastatic

2. Non–small-cell carcinomas of the lung

3. Carcinomas of the breast, biliary tract, bladder, and ovary

4. Non-Hodgkin lymphoma

5. Soft-tissue sarcoma.

Usual dosage and schedule

1. 1000 mg/m2 IV over 30 minutes once weeklyfor up to 7 weeks when used as a single agent. After 1 week of rest, subsequent cycles are given once weekly for 3 consecutive weeks out of 4.

2. 1000 to 1250 mg/m2 IV over 30 minutes once weekly for 2 or 3 successive weeks during each 3- or 4-week cycle, when used in combination regimens.

Special precautions. Prolongation of infusion time beyond 60 minutes increases toxicity.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-related and common. Overt hemolytic-uremic syndrome is rare, but milder cases with renal insufficiency may be more common.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but only occasionally severe. Diarrhea and constipation are occasional to common.

3. Mucocutaneous effects. Rash, alopecia, and mucositis are occasional.

4. Miscellaneous effects:

a. Transient elevations of serum transaminases and alkaline phosphatase are common. Serious hepatotoxicity is rare.

b. Mild proteinuria and hematuria are common.

c. Fever without documented infection is common.

d. Neurotoxicity: Mild paresthesias are occasional.

e. Dyspnea is occasional.

GEMTUZUMAB OZOGAMICIN

Other name. Mylotarg.

Mechanism of action. Gemtuzumab ozogamicin is a humanized recombinant monoclonal antibody against the CD33 antigen that is conjugated with the cytotoxic antitumor antibiotic calicheamicin. Once bound to the CD33 antigen, the agent is internalized, calicheamicin is released, and its reactive intermediate binds to DNA and causes DNA double-strand breaks and cell death.

Primary indication. Patients with CD33-positive AML who are older than 60 years and are not considered candidates for other cytotoxic chemotherapy.

Usual dosage and schedule

1. 9 mg/m2 as a 2-hour IV infusion on days 1 and 15

2. In combination therapy, 6 mg/m2 as a 2-hour infusion for induction and 3 mg/m2 for maintenance.

Special precautions

1. Infusion-related events may include fever, nausea, chills, hypotension, shortness of breath, and anaphylaxis. Pretreatment with acetaminophen and diphenhydramine should be given prior to treatment to lessen these effects, and prior methylprednisolone may also be of benefit.

2. If dyspnea or significant hypotension occurs, the infusion should be interrupted. Anaphylaxis, pulmonary edema, and acute respiratory distress syndrome usually necessitate discontinuation of therapy.

3. Hepatotoxicity, including veno-occlusive disease may occur, even in patients without a history of liver disease or hematopoietic stem cell transplant.

4. Tumor lysis syndrome may occur, particularlywhen the WBC count is higher than 30,000/µL.

Toxicity

1. Myelosuppressionandotherhematologiceffects. Severetolife-threatening granulocytopenia and thrombocytopenia are universal. Severe or worse anemia is common.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, abdominal pain, and diarrhea are common but only occasionally severe.

3. Mucocutaneous effects. Rash, local reaction, petechiae, stomatitis, pharyngitis, and rhinitis are occasional to common. Herpes simplex is common. Alopecia is not seen.

4. Immunologic effects and infusion reactions. Chills, fever, headache, nausea, and vomiting are common but usually resolve within 4 hours of end of infusion. Fewer after second dose.

5. Miscellaneous effects:

a. Hyperglycemia and dyspnea are occasional. Hypoxia is uncommon (about 5%).

b. Increased cough, dyspnea, and epistaxis are common. Severe dyspnea or pneumonia is occasional. Pleural effusions, noncardiogenic pulmonary edema, and acute respiratory distress syndrome are rare.

c. Severe or life-threatening infections are common. These include sepsis, pneumonia, and opportunistic infections.

d. Hypertension, hypotension, and tachycardia are occasional.

e. Reversible abnormalities in liver function are common and occasionally severe or life-threatening. Fatal liver abnormalities including veno-occlusive disease are rare. Findings that may indicate severe hepatotoxicity include rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, and elevations in liver function tests.

GONADOTROPIN-RELEASING HORMONE ANALOGS

Other names. LHRH analogs, Leuprolide (Lupron, Lupron depot, Viadur), goserelin (Zoladex depot), triptorelin pamoate (Trelstar depot).

Mechanism of action. Initial release of FSH and LH from the anterior pituitary, followed by diminution of gonadotropin secretion owing to desensitization of the pituitary to gonadotropin-releasing hormone (GnRH) and consequent decrease in the respective gonadal hormones. May also have direct effects on cancer cells, at least in cancer of the breast, in which GnRH-binding sites have been demonstrated.

Primary indications

1. Metastatic prostate carcinoma

2. Breast carcinoma in premenopausal and perimenopausal women with metastatic disease (goserelin).

Usuall dosage and schedule

1. Leuprolide depot 7.5 mg IM monthly, 22.5 mg IM every 3 months, or 30 mg IM every 4 months

2. Goserelin depot 3.6 mg SC every 4 weeks or10.8 mg SC every 12 weeks. Use only 3.6 mg implant for breast carcinoma.

3. Triptorelin depot 3.75 mg IM monthly; triptorelin depot 22.5 mg IM every 6 months.

Special precautions. Worsening of symptoms may occur during the first few weeks.

Toxicity

1. Myelosuppression and other hematologic effects. Rare, if at all.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and constipation are uncommon.

3. Mucocutaneous effects. Erythema and ecchymosis at the injection site, rash, hair loss, and itching are uncommon.

4. Cardiovascular effects. Congestive heart failure, hypertension, and thrombotic episodes are uncommon. Peripheral edema is occasional.

5. Miscellaneous effects:

a. CNS: Dizziness, pain, headache, and paresthesias are uncommon.

b. Endocrine: Hot flashes are common; decreased libido is common; gynecomastia with or without tenderness is uncommon; impotence is occasional to common.

c. Bone pain, or “flare,” is common on initiation of therapy in patients with bony metastasis. This can be minimized by pretreating with flutamide or another androgen antagonist in men with prostate cancer.

d. Hypersensitivity reactions with rare angioneurotic edema and anaphylaxis have been reported.

HYDROXYUREA

Other names. Hydroxycarbamide, Hydrea, Droxia.

Mechanism of action. Interferes with DNA synthesis, at least in part by inhibiting the enzymatic conversion of ribonucleotides to deoxyribonucleotides.

Primary indications

1. Head and neck carcinomas

2. CML; ALL and acute nonlymphocytic leukemia with high blast counts

3. Essential thrombocythemia

4. Polycythemia rubra vera

5. Prevention of retinoic acid syndrome in acute promyelocytic leukemia

6. Sickle cell anemia with frequent painful crises.

Usual dosage and schedule

1. 800 to 2000 mg/m2 by mouth as a single or divided daily dose. Dose is adjusted up or down, depending on efficacy and tolerability.

2. 3200 mg/m2 by mouth as a single dose every third day (not for leukemias).

3. Starting dose in sickle cell anemiais 15 mg/kg/day, with increments of 5 mg/kg every 12 weeks, as long as ANC is greater than 2000 cells/μL and platelets are greater than 80,000/μL.

Special precautions. The daily dose must be adjusted for blood count trends. Be careful not to change dose too often, because there is a delay in response. Severe cutaneous vasculitic toxicities, including ulcers and gangrene, have been seen, particularly in association with current or prior interferon therapy. Toxic reactions may be greater in patients with impaired renal function, such as may be seen in elderly patients. Reduce doses by 50% if creatinine clearance less than 60.

Toxicity

1. Myelosuppression and other hematologic effects. Occurs at doses of more than 1600 mg/m2 daily by day 10. Recovery is usually prompt. Increased red cell mean corpuscular volume is common.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea is common at high doses. Other gastrointestinal symptoms are uncommon. Pancreatitis may be seen in patients with HIV disease being treated with didanosine and other antiviral agents.

3. Mucocutaneous effects. Stomatitis is rare. Maculopapular rash may be seen. Inflammation of mucous membranes caused by radiation may be exaggerated.

4. Miscellaneous effects:

a. Temporary renal function impairment or dysuria is uncommon.

b. CNSdisturbancesarerare.

c. Maybe leukemogenic or teratogenic.

IBRITUMOMAB TIUXETAN

Other names. Zevalin, IDEC-Y2B8.

Mechanism of action. Ibritumomab is a murine monoclonal anti-CD20 antibody conjugated to tiuxetan that chelates to the pure beta-emitting yttrium-90 (90Y). The mechanism of action includes antibody-mediated cytotoxicity and cellularly targeted radiotherapy (radioimmunotherapy).

Primary indications

1. Non-Hodgkin lymphoma, low-grade or follicular B-cell, CD20-positive, rituximab refractory

2. Previously untreated patients with follicular non-Hodgkin lymphoma who achieve a partial or complete response to first-line chemotherapy.

Usual dosage and schedule

Day 1: Administer rituximab 250 mg/m2 by IV infusion. Within 4 hours after rituximab infusion, administer 5 mCi indium-111 Zevalin IV Assess biodistribution by radionuclide scan 48 to 72 hours after In-111 Zevalin. Only if biodistribution is acceptable, proceed to day 7 (or 8 or 9).

Day 7, 8, or 9: Administer rituximab 250 mg/m2 by IV infusion.

1. If platelets are at least 150,000/mm4:Within 4 hours after rituximab infusion, administer 0.4 mCi/kg (14.8 MBq per kg) 90Y Zevalin IV Maximum allowable dose of 90Y Zevalin is 32 mCi.

2. Ifplatelets are at least 100,000 but no more than 149,000/mm3 in relapsed or refractory patients: Within 4 hours after rituximab infusion, administer 0.3 mCi/kg (11.1 MBq per kg) 90Y Zevalin IV

3. Do not treat if platelets are less than 100,000.

Special precautions. Use with caution in patients with at least 25% marrow involvement with lymphoma, prior external beam radiotherapy to at least 25% of the bone marrow, or a history of human antimouse antibodies (HAMAs) or HACAs. Because the drug does not emit gamma radiation, hospitalization is not required.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia, lymphopenia, anemia, and thrombocytopenia are common and related to the radionuclide dose. At the higher end of the dosing, 25% will develop nadir neutrophil counts of less than 500/(xL. Cytopenias are prolonged in most patients.

2. Nausea, vomiting, and other gastrointestinal effects. Low-grade nausea and vomiting are common. Diarrhea is occasional.

3. Mucocutaneous effects. Severe cutaneous and mucocutaneous reactions, some fatal, can occur but are rare. Urticaria and pruritis are occasional.

4. Immunologic effects and infusion reactions. Infusion-related fever, chills, dizziness, asthenia, headache, back pain, arthralgia, and hypotension are occasional and may be severe. HAMA or HACA may develop.

5. Miscellaneous effects: Leukemia and MDS have been seen in 1%to 5% of patients treated.

IDARUBICIN

Other names. 4-Demethoxydaunorubicin, IDA, Idamycin.

Mechanism of action. DNA-strand breakage mediated by anthracycline effects on topoisomerase II or free radicals; DNA intercalation; DNA polymerase inhibition.

Primary indications

1. Acute nonlymphocytic leukemia

2. Blast crisis of CML

3. ALL.

Usual dosage and schedule. 12 to 13 mg/m2 IV daily for 3 days (usually in a combination with cytarabine) during induction; 10 to 12 mg/m2 IV daily for 2 days during consolidation.

Special precautions. Administer over several minutes into the sidearm of a running IV infusion, taking care to avoid extravasation. Cardiac toxicity may be less than that with daunorubicin. Maximum dose not yet established. Cumulative doses greater than 150 mg/m2 have been associated with decreased cardiac ejection fraction.

Toxicity

1. Myelosuppression and other hematologic effects. Universal and dose-limiting.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and anorexia are common. Diarrhea is occasional to common.

3. Mucocutaneous effects. Alopecia is common; mucositis is common but usually not severe.

4. Miscellaneous effects:

a. Hepatic dysfunction is common but usually not severe and not clearly due to the idarubicin.

b. Renal effects are common but usually not clinically significant.

c. Cardiac effects are uncommon during induction and consolidation (1% to 5%).

d. Tissue damage is probable ifinfiltration occurs.

e. Neurologic effects are occasional.

IFOSFAMIDE

Other name. Ifex.

Mechanism of action. Metabolic activation by microsomal liver enzymes produces biologically active intermediates that attack nucleophilic sites, particularly on DNA.

Primary indications

1. Testicular and lung cancers

2. Bone and soft-tissue sarcomas

3. Lymphoma.

Usual dosage and schedule

1. 1.2 g/m2 IV over 30 minutes or more daily for 5 consecutive days every 3 or 4 weeks, usually with other agents. Mesna 120 mg/m2 is given just before ifosfamide, then mesna 1200 mg/m2 as a daily continuous infusion is given until 16 hours after the last dose of ifosfamide.

2. 3.6 g/m2 IV daily as a 4-hour infusion for 2 consecutive days, usually with other agents. Mesna is given at a dose of 750 mg/m2 IV just prior to and at 4 and 8 hours after the start of the ifosfamide.

Higher dosage schedules have been used experimentally with up to 14 g/m2 being used per course over a 6-day period, with equal or greater doses of mesna.

Special precautions. Must be used with mesna to prevent hemorrhagic cystitis. Mesna dose is at least 20% of the ifosfamide dose (on a weight basis), administered just prior to (or mixed with) the ifosfamide dose and again at 4 and 8 hours after the ifosfamide to detoxify the urinary metabolites that cause the hemorrhagic cystitis. Higher doses of ifosfamide may require higher doses and longer durations of mesna. Neither mesna nor its only metabolite, mesna disulfide, affect ifosfamide or its antineoplastic metabolites. Mesna disulfide is reduced in the kidney to a free thiol compound, which then reacts chemically with urotoxic metabolites, resulting in their detoxification. Vigorous hydration is also required with a minimum of 2 L of oral or IV hydration daily. Administer as a slow IV infusion over a period of at least 30 minutes.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression is dose-limiting. Platelets are relatively spared. Granulocyte nadirs are commonly reached at 10 to 14 days, and recovery is seen by day 21. Thrombocytopenia may be seen with higher doses.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common without standard antiemetics.

3. Mucocutaneous effects. Alopecia is common; mucositis is rarely seen at standard doses; dermatitis is rare.

4. Hemorrhagic cystitis. Common and dose-limiting unless a uroprotective agent such as mesna is used. With mesna, the incidence of hemorrhagic cystitis is 5% to 10%, and gross hematuria is uncommon. Increasing the duration of mesna may alleviate the problem during subsequent cycles.

5. Miscellaneous effects:

a. CNS toxicity (somnolence, confusion, depressive psychosis, hallucinations, disorientation, and uncommonly seizures, cranial nerve dysfunction, or coma) is occasional with doses in the lower range; it is more common with larger doses.

b. Infertility is common in men and women, as with other alkylating agents.

c. Renal impairment is occasional to common. Fanconi syndrome dependent on dose. May be severe acidosis.

d. Liver dysfunction is uncommon.

e. Phlebitis is uncommon.

f. Fever is rare.

g. Peripheral neuropathy with high-dose therapyis uncommon.

IMATINIB MESYLATE

Other names. Gleevec, signal transduction inhibitor 571.

Mechanism of action. Inhibitor of the constitutively activated Bcr-Abl tyrosine kinase that is created as a consequence of the (9;22) chromosomal translocation and is required for the transforming function and excess proliferation seen in CML. It also inhibits the RTKs for platelet-derived growth factor (PDGF), stem cell factor, and c-Kit, the latter of which is activated in gastrointestinal stromal tumors (GISTs).

Primary indications

1. CML in chronic, accelerated, or blast phase of the disease

2. ALL, Ph+

3. GIST thatis Kit+ (CD117), adjuvant and metastatic disease

4. MDS or myeloproliferative diseases (MPD) with PDGF receptor gene rearrangements

5. Aggressive systemic mastocytosis (ASM) without D816V c-Kit mutation or with c-Kit mutation status unknown

6. Hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) with the FIP1L1-PDGFRα fusion kinase (CHIC2 deletion; and also if fusion kinase negative or unknown)

7. Dermatofibrosarcoma protuberans (DFSP).

Usual dosage and schedule

1. 400 mg by mouth daily in the chronic phase of CML, MDS or MPD, or GISTs. Reduce to 300 mg/day with severe liver impairment or moderate renal impairment.

2. 600 mg by mouth daily in the accelerated phase or blast crisis of CML or Ph+ALL

3. 100 to 400 mg by mouth daily in ASM, HES, or CEL

4. 800 mg by mouth daily in DFSP.

Special precautions. Use caution when giving to patients with cardiac disease, who have an increased likelihood of developing severe congestive heart failure, edema, and severe fluid retention. Risk is particularly high in patients with high eosinophil counts who may develop cardiogenic shock. Gastrointestinal perforations have been reported, as have bullous dermatologic reactions. Patients who require anticoagulation should not receive warfarin. Imatinib is an inhibitor of and primarily metabolized by CYP3A4.

Toxicity

1. Myelosuppression and other hematologic effects. Moderate neutropenia and thrombocytopenia are common in all phases, but severe neutropenia or thrombocytopenia is uncommon unless patients are in the accelerated phase or blast crisis of CML.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, abdominal pain, and diarrhea are common, but it is uncommon that they are severe.

3. Mucocutaneous effects. Skin rash and nasopharyngitis are common; pruritis and petechiae are occasional. Erythema multiforme and Stevens-Johnson syndrome have been reported.

4. Miscellaneous effects:

a. Fluid retention and edema are common. Pleural effusion and as-cites are occasional.

b. Musculoskeletal pain or cramps, arthralgia, headache, fever, and fatigue are common, but it is uncommon that they are severe or life-threatening.

c. Dyspnea and cough are occasional.

d. Elevated liver function tests are occasional. Rare cases of severe hepatotoxicity have been seen.

e. Rise in serum creatinine and hypokalemia are occasional but rarely severe.

f. Congestive heart failure is uncommon but may lead to pulmonary edema and rarely pericardial effusion. It may be related to imatinib inhibition of Abl, which in turn may be related to mito-chondrial function in the heart.

g. Monitor TSH levels during imatinib treatment in patients who have had thyroidectomy and are on levothyroxine.

INTERFERON ALPHA

Other names. Roferon-A (interferon alfa-2a, recombinant alpha-A inter-feron), Intron A (interferon alfa-2b, recombinant alpha-2 interferon).

Mechanism of action. Believed to involve direct inhibition of tumor cell growth and modulation of the immune response of the host, including activation of NK cells, modulation of antibody production, and induction of major histocompatibility antigens.

Primary indications

1. Melanoma (both as adjuvant and metastatic disease therapy)

2. Renal cell carcinoma

3. Multiple myeloma

4. Kaposi sarcoma, HIV-associated

5. CML

6. Non-Hodgkin lymphoma (low-grade), mycosis fungoides

7. Condyloma acuminatum (intralesional)

8. Chronic hepatitis B and C.

Usual dosage and schedule

1. 3 to 10 million IU, IM or SC in various schedules. Daily dosing is often used for several weeks or months, followed by three times a week dosing.

2. As adjuvant therapy for high-risk melanoma, 20 million IU/m2 IV 5 consecutive days weekly for 4 weeks, then 10 million IU/m2 SC three times weekly for 48 weeks

3. For HIV-related Kaposi sarcoma, 1 to 5 million IU SC daily, with dose modifications based on toxicity

4. Investigationally, doses have been higher (up to 50 million IU/m2 per dose), usually IV at doses higher than 10 million IU/m2.

Special precautions. May cause or aggravate life-threatening or fatal neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy.

Toxicity

1. Myelosuppressionandotherhematologiceffects. Commonbutusually mild to moderate and transient, even with continued therapy. Higher doses may be associated (25% of patients receiving the recommended adjuvant therapy for melanoma) with granulocyte counts of less than 750/(µL and consequent increased risk for infection.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia and nausea are common, occurring in up to two-thirds of all patients, but vomiting is only occasional. Diarrhea or loose stools are occasional to common.

3. Mucocutaneous effects. Rash, dryness, inflammation of the oropharynx, dry skin or pruritus, and partial alopecia are occasional to common.

4. Miscellaneous effects:

a. Flulike syndrome with fatigue, fever, chills, sweating, myalgias, arthralgias, and headache is common to universal with greater severity at higher doses. Tends to diminish with continuing therapy and acetaminophen.

b. Neurologic effects:

(1) Peripheral nervous system: Occasional paresthesias or numbness

(2) CNS toxicity is uncommon at lower doses, but with higher doses there is an increased likelihood of problems, including headache, dizziness, somnolence, anxiety, depression (including suicidal behavior), confusion, hallucinations, cerebellar dysfunction, and emotional lability.

c. General systemic effects: Fatigue, anorexia, and weight loss are common with chronic administration.

d. Cardiovascular effects: Mild hypotension is common but rarely symptomatic. Rarely to uncommonly seen are hypertension, chest pain, arrhythmias, or other cardiovascular disorders.

e. Respiratory effects: Dyspnea and cough are occasional at higher doses.

f. Infectious effects: Exacerbation of herpetic eruptions and non-herpetic cold sores is uncommon.

g. Miscellaneous effects: Leg cramps, insomnia, urticaria, hot flashes, and coagulation disorders are uncommon. Visual problems, including blurring, diplopia, dry eyes, nystagmus, and photophobia are uncommon.

h. Metabolic effects and laboratory abnormalities:

(1) Elevated liver enzymes are common.

(2) Mild proteinuria and increase in serum creatinine is occasional.

(3) Hypercalcemiais occasional.

(4) Hypothyroidism and hyperthyroidism with or without antithyroid antibodies.

(5) Hypertriglyceridemia is rare.

(6) Antibody development (binding and neutralizing) occurs more readily with interferon alfa-2a than with interferon alfa-2b. The significance of this is not clear, though it may be associated with the development of clinical resistance in some patients.

IPILIMUMAB

Other names. MDX 010, MDX-CTLA 4.

Mechanism of action. Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), a negative regulator of the immune system, thus potentiating antitumor T-cell response.

Primary indication. Melanoma that is advanced or metastatic.

Usual dosage and schedule. 3 to 10 mg/kg over 90 minutes every 3 weeks for four doses. Treatment is repeated every 12 weeks in responders (complete or partial response or stable disease).

Special precautions. Diarrhea progressing to severe colitis, including abdominal perforation, has been seen, appears to be immunologic in etiology, and requires emergent therapy following standardized diarrhea treatment guidelines, including corticosteroids when evidence for severe diarrhea or documented colitis is present.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and lymphopenia are common, but only occasionally grade 3 or more. Venous thrombosis is uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but usually not severe. Diarrhea is also common and occasionally severe (grade 3) and may be associated with colitis.

3. Mucocutaneous effects. Pruritis is common (>40%), as is skin rash.

4. Immunologic effects and infusion reactions. Many of the nonhematologic effects, particularly skin and gastrointestinal, may be immunologic in etiology and require emergent treatment.

5. Miscellaneous effects:

a. Fatigue is common and occasionally severe.

b. Increased transaminases are common and occasionally (8%) grade 3 to 4. Significant rise in bilirubin may also be seen as well as pancreatitis.

c. Endocrine: Adrenal insufficiency, hypothyroidism, and hypopituitarism are rare to uncommon.

d. Dyspnea is common.

e. Pain is common.

f. Confusion is occasional.

IRINOTECAN

Other names. Camptosar, CPT-11.

Mechanism of action. Irinotecan, a semisynthetic water-soluble derivative of camptothecin, is a prodrug for the lipophilic metabolite SN38, a potent inhibitor of topoisomerase I, an enzyme essential for effective replication and transcription. It binds to the topoisomerase I-DNA cleavable complex, preventing religation after cleavage by topoisomerase I.

Primary indications

1. Carcinoma of the colon or rectum, esophagus, or stomach

2. Carcinoma of the lung

3. Glioblastoma multiforme.

Usual dosage and schedule

1. 80 to 125 mg/m2 IV over 90 minutes weekly for 4 weeks followed by a 2-week rest to complete one cycle when used either as a single agent or in combination with fluorouracil and leucovorin.

2. 180 mg/m2 IV over 90 minutes every 2 weeks when used with leu-covorin (over 2 hours) plus bolus fluorouracil followed by a 22-hour infusion of fluorouracil. In patients being concurrently treated with enzymeinducing antiepileptic drugs, doses must be increased approximately fourfold.

For severe or worse diarrhea (at least seven stools over pretreatment), doses should be held. When the diarrhea has improved (no more than 7 stools over pretreatment) treatment may be restarted with doses modified downward by 25 to 30 mg/m2 during the current and subsequent cycles if there was an increase in stools of 7 to 9 per day, and by 50 to 60 mg/m2 if there was an increase in stools of 10 or more. Doses are also held during treatment and reduced in the same and subsequent cycles for severe neutropenia (ANC 1000).

Special precautions. Both early and late diarrhea may occur. That which occurs within 24 hours (a cholinergic effect) should be treated with atropine 0.25 to 1 mg IV. Late diarrhea should be treated promptly with loperamide (up to 2 mg every 2 hours until the patient is free of diarrhea for 12 hours) and prompt fluid and electrolyte replacement as indicated, if the diarrhea becomes severe (increase of seven or more stools per day) or there is dehydration or postural hypotension. Consideration should be given to antibiotic therapy, such as with an oral fluoroquinolone, particularly if the patient is neutropenic. A vascular syndrome characterized by sudden unexpected thromboembolic events has also been described.

Dose must be reduced in patients who are homozygous for the UGT1A1*28 allele, a variation of a uridine diphosphate glucuronosyltrans-ferase gene and its corresponding enzyme (UGT1A1), which is responsible for glucuronidation of bilirubin and involved in deactivation of irinotecan’s toxic active metabolite SN-38. Testing may be done by the Invader UGT1A1 Molecular Assay (Hologic, Bedford, MA).

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia is common and often severe, particularly in combination therapy; anemia and thrombocytopenia are common, but uncommonly severe, unless homozygous for UGT1A1*28.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting are common and are occasionally severe. Early diarrhea is common but is uncommonly severe. Late diarrhea is common (85%) and is occasionally severe (15%) to life-threatening (5% to 10%). Severe diarrhea may be more common if homozygous for UGT1A1*28. Abdominal cramping is common and occasionally severe. Anorexia is common. Constipation and dyspepsia are occasional. Ileus, colitis, or toxic megacolon are seen rarely.

3. Mucocutaneous effects. Alopecia and mucositis are common. Rash and sweating occur occasionally.

4. Miscellaneous effects:

a. Fever is common and rarely severe.

b. Headache, back pain, chills, and edema are occasional.

c. Grade 1 to 2 increases in liver function tests are common; it is uncommon for liver function abnormalities to be severe, except in patients with known liver metastasis.

d. Dyspnea, cough, or rhinitis is occasional to common but usually not severe.

e. Insomnia or dizziness is occasional.

f. Flushing is occasional.

g. Anaphylactic reactions are rare.

IXABEPILONE

Other name. Ixempra.

Mechanism of action. Ixabepilone is an analog of epothilone B that binds to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics, which blocks the cell in mitosis, leading to cell death.

Primary indication. Carcinoma of the breast, usually after failure with an-thracyclines and taxanes. Often given in combination with capecitabine.

Usual dosage and schedule. 40 mg/m2 IV over 3 hours every 3 weeks. All patients should be pretreated with both an H1- and H2-histamine–receptor antagonist.

Special precautions. Patients with a history of hypersensitivity reactions to ixabepilone or other agents containing polyoxyethylated castor oil must be pretreated with dexamethasone. If the reactions were severe, do not treat. Coadministration with potent inhibitors of CYP3A4, such as ketoconazole, increases ixabepilone AUC, and dose reduction should be considered. Strong inducers of CYP3A4, such as dexamethasone or phenytoin, may decrease ixabepilone concentrations. Do not give in combination with capecitabine in patients with aspartate aminotransferase (AST) or alanine aminotran-ferease (ALT) greater than 2.5 ULN or bilirubin greater than 1 × ULN. Dose reductions are required in patients with moderate hepatic impairment (AST or ALT >2.5 ULN or bilirubin >1.5 ULN).

Toxicity

1. Myelosuppression and other hematologic effects. Severe (grade 3 to 4) neutropenia is common. Severe anemia and thrombocytopenia are only occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea are common, but it is uncommon that they are severe. Constipation and abdominal pain are occasional but rarely severe.

3. Mucocutaneous effects. Mucositis is common, but it is uncommon that it is severe. Alopecia is common. Skin rash, nail disorders, palmar-plantar erythrodysesthesia, and pruritis are occasional. Hyperpigmentation and skin exfoliation are uncommon.

4. Immunologic effects and infusion reactions. One percent of patients may have hypersensitivity reactions.

5. Miscellaneous effects:

a. Neurologic: Peripheral neuropathy is common and cumulative and occasionally severe (grade 3 to 4). It is the most frequent toxicity responsible for drug discontinuation. Headache, dizziness, insomnia, and altered taste are occasional.

b. Musculoskeletal: Myalagia and arthralgia are common.

c. Fatigue and asthenia are common. Edema and fever are occasional.

d. Cardiorespiratory:Useofixabepiloneincombinationwithcapecit-abine may increase cardiac adverse reactions such as myocardial ischemia or ventricular dysfunction (1.9%). Cough and dyspnea are occasional.

LAPATINIB

Other name. Tykerb.

Mechanism of action. Lapatinib is a dual tyrosine kinase inhibitor with specificity for EGFR and human epidermal receptor type 2 (HER2).

Primary indication. Advanced or metastatic carcinoma of breast that over-expresses the HER2 receptor in combination with the following:

bull Capecitabine in women who have received prior therapy including an anthracycline, a taxane, and trastuzumab

bull Letrozole in postmenopausal women with receptor-positive meta-static breast cancer

bull Trastuzumab in women who have progressed on this drug (may be effective because of different mechanism of action on HER2).

Usual dosage and schedule. 1250 mg by mouth daily with capecitabine. 1500 mg by mouth daily with letrozole.

Special precautions. Confirm left ventricular ejection fraction before starting therapy. Monitor liver function tests before and every 4 to 6 weeks during therapy. Reduce dose for severe hepatic impairment (Child-Pugh class C). Discontinue therapy for severe pulmonary symptoms. Avoid strong CYP3A4 inhibitors, which will increase plasma concentrations of lapatinib.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression is not an effect of lapatinib. Other EGFR inhibitors may potentiate warfarin and cause unexpected rise in INR.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and diarrhea are common; diarrhea may be severe; vomiting and anorexia are occasional. Other EGFR inhibitors are associated with transaminase elevations and occasionally with increased bilirubin.

3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia (with capecitabine) and rash (with letrozole) are common. Dry skin, alopecia, pruritis, and nail disorders are occasional. Epistaxis is occasional.

4. Miscellaneous effects:

a. Left ventricular ejection fraction decrease is uncommon and rarely severe. Prolongation of QT interval is uncommon.

b. Interstitial lung disease is rare to uncommon.

c. Asthenia, fatigue, and headache are occasional to common

d. Elevated liver enzymes or bilirubin is common, but severe (grade 3 to 4) is uncommon.

LENALIDOMIDE

Other name. Revlimid.

Mechanism of action. Multiple potential mechanisms, including immuno-modulatory and antiangiogenic effects. Precise mechanism not delineated.

Primary indications

1. MDS, low- or intermediate-risk, associated with deletion of 5q31 (del 5q). Also effective in some patients without 5q deletion.

2. Multiple myeloma.

Usual dosage and schedule

1. MDS: 10 mg by mouth daily, with dosing interruptions and subsequent dose reduction to 5 mg daily as determined by cytopenias or other toxicity.

2. Multiple myeloma: 25 mg by mouth daily for 21 of 28 days. Renal insufficiency is associated with decreased clearance and need for reduced starting doses.

Special precautions. Severe and life-threatening birth defects, primarily phocomelia, may be caused by this analog of thalidomide, a known human teratogen. For this reason, special precautions must be taken to assure that female patients are not pregnant when the drug is started, and that both female and male patients practice strict birth control measures.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are common and dose-limiting. Febrile neutropenia is uncommon. Anemia is occasional and may be autoimmune in nature (uncommon). Hypercoagulability with thromboembolic events, including pulmonary emboli (2% to 3%), have been seen in patients treated with lenalidomide combination therapy but are uncommon to occasional. The relative benefit of prophylactic anticoagulation or antiplatelet therapy is uncertain, but some form of prophylaxis is generally recommended, particularly in patients with myeloma or others receiving concurrent corticosteroids.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrhea is common; constipation is common but less often than diarrhea. Nausea is common, but vomiting only occasional. Abdominal pain is occasional.

3. Mucocutaneous effects. Macular rash, dryness of the skin, increased sweating, and pruritis are common. Urticaria is occasional.

4. Miscellaneous effects:

a. Cough, nasopharyngitis, dyspnea, and bronchitis are occasional.

b. Myalgia, arthralgia, muscle cramps, or limb pain are occasional.

c. Fatigue and fever are common, but rigors are uncommon.

d. Headache and dizziness are occasional. Peripheral neuropathy is uncommon (5%). Insomnia and depression are occasional.

e. Hypothyroidism is occasional.

f. Palpitations, hypertension, chest pain, and peripheral edema are occasional.

g. Hypokalemia and hypomagnesemia are occasional.

h. Birth defects (see Specialprecautions).

LETROZOLE

Other name. Femara.

Mechanism of action. Decreases estrogen biosynthesis by selective, competitive inhibition of the aromatase enzyme in peripheral tissues, thereby reducing the conversion of the adrenal androgens testosterone and androstenedione to estradiol and estrone respectively.

Primary indications

1. Carcinoma of the breast, advanced or metastatic, that is hormone-receptor–positive or unknown in postmenopausal women as first-line treatment, or in hormone-responsive postmenopausal women with progression following antiestrogen therapy.

2. Carcinoma of the breast as adjuvant therapy in hormone-receptor–positive postmenopausal women.

Usual dosage and schedule. 2.5 mg by mouth daily.

Special precautions. Potential hazard to fetus if given during pregnancy. Because of the potential fracture risk, calcium and vitamin D with or without bisphosphonates are often used.

Toxicity

1. Myelosuppression and other hematologic effects. No dose-related effect. Thromboembolic events are uncommon to rare and less than with tamoxifen.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, constipation, and diarrhea are uncommon to occasional.

3. Mucocutaneous effects. Rash is uncommon.

4. Miscellaneous effects:

a. Hot flushes are common, and night sweats are occasional.

b. Musculoskeletal pain (arthralgia or bone) is occasional to c ommon.

c. Weight increase is occasional (lower than with megestrol).

d. Fatigue is occasional.

e. Acceleration of osteoporosis is occasional; increase in fracture risk is uncommon.

f. Headache is uncommon.

g. Peripheral edema is occasional (lower than with megestrol).

h. Dyspnea and cough are uncommon to occasional.

i. Hypercalcemia is rare.

j. Endometrial cancer is rare (0.2%) and less likely than with t amoxifen.

LOMUSTINE

Other names. CCNU, CeeNU.

Mechanism of action. Alkylation and carbamoylation by lomustine metabolites interfere with the synthesis and function of DNA, RNA, and proteins. Lomustine is lipid-soluble and easily enters the brain.

Primary indication. Malignant brain tumors.

Usual dosage and schedule. 100 to 130 mg/m2 by mouth once every 6 to 8 weeks (lower dose used for patients with compromised bone marrow function). Limit cumulative dose to 1000 mg/m2 to limit pulmonary and renal toxicity.

Special precautions. Because of delayed myelosuppression (3 to 6 weeks), do not treat more often than every 6 weeks. Await a return of normal platelet and granulocyte counts before repeating therapy.

Toxicity

1. Myelosuppression and other hematologic effects. Universal and dose-limiting. Leukopenia and thrombocytopenia are delayed 3 to 6 weeks after therapy begins and may be cumulative with successive doses.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting may begin 3 to 6 hours after therapy and last up to 24 hours.

3. Mucocutaneous effects. Stomatitis and alopecia are rare.

4. Miscellaneous effects:

a. Confusion, lethargy, and ataxia are rare.

b. Mild hepatotoxicity is infrequent.

c. Secondary neoplasia is possible.

d. Pulmonary fibrosis is uncommon at doses of less than 1000 mg/m2.

e. Renal toxicityis uncommon at doses ofless than 1000 mg/m2.

MECHLORETHAMINE

Other names. Nitrogen mustard, HN2, Mustargen.

Mechanism of action. Mechlorethamine is a prototype alkylating agent. Its action involves transfer of the alkyl group to amino, carboxyl, hydroxyl, imidazole, phosphate, and sulfhydryl groups within the cell, altering structure and function of DNA (primarily), RNA, and proteins.

Primary indications

1. Hodgkin lymphoma

2. Malignant pleural and, less commonly, peritoneal or pericardial effusions

3. CTCLs (topically).

Usual dosage and schedule

1. 6 mg/m2 IV on days 1 and 8 every 4 weeks (in mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone [MOPP] regimen for Hodgkin disease)

2. 8 to 16 mg/m2 by intracavitary injection

3. 10 mg in 60 mL of tap water applied to entire body surface (avoid eyes).

Special precautions

1. Administer over several minutes into the sidearm of a running IV infusion, taking care to avoid extravasation.

2. Because mechlorethamine is a potent vesicant, extreme care must be exercised while preparing and administering the drug. Gloves and eyeglasses are recommended to protect the preparer. If accidental eye contact should occur, institute copious irrigation with normal saline and follow by prompt ophthalmologic consultation. If accidental skin contact occurs, irrigate the affected part immediately with water for at least 15 minutes and follow by 2.6% sodium thiosulfate solution (1/6 M).

3. Mechlorethamine should be used soon after preparation (15 to 30 minutes) as it decomposes on standing. It must not be mixed in the same syringe with any other drug.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting, with the nadir at about 1 week and recovery by 3 weeks.

2. Nausea, vomiting, and other gastrointestinal effects. Universal. They usually begin within the first 3 hours and last 4 to 8 hours.

3. Mucocutaneous effects. Severe painful inflammation and necrosis are likely if extravasation occurs. May be ameliorated with sodium thiosulfate (see Table 26.1). Maculopapular rash is uncommon.

4. Miscellaneous effects:

a. Phlebitis, thrombosis, or both of the vein used for the injection are common.

b. Amenorrhea and azoospermia are common.

c. Hyperuricemia with rapid tumor destruction.

d. Weakness, sleepiness, and headache are uncommon.

e. Severe allergic reactions, including anaphylaxis, are rare.

f. Secondary neoplasms, including myelodysplasia, acute leukemia, and carcinomas, are possible.

MELPHALAN

Other names. Phenylalanine mustard, L-sarcolysin, L-PAM, Alkeran.

Mechanism of action. Alkylating agent with primary effect on DNA. Amino acid–type structure may result in cellular transport that is different from other alkylating agents.

Primary indications

1. Multiple myeloma

2. Stem cell transplant preparative regimens.

Usual dosage and schedule

1. 8 mg/m2 by mouth on days 1 to 4 every 4 weeks, or

2. 10 mg/m2 by mouth on days 1 to 4 every 6 weeks, or

3. 3 to 4 mg/m2 by mouth daily for 2 to 3 weeks, then 1 to 2 mg/m2 by mouth daily for maintenance.

4. High-dose regimens of 140 to 200 mg/m2 IV have been used, followed by stem cell rescue (e.g., bone marrow transplantation).

Special precautions

1. Myelosuppression and other hematologic effects may be delayed and prolonged to 4 to 6 weeks. Reduce IV dose by 50% for creati-nine that is greater than 1.5 × normal.

2. Use in early myeloma may preclude harvest of sufficient numbers of peripheral stem cells for autologous transplantation.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting; nadir at days 14 to 21.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are uncommon at standard doses, but common with high-dose regimens.

3. Mucocutaneous effects. Alopecia, dermatitis, and stomatitis are uncommon at standard doses; alopecia and mucositis are common with high-dose regimens.

4. Miscellaneous effects:

a. Acute nonlymphocytic leukemia and myelodysplasia are rare but well documented.

b. Pulmonary fibrosisis rare.

MERCAPTOPURINE

Other names. 6-Mercaptopurine, 6-MP, Purinethol.

Mechanism of action. A purine antimetabolite that, when converted to the nucleotide, inhibits the formation of nucleotides necessary for DNA and RNA synthesis.

Primary indication. ALL.

Usual dosage and schedule

1. 100 mg/m2 by mouth daily if used alone

2. 50 to 90 mg/m2 by mouth dailyif used with methotrexate or other cytotoxic drugs.

Special precautions

1. Decrease dose by 75% when used concurrently with allopurinol.

2. Increase interval between doses or reduce dose in patients with renal failure.

Toxicity

1. Myelosuppression and other hematologic effects. Common but mild at recommended doses.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting are uncommon. Diarrhea is rare.

3. Mucocutaneous effects. Stomatitis maybe seen with very large doses. Dry, scaling rash is uncommon.

4. Miscellaneous effects:

a. Intrahepatic cholestasis and mild focal centrolobular necrosis with jaundice are uncommon.

b. Hyperuricemia with rapid leukemia cell lysis is common.

c. Fever is uncommon.

MESNA

Other name. Mesnex.

Mechanism of action. Mesna disulfide is reduced in the kidney to a free thiol compound, which then reacts chemically with urotoxic metabolites of ifosfamide or cyclophosphamide, resulting in their detoxification.

Primary indication. Prophylaxis for ifosfamide- or high-dose cyclophospha-mide–induced hemorrhagic cystitis.

Usual dosage and schedule. Mesna dose is at least 20% of the ifosfamide dose (on a weight [mg] basis), administered just prior to (or mixed with) the ifosfamide dose, and again at 4 and 8 hours after the ifosfamide dose to detoxify the urinary metabolites that cause the hemorrhagic cystitis. Higher doses of ifosfamide may require higher doses and longer durations of mesna.

Special precautions. Contraindicated if patient is sensitive to thiol compounds. Does not prevent or ameliorate any adverse effects of ifosfamide or cyclophosphamide other than hemorrhagic cystitis. Neither mesna nor its only metabolite, mesna disulfide, affect ifosfamide, cyclophosphamide, or their antineoplastic metabolites.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are occasional. Nausea and vomiting more commonly from ifosfamide.

3. Mucocutaneous effects. Bad taste in the mouth is common.

4. Miscellaneous effects:

a. Headache, fatigue, and limb pain are occasional.

b. Hypotension or allergic reactions are uncommon to rare.

c. Gives false positive test for urinary ketones.

METHOTREXATE

Other names. Amethopterin, MTX, Mexate, Folex, Trexall.

Mechanism of action. Inhibition of dihydrofolate reductase, which results in a block of the reduction of dihydrofolate to tetrahydrofolate. This blockage in turn inhibits the formation of thymidylate and purines, and arrests DNA (predominantly), RNA, and protein synthesis.

Primary indications

1. Breast, head and neck, gastric, and gestational trophoblastic carcinomas

2. Osteosarcomas (high-dose methotrexate)

3. ALL

4. Meningeal leukemia or carcinomatosis

5. Non-Hodgkin lymphoma.

Usual dosage and schedule

1. Gestational trophoblastic carcinoma: 15–30 mg by mouth or IM on days 1 to 5 every 2 weeks

2. Other carcinomas: 40 to 80 mg/m2 IV or by mouth 2 to 4 times monthly with a 7- to 14-day interval between doses

3. ALL: 15 to 20 mg/m2 by mouth or IV weekly (together with mer-captopurine)

4. Osteosarcoma: Up to 12 g/m2 with leucovorin rescue (high-dose methotrexate). This usage requires on-site monitoring of metho-trexate levels and a high degree of expertise to administer safely.

5. Intrathecally: 12 mg/m2 (not >20 mg) twice weekly.

Special precautions

1. High-dose methotrexate (>80 mg/m2) should be administered only by individuals experienced in its use and at institutions where serum methotrexate levels can be readily measured.

2. Intrathecal methotrexate must be mixed in buffered physiologic solution containing no preservative.

3. Avoid aspirin, sulfonamides, tetracycline, phenytoin, and other protein-bound drugs that may displace methotrexate and cause an increase in free drug.

4. Oral anticoagulants (e.g., warfarin) may be potentiated by metho-trexate; therefore, PTs/INRs should be followed carefully.

5. Oral antibiotics may decrease methotrexate absorption; penicillin and NSAIDs decrease clearance of methotrexate.

6. Monitor use with theophylline.

7. In patients with renal insufficiency, it may be necessary to markedly reduce the dose or discontinue methotrexate therapy.

8. Do not give if patient has a significant effusion because of “reservoir” effect.

Toxicity

1. Myelosuppression andother hematologic effects. Occurs commonly, with nadir at 6 to 10 days after a single IV dose. Recovery is rapid.

2. Nausea, vomiting, and other gastrointestinal effects. Occasional at standard doses.

3. Mucocutaneous effects:

a. Mild stomatitis is common and is a sign that a maximum tolerated dose has been reached. Higher doses may result in confluent or hemorrhagic stomal ulcers and bloody diarrhea. This requires prompt leucovorin therapy to limit duration and severity.

b. Erythematous rashes, urticaria, and skin pigment changes are uncommon.

c. Mild alopecia is frequent.

4. Miscellaneous effects:

a. Acute hepatocellular injury is uncommon at standard doses. Hepatic fibrosis is uncommon but seen at low chronic doses.

b. Pneumonitis is rare. Polyserositis is rare.

c. Renal tubular necrosis is rare at standard doses.

d. Convulsions and a Guillain-Barre-like syndrome following in-trathecal therapy are uncommon.

MIDOSTAURIN

Other name. PKC412.

Mechanism of action. A multikinase agent that inhibits fms-like tyrosine kinase 3 (FLT3), which is mutated in about 35% of patients with AML. Also directly or indirectly inhibits other molecular targets, including VEGF receptor 1, c-kit, H- and KRAS, and the multidrug resistance gene MDR.

Primary indications (all currently investigational)

1. AMLwithFLT3mutation

2. Systemic mastocytosis and mast cell leukemia

3. MDS.

Usual dosage and schedule

1. 50 mg twice daily for 14 days of each 28-day cycle with cytotoxic agents for induction or consolidation therapy

2. 50 mg twice daily continuously when used as a single agent, as for maintenance.

Special precautions. CYP3A4 inhibitors increase midostaurin blood levels and increase toxicity.

Toxicity

1. Myelosuppression and other hematologic effects. Generally mild and not dose-limiting, but anemia and leukopenia may be seen.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea are common.

3. Mucocutaneous effects. Rash is occasional.

4. Miscellaneous effects:

a. Laboratory: Transitory elevations of glucose, AST, ALT, and bili-rubin are occasional; decreases in potassium, phosphate, and calcium are occasional.

b. Pulmonary edema and pulmonary infiltrates are uncommon and possibly related to coadministration of azole antifungal drugs (CYP3A4 inhibitors).

c. Headache and fatigue are occasional.

MITOMYCIN

Other names. Mitomycin C, Mutamycin.

Mechanism of action. Alkylation and cross-linking by mitomycin metabolites interfere with structure and function of DNA.

Primary indications. Bladder (intravesical), esophagus, stomach, anal, and pancreas carcinomas.

Usual dosage and schedule

1. 20 mg/m2 IV on day 1 every 4 to 6 weeks, or

2. 2 mg/m2 IV on days 1 to 5 and 8 to 12 every 4 to 6 weeks

3. 10 mg/m2 IV on day 1 every 8 weeks in combination with fluorou-racil and doxorubicin for stomach and pancreatic carcinomas

4. 30 to 40 mg instilled into the bladder weekly for 4 to 8 weeks, then monthly for 6 months.

Special precautions. Administer as slow push or rapid infusion through the sidearm of a rapidly running IV infusion, taking care to avoid extravasation. Pulmonary, renal, and hematologic toxicity (microangiopathic anemia and thrombocytopenia) may result from endothelial cell damage.

Toxicity

1. Myelosuppression andotherhematologic effects. Myelosuppression is serious, cumulative, and dose-limiting. Nadir is reached usually by 4 weeks but may be delayed. Recovery is often prolonged over many weeks, and occasionally the cytopenia never disappears. Hemolytic-uremic syndrome is rare, but when it occurs, it may be poorly responsive to plasmapheresis and other therapies.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common at higher doses, but severity is usually mild to moderate.

3. Mucocutaneous effects. Stomatitis and alopecia are common.

4. Miscellaneous effects:

a. Renal toxicityis uncommon. Hemolytic-uremic syndrome is rare.

b. Pulmonary toxicityis uncommon but maybe severe.

c. Feverisuncommon.

d. Cellulitis at injection site is common if extravasation occurs.

e. Secondary neoplasia is possible.

MITOTANE

Other names. o,p’-DDD, Lysodren.

Mechanism of action. Suppresses adrenal steroid production, modifies peripheral steroid metabolism, and is cytotoxic to adrenal cortical cells.

Primary indications. Adrenocortical carcinoma.

Usual dosage and schedule. Begin with 2 to 6 g by mouth daily in three or four divided doses and build to a maximum tolerated daily dose that is usually 8 to 10 g, although it may range from 2 to 16 g. Glucocorticoid and mineralocorticoid replacements during mitotane therapy are necessary to prevent hypoadrenalism. Cortisone acetate (25 mg by mouth in the morning and 12.5 mg by mouth in the evening) and fludrocortisone acetate (0.1 mg by mouth in the morning) are recommended.

Special precautions. Patients who experience severe trauma, infection, or shock should be treated with supplemental corticosteroids. Because of the effect of mitotane on peripheral steroid metabolism, larger than usual replacement doses may be necessary.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and anorexia are common and may be dose-limiting. Diarrhea is o ccasional.

3. Mucocutaneous effects. Skin rash occurs occasionally.

4. CNS effects. Lethargy, sedation, vertigo, or dizziness in up to 40% of patients; may be dose-limiting.

5. Miscellaneous effects. Albuminuria, hemorrhagic cystitis, hypertension, orthostatic hypotension, and visual disturbances are uncommon.

MITOXANTRONE

Other names. Novantrone, dihydroxyanthracenedione, DHAD, DHAQ.

Mechanism of action. DNA-strand breakage mediated by anthracenedione effects on topoisomerase II.

Primary indications

1. Acute nonlymphocytic leukemia

2. Carcinoma of the breast or ovary

3. Non-Hodgkin and Hodgkin lymphoma.

Usual dosage and schedule

1. 12 to 14 mg/m2 IV as a 5- to 30-minute infusion once every 3 weeks for solid tumors

2. 12 mg/m2 IV as a 5- to 30-minute infusion dailyfor 3 days for acute nonlymphocytic leukemia.

Special precautions. Rarely causes extravasation injury if infiltrated. Cardiotoxicity probably less than with doxorubicin; prior anthracycline, chest irradiation, or underlying cardiac disease increases the risk of cardiotoxicity.

Toxicity

1. Myelosuppression and other hematologic effects. Universal.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common but less frequent and less severe than with doxorubicin. Diarrhea is uncommon.

3. Mucocutaneous effects. Alopecia is common, but its frequency and severity is less than with doxorubicin. Mucositis is occasional.

4. Miscellaneous effects:

a. Cardiac toxicity: Probably less than with doxorubicin; there is no clear maximum dose, though the risk appears to increase at 125 mg/m2 cumulative dose.

b. Local erythema and swelling with transient blue discoloration if extravasated, but rarely leads to severe skin damage.

c. Green or blue discoloration of urine.

d. Phlebitis is uncommon.

NELARABINE

Other name. Arranon.

Mechanism of action. Nelarabine is a prodrug of arabinofuranosylguanine (ara-G), a cytotoxic analog of deoxyguanosine. When converted to triphos-phorylated ara-G, it is incorporated into DNA (preferentially into T-cells), inducing fragmentation and apoptosis.

Primary indications. T-cell ALL and T-cell lymphoblastic lymphoma that have relapsed or are refractory to at least two prior chemotherapy regimens.

Usual dosage and schedule

1. Adults: 1500 mg/m2 IV over 2 hours on days 1, 3, and 5; repeated every 21 days

2. Children: 650 mg/m2 IV over 1 hour daily for 5 consecutive days; repeated every 21 days.

Special precautions. Close monitoring for neurologic events is recommended, owing to the possibility of severe neurologic complications of therapy. Prophylaxis against tumor lysis syndrome recommended.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common. Febrile neutropenia is occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, diarrhea, and constipation are common but usually low-grade. Abdominal pain is occasional.

3. Mucocutaneous effects. Stomatitis is occasional.

4. Neurologic effects:

a. Headache is occasional.

b. Somnolence and confusion are occasional.

c. Peripheral neuropathy is occasional. Mayrange from numbness and paresthesias to motor weakness and paralysis.

d. Ataxia is occasional.

e. Insomnia is occasional.

f. Convulsions and coma are rare.

g. Leukoencephalopathy and demyelination and ascending peripheral neuropathy are rare.

5. Miscellaneous effects:

a. Fatigue, weakness, and fever (occasionally with rigors) are common.

b. Cough, dyspnea, and pleural effusion are common to occasional.

c. Abnormal liver function tests are occasional.

d. Hypokalemia, hypomagnesemia, hypocalcemia, and increased creatinine are occasional.

e. Edema is occasional.

f. Sinus tachycardia is occasional.

g. Musculoskeletal pain is occasional.

NILOTINIB

Other names. Tasigna, AMNI07.

Mechanism of action. Selective inhibitor of the constitutively activated Bcr-Abl tyrosine kinase that is created as a consequence of the (9;22) chromosomal translocation and is required for the transforming function and excess proliferation seen in CML. In vitro, nilotinib is active against many Bcr-Abl mutations associated with imatinib resistance.

Primary indications

1. CML, chronicphase, newly diagnosed

2. CML in chronic or accelerated phase in patients resistant or intolerant to imatinib

3. Investigational:

a. Ph+ ALL

b. GIST.

Usual dosage and schedule

1. Newly diagnosed chronic-phase CML: 300 mg orally twice daily

2. Resistant or intolerant chronic-phase CML and accelerated-phase CML: 400 mg orally twice daily

3. Lower doses recommended for hepatic impairment or for toxicity.

Special precautions. Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. ECGs should be obtained to monitor the corrected QT (QTc) at baseline, 7 days after initiation, and periodically thereafter. Do not give if QTc is greater than 480 msec.

Toxicity

1. Myelosuppression and other hematologic effects. Thrombocytopenia and neutropenia are common. Anemia is occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are occasional.

3. Mucocutaneous effects. Skin rash is common; alopecia, dry skin, and pruritis are occasional.

4. Miscellaneous effects:

a. Abnormal liver function tests, including elevations in bilirubin (primarily unconjugated), are occasional.

b. Increase in the QTC interval by 5 to 15 msec is rare but has been seen and may result in sudden death.

c. Increase in lipase and amylase are uncommon.

d. Grade 3or4 hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia are occasional to uncommon.

e. Arthralgia, myalagia, muscle spasms, and bone pain are occasional.

f. Fatigue and insomnia are common; fever and weakness are occasional.

g. Peripheral edema is occasional.

h. Cough and dyspnea are occasional.

NILUTAMIDE

Other name. Nilandron.

Mechanism of action. Competitive inhibitor of androgens at the cellular androgen receptor in prostate cancer cells. Complements surgical castration.

Primary indication. Metastatic carcinoma of the prostate, in combination with surgical castration or LHRH agonist.

Usual dosage and schedule. 300 mg by mouth once daily for 30 days, followed by 150 mg by mouth once daily thereafter.

Special precautions. Should be restricted to patients with normal liver function test values. A routine chest radiograph should be obtained before therapy and any time that the patient reports new exertional dyspnea or worsening of pre-existing dyspnea. Inhibits activity of liver cytochrome P450 isoenzymes and may delay elimination of drugs such as warfarin, phenytoin, and theophylline.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, constipation, and anorexia are occasional to common. Vomiting is uncommon.

3. Mucocutaneous effects. Rash, dry skin, and sweating are uncommon.

4. Miscellaneous effects:

a. Hepatitis is rare (1%). Increased liver function test values are uncommon.

b. Interstitial pneumonitis with dyspnea is uncommon (2%). May be higher in patients with Asian ancestry.

c. Inhibits activity ofliver cytochrome P450 isoenzymes and may delay elimination of drugs such as warfarin, phenytoin, and theophylline.

d. Hot flashes are common.

e. Impaired adaptation to dark is common (57%).

f. Cardiac and other lung disorders are uncommon.

OFATUMUMAB

Other name. Arzerra.

Mechanism of action. Ofatumumab is a recombinant human monoclonal antibody that binds to extracellular loops of the CD20 molecule, resulting in B-cell lysis, possibly through both complement-dependent and cell-mediated cytotoxicity.

Primary indication. CLL, refractory to fludarabine and alemtuzumab.

Usual dosage and schedule. 12 doses administered as follows:

bull 300 mg initial dose, followed 1 week later by

bull 2000 mg weekly for seven doses, followed 4 weeks later by

bull 2000 mg every 4 weeks for four doses.

Special precautions. Dose 1 should be infused at an initial rate of 3.6 mg/ hr, dose 2 at an initial rate of 24 mg/hr, and doses 3 to 12 at an initial rate of 50 mg/hr. In the absence of infusion reactions, the infusion rate may be doubled every 30 minutes for a maximum of four doublings. Premedication with acetaminophen, an H1-histamine-receptor antagonist, and cor-ticosteroid is required.

Toxicity

1. Myelosuppression and other hematologic effects. Grade 3or4 neutropenia is common and may persist for over 1 week. Anemia is occasional to common. Seventy percent of patients in one trial developed bacterial, viral, or fungal infections, which were fatal in 12% of patients treated.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and diarrhea are occasional.

3. Mucocutaneous effects. Rash and urticaria are occasional.

4. Immunologic effects and infusion reactions. Infusion reactions occur in 44% on the first day of infusion, 29% on the second day, and less frequently during subsequent infusions.

5. Miscellaneous effects:

a. Neurologic: Progressive multifocal leukoencephalopathy, including a fatal case, has occurred with ofatumumab, but is rare. Insomnia is occasional. Headache is occasional.

b. Infections: Hepatitis B reactivation is possible as with other anti-CD20 antibodies. Pneumonia is occasional to common; bronchitis, sepsis, nasopharyngitis, and herpes zoster are occasional.

c. Fever and chills, fatigue, headache, and peripheral edema are occasional.

d. Respiratory: Cough and dyspnea are occasional.

e. Cardiovascular: Hypertension, hypotension, and tachycardia are uncommon.

OLAPARIB and other PARP1 inhibitors

Other names. AZ2281, iniparib (BSI-201), veliparib (ABT888).

Mechanism of action. Inhibition of PARP1, one of a large family of poly(ADP-ribose) polymerases, which inhibits repair of DNA single-strand breaks.

Primary indications

1. Metastatic carcinoma of the breast with BRCA1 or BRCA2 mutation (olaparib)

2. Triple negative (estrogen receptor-/progesterone receptor-/HER2-negative) metastatic carcinoma of the breast (BSI-201)

3. BRCA-deficient ovarian cancer.

Usual dosage and schedule

1. Olaparib 100 to 400 mg by mouth twice daily, alone or with other agents

2. Iniparib 5.6 mg/kg IV on days 1,4, 8, and 11 every 21 days, together with gemcitabine and carboplatin on days 1 and 8.

Special precautions. Too early in development to have complete information.

Toxicity

1. Myelosuppression and other hematologic effects. Occasionally low-grade.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but low-grade. Diarrhea is occasional.

3. Mucocutaneous effects. None reported.

4. Miscellaneous effects. Fatigue and dizziness are occasional.

OPRELVEKIN

Other names. Neumega, IL-11.

Mechanism of action. Stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation, resulting in increased platelet production.

Primary indication. Prevention of severe thrombocytopenia after chemotherapy in patients with nonmyeloid malignancies. Not indicated after myeloablative therapy.

Usual dosage and schedule. 50 μg/kg SC once daily, starting 6 to 24 hours after completion of chemotherapy. Continue until the postnadir count is at least 50,000/μ L. (Treatment for more than 21 days in a row is not recommended.) The next planned cycle of chemotherapy should begin at least 2 days after discontinuation of oprelvekin.

Special precautions. Use with caution in patients with history of atrial arrhythmia or congestive heart failure. Allergic and anaphylactic hypersensitivity reactions have occurred.

Toxicity

1. Myelosuppression and other hematologic effects. None. Mild decrease in hemoglobin concentration (10% to 15%), predominantly due to increase in plasma volume.

2. Nausea, vomiting, and other gastrointestinal effects. None.

3. Mucocutaneous effects. Occasional rash, particularly at injection site.

4. Miscellaneous effects:

a. Cardiovascular: Atrial arrhythmia (flutter or fibrillation) and palpitations are occasional (about 10%), but usually transient. Syncope is occasional.

b. Fluid retention with edema (renal sodium and water retention) or dyspnea on exertion is common, but usually mild to moderate. Not associated with capillary leak syndrome.

c. Conjunctival injection and mild visual blurring is occasional. Papilledema is uncommon, but may be more common in children. Caution should be exerted in patients with pre-existing papilledema or tumors of the CNS.

d. Asthenia is occasional.

OXALIPLATIN

Other name. Eloxatin.

Mechanism of action. Similar to alkylating agents with respect to binding and cross-linking strands of DNA, forming DNA adducts, and thereby inhibiting DNA replication and transcription.

Primary indications

1. Carcinoma of the colon and rectum

2. Carcinoma of the stomach

3. Carcinomas of the pancreas and biliary tract.

Usual dosage and schedule

1. Combination therapy: 85 to 100 mg/m2 as a 2-hour infusion every 2 weeks in combination with fluorouracil (often as a continuous infusion)

2. Single agent: 130 mg/m2 as a 2-hour infusion every 3 weeks or 85 mg/m2 as a 3-hour infusion every 2 weeks.

Special precautions. Acute neurosensory and neuromotor symptoms may develop with the infusion. Laryngospasm may be minimized by avoiding cold drinks or food for a few days following treatment. Chronic neurosensory symptoms are dose-limiting. Must never be diluted with or administered with sodium chloride or other chloride-containing solutions.

Toxicity

1. Myelosuppression and other hematologic effects. Low-grade myelo-suppression is common, but grade 3 or 4 neutropenia, thrombocytopenia, or anemia is uncommon (about 5%) when used as single agent. Its use with fluorouracil and leucovorin increases the neutropenia and its severity. Hemolytic anemia is rare.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common. Severe diarrhea may lead to hypokalemia. May be worsening of cholinergic syndrome when given with irinotecan. Hepatotoxicity is common with oxaliplatin, in some cases associated with fibrosis or severe veno-occlusive lesions, but grade 3 to 4 toxicity is uncommon.

3. Mucocutaneous effects. Alopecia is uncommon. Stomatitis is increased when used with fluorouracil.

4. Miscellaneous effects:

a. Neurotoxicity, consisting of paresthesias and cold-induced dys-esthesias in the stocking glove or perioral distribution, are common as acute transient changes that begin with the infusion and last for less than 1 week. Chronic sensory neuropathy, fine motor disturbance, or ataxia is occasional to common with cumulative dosing (cumulative dose-dependent) and may last for months. It is occasionally grade 3 to 4. Neurotoxicity incidence and severity can be reduced by giving 1 g magnesium sulfate and 1 g calcium gluconate both before and after the oxaliplatin infusion.

b. Laryngospasm may develop during or within 2hoursof the infusion and can last up to 5 days. Cold temperatures may induce; warm liquids or a hot-pack may ameliorate.

c. Fever is common.

d. Nephrotoxicityis uncommon.

e. Ototoxicity is rare.

f. Allergic reactions are occasional. High-grade reactions or ana-phylaxis are uncommon to rare.

PACLITAXEL

Other names. Taxol, Onxol.

Mechanism of action. Enhanced formation and stabilization of microtubules. Antineoplastic effect may result from nonfunctional tubules or altered tubulin–microtubule equilibrium. Mitotic arrest is seen and is associated with accumulated polymerized microtubules.

Primary indications

1. Carcinomas of the ovary, breast, lung, head and neck, bladder, and cervix

2. Melanoma

3. Kaposi sarcoma, AIDS-related.

Usual dosage and schedule

1. 135to 225 mg/m2 as a 3-hour infusion every 3 weeks

2. 135 to 200 mg/m2 as a 24-hour infusion every 3 weeks

3. 100 to 135 mg/m2 as a 3-hour infusion every 2 to 3 weeks for the treatment of AIDS-related Kaposi sarcoma

4. 80 to 100 mg/m2 as a 1-hour weeklyinfusion

5. 200 mg/m2 as a 1-hour infusion every 3 weeks.

Special precautions. Anaphylactoid reactions with dyspnea, hypotension (or occasionally hypertension), bronchospasm, urticaria, and erythematous rashes may occur as a result of the paclitaxel itself or the polyoxyethylated castor oil vehicle required to make paclitaxel water-soluble. Such reaction is minimized but not totally prevented by pretreatment with antihistamines and corticosteroids and by prolonging the infusion rate (to 24 hours). Paclitaxel must be filtered with a 0.2-μm in-line filter.

Standard pretreatment regimen

1. Dexamethasone 20 mg IVfor doses greater than 100 mg/m2 and 10 mg IV for doses no more than 100 mg/m2 30 to 60 minutes prior to treatment.

2. Diphenhydramine 50 mg IV 30 to 60 minutes before treatment.

3. Histamine H2-receptor–antagonist IV 30 to 60 minutes before treatment (e.g., cimetidine 300 mg).

Toxicity

1. Myelosuppression and other hematologic effects. Granulocytopenia is universal and dose-limiting; thrombocytopenia is common; anemia is occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Common but usually not severe.

3. Mucocutaneous effects. Alopecia is universal; mucositis is occasional at recommended doses.

4. Immunologic effects and infusion reactions. Dyspnea, hypotension (or occasionally hypertension), bronchospasm, urticaria, and erythematous rashes are occasionally seen, despite precautions.

5. Miscellaneous effects:

a. Sensory neuropathy is common (30% to 35%) and may be progressively worse with time. Recovery may take months to years.

b. Hepatic dysfunction is uncommon.

c. Diarrheais occasionalandmild.

d. Myalgias and arthralgias are common (25%).

e. Seizures are rare.

f. Abnormal electrocardiogram is occasional. If clinically significant bradycardia, stop drug. Restart at slower rate when stable.

PACLITAXEL, PROTEIN-BOUND

Other names. Nanometer albumin bound paclitaxel (nab-paclitaxel), Abraxane.

Mechanism of action. Albumin binding circumvents the requirement for poly-oxyethylated castor oil vehicle for paclitaxel and its associated toxicity; it also exploits albumin-receptor-mediated endothelial transport. As with parent compound, intratumor paclitaxel results in enhanced formation and stabilization of microtubules. An antineoplastic effect may result from nonfunctional tubules or altered tubulin–microtubule equilibrium. Mitotic arrest is seen and is associated with accumulated polymerized microtubules.

Primary indications

1. Metastatic carcinoma of the breast

2. Non–small-cell carcinoma of the lung.

Usual dosage and schedule. 260 mg/m2 IV over 30 minutes every 3 weeks.

Special precautions. Hypersensitivity reactions may occur during the infusion of nab-paclitaxel, but are rare. Premedication, as is used with pacli-taxel with polyoxyethylated castor oil, is not required.

Toxicity

1. Myelosuppression and other hematologic effects. Granulocytopenia is common and dose-limiting; anemia is common as well but is rarely severe. Thrombocytopenia is uncommon. Febrile neutropenia is rare.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are occasional to common but usually not severe. Diarrhea is common but rarely severe.

3. Mucocutaneous effects. Alopecia is universal; mucositis is occasional.

4. Hypersensitivity reactions. Uncommonandrarelysevere.

5. Miscellaneous effects:

a. Cardiovascular events during the infusion, including hypotension or bradycardia, are uncommon to rare. Late cardiovascular effects are also uncommon. Abnormal ECGs are common but not associated with symptoms and usually require no intervention. Edema is occasional.

b. Sensory neuropathy is common and may be progressively worse with time. Recovery may take months to years.

c. Astheniais common.

d. Ocular or visual disturbances are occasional.

e. Cough and dyspnea are occasional.

f. Abnormal liver junction tests are common and occasionally severe.

g. Myalgias and arthralgias are common.

h. Seizures are rare.

PAMIDRONATE

Other name. Aredia.

Mechanism of action. A bisphosphonate that inhibits osteoclastic resorption of bone and calcium release induced by tumor cytokines.

Primary indications

1. Hypercalcemia associated with malignancy

2. Osteolytic bone metastases of breast cancer

3. Osteolytic and osteoporotic bone lesions of multiple myeloma

4. Paget disease.

Usual dosage and schedule

1. Multiple myeloma: 90 mg IV as a 4-hour infusion every month

2. Breast cancer: 90 mg IV as a 2-hour infusion every 3 to 4 weeks

3. Hypercalcemia of malignancy: 60 to 90 mg IV as a 4- to 24-hour infusion. May be repeated every 1 to 8 weeks, as needed.

4. Paget disease: 30 mg IV daily as a 4-hour infusion on 3 consecutive days.

Special precautions

1. Potential for renal tubular damage, particularly if infused more rapidly. Renal clearance parallels creatinine clearance, but adverse effects do not appear to be worse with decreased clearance when given on a monthly basis. Older patients (>75 years) may be more susceptible. Serum electrolytes and renal function should be monitored closely.

2. Osteonecrosis of the jaw has been reported, primarily in association with dental procedures such as tooth extraction; such procedures should be avoided during and following bisphosphonate treatment, if possible.

Toxicity

1. Myelosuppression and other hematologic effects. Rare.

2. Nausea, vomiting, and other gastrointestinal effects. Abdominal pain, anorexia, constipation, nausea, and vomiting are uncommon to occasional.

3. Mucocutaneous effects. Infusion site reaction is occasional.

4. Miscellaneous effects:

a. Fatigue is occasional.

b. Laboratory abnormalities are occasional (hypocalcemia, hypokalemia, hypomagnesemia, and hypophosphatemia, particularly at the 90-mg dose).

c. Uveitis, iritis, scleritis, and episcleritis are rare.

d. Bone pain or generalized pain is occasional.

e. Osteonecrosis of the jaw is uncommon to rare.

PANITUMUMAB

Other names. Vectibix, EGFR antibody, rHuMAb-EGFR.

Mechanism of action. Fully humanized EGFR antibody that blocks the ligand-binding site and inhibits proliferation of cells. It is thought potentially most useful in those tumors that overexpress EGFR, but correlation with percent of positive cells or intensity of EGFR expression is lacking.

Primary indication. Colorectal cancer.

Usual dosage and schedule. 6 mg/kg (220 mg/m2) IV over 60 to 90 minutes every 14 days.

Special precautions. Antipanitumumab antibodies have not been seen but are possible. Severe hypomagnesemia may be seen, and all patients should have magnesium levels monitored throughout the persistence of cetux-imab (8 weeks).

All patients with metastatic colorectal cancer who might be candidates for panitumumab should have their tumor tested for KRAS or BRAF mutations. IfKRAS mutation in codon 12 or 13 or BRAF V600E mutation is detected, panitumumab should not be given, as the patient is unlikely to benefit.

Toxicity

1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea are occasional to common, but high-grade effects are uncommon. Abdominal pain is common.

3. Mucocutaneous effects. Acnelike rash and other skin changes are universal and occasionally high-grade. Exposure to sunlight may exacerbate. Pruritis, erythema, nail changes, and fissures are common. Irritation of the eyes is occasional. Growth of the eyelashes is occasional. Stomatitis is occasional.

4. Immunologic effects and infusion reactions. Infusion reactions with allergic or hypersensitivity reactions, fever, chills, or dyspnea are uncommon and rarely high-grade (1%). Binding antibodies develop in 1% to 5% of patients, but there has been no effect on the pharmacokinetic or toxicity profile.

5. Miscellaneous effects:

a. Fatigue, headache, and back pain are common to occasional.

b. Weight loss, peripheral edema, and dehydration are occasional.

c. Electrolyte depletion, particularly hypomagnesemia, occurs commonly. Hypomagnesemia is occasionally severe.

d. Pulmonaryfibrosisis rare.

PAZOPANIB

Other name. Votrient.

Mechanism of action. An oral multitargeted receptor tyrosine kinase inhibitor of VEGF receptor, PDGF receptor, fibroblast growth factor receptor, and c-kit that blocks tumor growth and inhibits angiogenesis. Metabolized primarily by CYP3A4 and excreted in the stool.

Primary indication. Advanced renal cell carcinoma.

Usual dosage and schedule

1. 800 mg by mouth daily without food

2. 200 mg by mouth daily without food, if moderate hepatic impairment

3. 400 mg or less by mouth if strong inhibitors of CYP3A4 cannot be avoided.

Special precautions. May cause severe liver toxicity; therefore, liver function tests should be monitored closely before and during treatment. Do not give pazopanib if severe hepatic impairment is present. Fatal hemorrhagic events have been seen, and use in patients with history of gastrointestinal hemorrhage, hemoptysis, or cerebral hemorrhage should be avoided. If possible, avoid use of strong inhibitors of CYP3A4, which may increase concentration of pazopanib. CYP3A4 inducers may decrease pazopanib concentrations.

Toxicity

1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and lymphocytopenia are common but rarely severe. Arterial thrombotic events have been observed and can be fatal. Fatal hemorrhagic events have also been observed.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrhea is common, as are nausea, vomiting, and anorexia. Gastrointestinal perforation has been observed but is probably rare. Abdominal pain is occasional.

3. Mucocutaneous effects. Hair color change (depigmentation) is common. Hand-foot syndrome is occasional. Skin depigmentation is uncommon.

4. Immunologic effects and infusion reactions. None.

5. Miscellaneous effects:

a. Systemic effects: Fatigue, asthenia, and headache are occasional to common.

b. Hepatotoxicity: ALT and AST elevations are common and occasionally (12%) severe.

c. Cardiovascular: Hypertension is common, but grade 3 or 4 hypertension is uncommon. Prolonged QT intervals and tor-sades de pointes have been observed but are rare. Chest pain is uncommon.

d. Hyponatremia, hypomagnesemia, and hypophosphatemia are occasional.

e. Hypothyroidism is occasional.

f. Proteinuria is occasional but rarely severe.

PEGFILGRASTIM

Other names. Neulasta, pegylated G-CSF.

Mechanism of action. Pegfilgrastim is recombinant G-CSF that is conjugated to polyethylene glycol. This delays renal clearance and increases the serum half-life from about 3.5 to about 15 to 80 hours after a single SC injection. Promotes growth and differentiation of myeloid progenitor cells. May improve survival and function of granulocytes.

Primary indication. Prophylaxis of granulocytopenia and associated infection in patients who are at high risk from chemotherapy for nonmyeloid malignancies.

Usual dosage and schedule. 6 mg SC once (usually on day 2) for each 21- or 28-day chemotherapy cycle. Should not be given between 14 days before or 24 hours after each chemotherapy cycle.

Special precautions

1. Use with caution in disorders of myeloid stem cells as it may promote growth of leukemic cells.

2. The fixed-dose formulation should not be used in infants, children, and others weighing less than 45 kg.

Toxicity

1. Myelosuppression and other hematologic effects. None (leukocytosis with immature forms in the peripheral blood is common).

2. Nausea, vomiting, and other gastrointestinal effects. Rare to uncommon.

3. Mucocutaneous effects. Exacerbation of pre-existing dermatologic conditions is occasional; pyoderma gangrenosum is possible.

4. Miscellaneous effects. Usually mild and short-lived.

a. Bone pain, musculoskeletal symptoms such as cramps, and back or leg pain are common, but uncommonly greater than in placebo-treated patients.

b. Splenomegaly with prolonged use is possible. Splenic rupture has been reported with the parent compound filgrastim.

c. Exacerbation of pre-existing inflammatory or autoimmune disorders is rare.

d. Mild elevation ofLDH and alkaline phosphatase.

e. Allergic-type reactions may occur, as they have been seen with the parent compound filgrastim.

f. Adultrespiratorydistresssyndromehasbeenreportedinneutropenic patients receiving filgrastim and is possible with pegfilgrastim.

PEMETREXED

Other name. Alimta.

Mechanism of action. Interference with folate-dependent metabolic processes, including inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, largely after being converted to polyglutamate forms.

Primary indications

1. Malignant pleural mesothelioma that is unresectable or not amenable to curative surgery. Given in combination with cisplatin.

2. Nonsquamous, non–small-cell lung cancer, as first- or second-line therapy and as maintenance after remission induction

3. Carcinoma of the ovary.

Usual dosage and schedule. 500 mg/m2 IV over 10 minutes on day 1 of each 21-day cycle. For mesothelioma, it is followed in 30 minutes by cisplatin 75 mg/m2 over 2 hours.

Special precautions

1. Folic acid 1 to 2 mg by mouth daily in divided doses, starting 7 days prior to pemetrexed and continuing for 21 days after the last dose, and vitamin B12 1000 µg IM during the week prior to pemetrexed and every three cycles thereafter must be taken as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity.

2. Dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after pemetrexed should be given to reduce skin rash.

3. If creatinine clearance is less than 45 mL/min, give with caution and avoid NSAIDs.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia and neutropenia are common when used with cisplatin and only occasional when used as a single agent; severe episodes are only occasional; thrombocytopenia is occasional.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea are occasional. Liver function abnormalities are occasional.

3. Mucocutaneous effects. Rash and pruritis are occasional. Stomatitis and pharyngitis are common. Alopecia is occasional. Taste disturbances are occasional. Conjunctivitis is uncommon.

4. Immune suppression can occur.

5. Miscellaneous effects:

a. Fever is uncommon.

b. Serum creatinine elevation is occasional; renal failure is rare.

c. Fatigue is common. Myalgia and arthralgia are occasional. Sensory neuropathy is occasional.

d. Hypersensitivity reactions are occasional but rarely severe.

e. Supraventricular arrythmias are rare.

PENTOSTATIN

Other names. 2′-deoxycoformycin, Nipent.

Mechanism of action. Inhibition of adenosine deaminase, particularly in the presence of adenosine or deoxyadenosine, leads to cytotoxicity. Is associated with block of DNA synthesis through inhibition of ribonucleotide reductase. Other effects that may contribute to cytotoxicity include inhibition of RNA synthesis and increased DNA damage.

Primary indication. Hairy-cell leukemia.

Usual dosage and schedule. 4 mg/m2 IV push over 1 to 2 minutes or diluted in a larger volume over 20 to 30 minutes. Patients should be given hydration with 500 to 1000 mL of 5% dextrose in 0.5 N saline or equivalent before pentostatin administration and 500 mL after the drug is given. Repeat every 2 weeks.

Special precautions. Hydration is required to ensure urine output of 2 L daily on the day pentostatin is administered. Patients often are hospitalized for their first drug administration. Allopurinol 300 mg twice a day is recommended in patients with a large tumor mass. Sedative and hypnotic drugs should be used with caution or not at all because CNS toxicity may be potentiated. Dose reduction or discontinuation needed for renal impairment (creatinine clearance 50 mL/minute).

Should not be used in combination with fludarabine because of a high probability of severe or fatal pulmonary toxicity.

Toxicity

1. Myelosuppression and other hematologic effects. Common but severity variable.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common but usually not severe. Diarrhea is occasional. Hepatic dysfunction is occasional at recommended doses.

3. Mucocutaneous effects. Mucositis is rare; skin rashes and pruritis are occasional to common.

4. Miscellaneous effects.

a. Fatigueiscommon.

b. Cough is common and dyspnea is occasional. Higher doses or use in combination with fludarabine may lead to severe pulmonary toxicity.

c. Chills and fever are common.

d. Infections, probably related both to myelosuppression and lymphocytopenia, are occasional.

e. Renal insufficiency is rare at usual doses.

f. Neuropsychiatric effects: High doses may cause serious neurologic and psychiatric symptoms, including seizures, mental confusion, irritability, and coma.

PRALATREXATE

Other name. Folotyn.

Mechanism of action. Pralatrexate is a folate analog that competitively inhibits dihydrofolate reductase. It is also an inhibitor for polyglutamylation by folylpolyglutamyl synthetase.

Primary indication. Relapsed or refractory peripheral T-cell lymphoma.

Usual dosage and schedule. 30 mg/m2 IV push over 3 to 5 minutes weekly for 6 weeks in 7-week cycles.

Patients should take 1 to 1.25 mg oral folic acid daily starting 10 days prior to the first dose of pralatrexate as well as 1 mg of vitamin B12 IM, which should be administered every 8 to 10 weeks during treatment.

Special precautions. Omitting a dose, with or without subsequent dose modifications, is required for mucositis that is greater than grade 1 and significant cytopenias (ANC 1000/µL; platelets 50,000/µL).

Toxicity

1. Myelosuppression and other hematologic effects. Thrombocytopenia, anemia, and neutropenia are common. Grade 3 or 4 thrombocytopenia is common, but grade 3 or 4 neutropenia is less frequent (~20%).

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common, but it is rare to uncommon that they are severe. Constipation is common. Anorexia and abdominal pain are occasional.

3. Mucocutaneous effects. Mucositis is very common (70%) and may be associated with a sore throat; grade 3 to 4 mucositis occurs about 20% of the time. Epistaxis is common. Rash and pruritis are occasional.

4. Immunologic effects and infusion reactions. Not reported.

5. Miscellaneous effects:

a. Fatigue and fever are common.

b. Cardiorespiratory effects: Cough, dyspnea, and edema are common. Tachycardia is occasional.

c. Hypokalemia and elevated transaminases are occasional.

PROCARBAZINE

Other names. Matulane, Natulan.

Mechanism of action. Uncertain but appears to affect preformed DNA, RNA, and protein.

Primary indications

1. Hodgkin and non-Hodgkin lymphomas

2. Brain tumors

3. Melanoma.

Usual dosage and schedule. 60 to 100 mg/m2 by mouth daily for 7 to 14 days every 4 weeks (in combination with other drugs).

Special precautions. Many food and drug interactions are possible, although their clinical significance may be low.

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Toxicity

1. Myelosuppression and other hematologic effects. Pancytopenia is dose-limiting. Recovery may be delayed.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseais frequent during first few days until tolerance develops. Diarrhea is uncommon.

3. Mucocutaneous effects. Stomatitis is uncommon. Alopecia, pruritus, and drug rash are uncommon.

4. CNS effects. Paresthesias, neuropathies, headache, dizziness, depression, apprehension, nervousness, insomnia, nightmares, hallucinations, ataxia, confusion, convulsions, and coma have been reported with varying frequency.

5. Miscellaneous effects:

a. Secondary neoplasia is possible.

b. Visual disturbances are rare.

c. Posturalhypotensionisrare.

d. Hypersensitivity reactions are rare.

e. Teratogenesis is strong potential.

PROGESTINS

Other names. Medroxyprogesterone acetate (Provera, Depo-Provera), hydroxyprogesterone caproate (Delalutin), megestrol acetate (Megace).

Mechanism of action. Mechanisms of antitumor effects or for appetite stimulation are not clear.

Primary indications

1. Endometrial carcinoma

2. Appetite stimulation.

Usual dosage and schedule

1. Megestrol acetate 80 to 320 mg by mouth daily

2. Medroxyprogesterone acetate 1000 to 1500 mg IM weekly or 400 to 800 mg by mouth twice weekly

3. Hydroxyprogesterone caproate 1000 to 1500 mg IM weekly.

Special precautions. Acute local hypersensitivity or dyspnea due to oil in IM preparations is uncommon. Hypercalcemia with initial therapy is occasional, particularly in patients with bone metastasis.

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Rare; is an appetite stimulant (800 mg by mouth daily).

3. Mucocutaneous effects. Mild alopecia or skin rash are uncommon.

4. Miscellaneous effects:

a. Mild fluid retention is occasional to common.

b. Mild liver function abnormalities are occasional; intrahepatic cholestasis may occur.

c. Menstrual irregularities are common.

d. Increased appetite and weight gain are common.

RALOXIFENE

Other name. Evista.

Mechanism of action. A selective estrogen-receptor modulator that inhibits estrogen effects by competing with estrogen for binding on the cytosol estrogen-receptor protein in normal and cancer cells. The receptor-hormone complex ultimately controls the promoter region of genes that affect cell growth. Effects may manifest as estrogen agonistic (bone) or antagonistic (breast and uterus), depending on the tissue and other modifying factors.

Primary indications

1. Prevention of osteoporosis in postmenopausal women

2. Prevention of invasive breast cancer in postmenopausal women at increased risk. (No apparent decrease in ductal or lobular in situ carcinomas.)

Usual dosage and schedule. 60 mg by mouth daily.

Special precautions. Contraindicated in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. May cause fetal harm if administered to a pregnant woman.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon and mild.

2. Nausea, vomiting, and other gastrointestinal effects. Uncommon.

3. Mucocutaneous effects. Rash, sweating, and vaginitis are uncommon.

4. Miscellaneous effects:

a. Thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis, are rare. Lower risk than with tamoxifen.

b. Leg cramps are uncommon to occasional.

c. Hot flashes are common.

d. Lowers total cholesterol and low-density lipoprotein cholesterol.

5. Carcinogenesis. Risk for endometrial carcinoma is rare (0.5%) and lower than with tamoxifen (0.75%).

RITUXIMAB

Other name. Rituxan.

Mechanism of action. Rituximab is a genetically engineered chimeric (murine and human) monoclonal antibody directed against the CD20 antigen found on the surface of normal cells and in high copy number on malignant B-lymphocytes (but not stem cells). The Fab domain of rituximab binds to the CD20 antigen on B-lymphocytes and B-cell non-Hodgkin lymphomas, and the Fc domain recruits immune effector functions to mediate B-cell lysis.

Primary indications

1. Non-Hodgkin B-cell lymphoma that is low-grade or follicular, and CD20-positive, as a single agent or in combination or sequence with cytotoxic chemotherapy

2. Non-Hodgkin lymphoma, diffuse large B-cell and CD20-positive, in combination or sequence with cytotoxic chemotherapy

3. Other B-cell Non-Hodgkin lymphomas

4. CLL, usually in combination or sequence with fludarabine, cyclo-phosphamide, or both.

Usual dosage and schedule

1. 375 mg/m2 given as a slow IV infusion, initially at a rate of 50 mg/hr. If hypersensitivity or other infusion-related events do not occur, escalate in 50-mg/hr increments to a maximum of 400 mg/hr. Usually takes 4 to 6 hours to infuse initial therapy. Interrupt or slow the infusion rate for infusion-related events. As a single agent, often given once weekly for four to eight doses; in combination with cytotoxic chemotherapy, often given on day 1 or 2 of each cycle of chemotherapy. Premedication with acetaminophen and diphenhydramine may attenuate infusion-related symptoms. Corticosteroids should not be used for premedication.

2. For CLL when used with fludarabine and cyclophosphamide: 375 mg/m2 given as a slow IV infusion (as in 1) on the day prior to the first cycle of fludarabine and cyclophosphamide, then 500 mg/m2 as an IV infusion on day 1 of each subsequent 28-day cycle.

Special precautions

1. An infusion-related set of symptoms consisting of fever and chills, with or without true rigors, occurs commonly during the first infusion. Other hypersensitivity symptoms including nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling, rhinitis, vomiting, hypotension, flushing, and pain at disease sites may also be seen. Rarely, infusion-related events result in a fatal outcome. Fatal reactions have followed a symptom complex that includes hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Hypersensitivity reactions generally start within 30 to 120 minutes of starting the infusion. Most will resolve with slowing or interruption of the infusion and with supportive care, including IV saline, diphenhydramine, and acetaminophen. Severe reactions will additionally require aggressive cardiorespiratory support including oxygen, epinephrine, vasopressors, corticosteroids, and broncho-dilators and may preclude additional treatment with rituximab. The rate of infusion events decreases from 80% during the first infusion to 40% during subsequent infusions.

2. Abdominal pain, bowel obstruction, and perforation have been seen in patients receiving rituximab in combination with chemotherapy.

3. Hepatitis B reactivation with related fulminant hepatitis and other viral infections, including parvovirus B19, varicella-zoster, cytomegalovirus, and herpes simplex virus, have been reported. Obtaining a hepatitis panel (A, B, and C) is recommended. Hepatitis B surface antigen is a particular reason to monitor liver function closely. If HBsAG positive, consider monitoring serum viral load and administering antiviral prophylaxis.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon. However, B-cell depletion occurs in 70% to 80% of patients, with decreased immunoglobulins in a minority of patients. Infectious events occur in about 30% of patients treated with rituximab, but only uncommonly are they severe.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea is common (23%) but rarely severe. Vomiting and diarrhea are occasional. Bowel obstruction and perforation is rare.

3. Mucocutaneous effects. Pruritus, rash, urticaria, and night sweats are occasional. Severe mucocutaneous reactions including Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis are rare but have been reported from 1 to 13 weeks following rituximab exposure.

4. Immunologic effects and infusion reactions. Infusion-related hyper-sensitivity reaction (may include fever, chills, headache, myalgia, weakness, nausea, urticaria, pruritus, throat irritation, rhinitis, dizziness, and hypertension) is common but usually resolves with interrupting or slowing the rate of the infusion and administration of supportive therapy (see Special precautions).

5. Miscellaneous effects:

a. Myalgia and arthralgia are occasional. Rarely, a serum sicknesslike reaction may be seen that requires corticosteroid therapy.

b. Hypotension is occasional but rarely severe. Chest pain, bron-chospasm, tachycardia, increased cough, edema, and postural hypotension are uncommon. Severe though potentially fatal cardiac events, including angioedema, arrhythmia, and angina, are rare.

c. Renal failure, possibly requiring dialysis, has been seen, particularly in association with tumor lysis syndrome in patients with high tumor cell burden. Also may be seen if used in combination with cisplatin.

d. Hepatitis B reactivation with related fulminant hepatitis is rare.

e. Dizziness and anxiety are occasional.

f. Progressive multifocal leukoencephalopathy has been observed in patients with rheumatoid arthritis treated with rituximab.

ROMIDEPSIN

Other name. Istodax.

Mechanism of action. Inhibits histone deacetylases (HDACs), enzymes that catalyze the removal of acetyl groups from lysine residues in histone and thereby modulate gene expression. In some cancer cell lines, this inhibition allows the accumulation of acetylated histones and induces cell cycle arrest and apoptosis.

Primary indication. CTCL in patients who have received at least one prior systemic therapy.

Usual dosage and schedule. 14 mg/m2 IV over 4 hours on days 1, 8, and 15 of a 28-day cycle.

Special precautions. There is a risk of QT prolongation; be sure that potassium and magnesium are within the normal range before administration. Because romidepsin is metabolized by CYP3A4, avoid coadministration with strong inhibitors or inducers of CYP3A4 if possible.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia, neutropenia, lymphopenia, and thrombocytopenia are common. Infections are common and may be fatal.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and anorexia are common. Constipation is occasional to common.

3. Mucocutaneous effects. Dermatitis, including exfoliative dermatitis and pruritis, are occasional to common.

4. Miscellaneous effects:

a. Fatigue and fever are common.

b. ECG T-wave and ST-segment changes are common but of uncertain significance. Supraventricular arrythmias and ventricular arrythmias have been observed. There is risk of QT prolongation, particularly in those with a history of congenital long QT syndrome, significant cardiovascular disease, or taking medications that lead to significant QT prolongation. Monitoring of electrolytes and ECG at baseline and during treatment is recommended. Hypotension is occasional.

c. Hypomagnesemia, hypokalemia, hypocalcemia, and hyperuricemia are occasional to common but only rarely severe.

d. Elevated transaminases are occasional to common but only rarely severe. However, use caution when using warfarin (Cou-madin) or warfarin derivatives.

SARGRAMOSTIM

Other names. Granulocyte-macrophage colony-stimulating factor (GM-CSF), Leukine.

Mechanism of action. Promotes growth and differentiation of myeloid progenitor cells. May improve survival and function of granulocytes, eosinophils, monocytes, and macrophages. Induces release of secondary cytokines (IL-1 and tumor necrosis factor).

Primary indications

1. Myeloid reconstitution after peripheral blood or bone marrow progenitor cell transplantation

2. Neutrophil recovery following chemotherapy in AML

3. Mobilization of peripheral blood progenitor cells

4. Granulocytopenia from primary marrow disorders, such as MDS or aplastic anemia

5. Granulocytopenia associated with AIDS and its therapy.

Usual dosage and schedule

1. Myeloid reconstitution after autologous stem cell transplantation: 250 (µg/m2 IV daily as a 2-hour infusion beginning 2 to 4 hours after the autologous stem cell infusion and not less than 24 hours after the last dose of chemotherapy or less than 12 hours after the last dose of radiotherapy. Continue for 21 days or until the ANC reaches 20,000/(µL.

2. Bone marrow transplantation failure or engraftment delay: 250 µ g/m2 daily for 14 days as 2-hour IV infusion. If no marrow recovery, may be repeated in 7 days at same or higher dose (500 µg/m2). Dose and duration are dependent on the response.

3. Mobilization of peripheral blood progenitor cells: The recommended dose is 250 µg/m2/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of peripheral blood progenitor cell collection.

4. Neutrophil recovery following chemotherapy in AML: 250 μg/m2/ day administered IV over a 4-hour period starting 4 days following the completion of induction chemotherapy and continuing until the ANC is greater than 1500 cells/µ L for 3 consecutive days or a maximum of 42 days.

5. Aplastic anemia, MDS, and AIDS: Doses may be much lower (50 to 100 μg/m2 SC or IM daily).

Special precautions. Flushing, tachycardia, dyspnea, and nausea occur commonly with the first dose of IV therapy; do not infuse over less than 2 hours; longer infusion may help.

Toxicity

1. Myelosuppression and other hematologic effects. None (leukocytosis).

2. Nausea, vomiting, and other gastrointestinal effects. Occasional.

3. Mucocutaneous effects. Rash is uncommon; exacerbation of preexisting dermatologic conditions is occasional; mild local reactions at injection site are common.

4. Miscellaneous effects. Usually mild and short-lived at standard doses, but with increasing dose, may be more severe.

a. Bone pain, musculoskeletal symptoms such as cramps and back or leg pain are common.

b. Pericarditis, fluid retention, and venous thrombosis are dose-related and uncommon at standard doses.

c. Flulike symptoms (fever, chills, aches, headache) are occasional at standard doses and common at higher doses.

SIPULEUCEL-T

Other name. Provenge

Mechanism of action. The drug is a patient-specific (autologous) vaccine consisting of peripheral blood mononuclear cells, including antigen presenting cells (AP Cs), that have been collected by leukapheresis, sent to the manufacturing center, activated during a defined culture period with a recombinant human protein (prostatic acid phosphatase [PAP]-GM-CSF), and returned to the treating center for infusion. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface and returned to the patient, stimulating an immune response by the patient’s T-cells against tumor cells expressing PAP.

Primary indication. Hormone refractory carcinoma of the prostate.

Usual dosage and schedule. Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF.

The recommended course of therapyis three complete doses, given IV at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks); the maximum dosing interval has not been established.

If, for any reason, the patient is unable to receive a scheduled infusion of sipuleucel-T, the patient will need to undergo an additional leukaphere-sis procedure if the course of treatment is to be continued. Patients should be advised of this possibility prior to initiating treatment.

Special precautions. Severe infusion reactions are uncommon but are greater after the second than the first infusion.

Toxicity

1. Myelosuppression and other hematologic effects. None reported.

2. Nausea, vomiting, and other gastrointestinal effects. Occasional to common.

3. Mucocutaneous effects. Rash and sweating are uncommon.

4. Immunologic effects and infusion reactions. Chills, fever, fatigue, dyspnea, hypoxia, bronchospasm, back pain, nausea, vomiting, hypertension, tachycardia, joint ache, and headache are common. For most patients, these reactions are mild or moderate.

5. Miscellaneous effects:

a. Weakness and influenza-like illness are occasional.

b. Both hemorrhagic and ischemic strokes have been observed uncommonly.

SOMATOSTATIN ANALOGS

Other names. Octreotide, Sandostatin, Sandostatin LAR depot (other related analogs are pasireotide and lanreotide).

Mechanism of action. Somatostatin analog that inhibits release of polypeptide hormones, particularly in the pancreas and gut. Slows gastrointestinal transit time. Promotes water and electrolyte absorption, reflecting change from overall secretory to absorptive state.

Primary indications

1. Carcinoid tumors

2. Vasoactive intestinal peptide tumors and other amine precursor uptake and decarboxylation tumors

3. Chemotherapy-induced diarrhea

4. Acromegaly.

Usual dosage and schedule. 100 to 1500 μg/day SC of the nondepot prepration, in two to four divided doses. Doses are usually started at the lower end and titrated upward to the best symptomatic improvement. If patients respond favorably to the rapid acting SC injections, they may be maintained on 20 mg IM of the depot preparation by intragluteal injection every 4 weeks. Caution should be used in treating for more than 3 months.

Special precautions. Lower doses indicated if severe renal dysfunction (creatinine >5 mg/dL).

Toxicity

1. Myelosuppression and other hematologic effects. None.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, abdominal discomfort, bloating, and diarrhea are common, particularly in early therapy. Vomiting is only occasionally seen. Decreased gallbladder contractility and decreased bile secretion may result in biliary abnormalities. Gallstones develop in less than 2% if treatment is for 1 month or less but can be 25% if treatment is for 1 year or more. Ascending cholangitis and pancreatitis are uncommon to rare.

3. Mucocutaneous effects. Local site reactions are occasional; other effects are rare.

4. Miscellaneous effects:

a. Hypoglycemia or hyperglycemia is uncommon; hypothalamic pituitary dysfunction is rare.

b. Bradycardia and other conduction abnormalities occur in up to 25% of patients with acromegaly who are treated with octreotide.

SORAFENIB

Other name. Nexavar.

Mechanism of action. Inhibition of multiple tyrosine kinases and serine/ threonine kinases within tumor cells and tumor vasculature, resulting in decreased tumor cell proliferation and reduction of tumor angiogenesis.

Primary indications

1. Renal cell carcinoma

2. Angiosarcoma, GISTs

3. Hepatocellular carcinoma

4. Metastatic papillary, medullary, follicular, and Hürthle cell thyroid carcinoma.

Usual dosage and schedule. 400 mg by mouth twice daily either without food or with a moderate fat meal.

Special precautions. Increased risk of bleeding compared with placebo. In patients also taking warfarin, sorafenib may increase the PT and INR, resulting in increased risk of bleeding. May increase AUC of compounds metabolized by UGT1A1 pathway (e.g., irinotecan). Also increases AUC of docetaxel, doxorubicin, and in some patients, fluorouracil.

Toxicity

1. Myelosuppressionandotherhematologiceffects. Lymphopeniaiscommon; anemia, neutropenia, and thrombocytopenia are occasional; various bleeding events (including epistaxis, gastrointestinal hemorrhage, respiratory tract hemorrhage, hematomas) are common but only rarely life-threatening.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrheais common (33%); nausea and vomiting are occasional to common (10% to 20%); anorexia and constipation are occasional. Increased amylase and lipase are common, and transient increases in transaminases are occasional. Clinical pancreatitis is uncommon. Gastrointestinal perforation is rare.

3. Mucocutaneous effects. Hand-foot skin reaction is common (27%). Alopecia is common (23%). Pruritis is occasional to common (17%). Other skin changes are rare to uncommon.

4. Miscellaneous effects:

a. Hypertension, usually mild to moderate, is occasional. Hypertensive crisis is rare.

b. Fatigue is common.

c. Sensoryneuropathyis occasional(10%).

d. Hypophosphatemia is common (41%; unknown etiology).

e. Cardiac ischemia or infarction are uncommon.

STREPTOZOCIN

Other name. Zanosar.

Mechanism of action. Inhibition of DNA synthesis, possibly by interference with pyridine nucleotide synthesis. Streptozocin appears to have some specificity for neoplastic pancreatic endocrine cells. Glucose moiety attached to nitrosourea appears to diminish myelotoxicity.

Primary indications

1. Pancreatic islet cell and pancreatic exocrine carcinomas

2. Carcinoid tumors.

Usual dosage and schedule

1. 1.0 to 1.5 g/m2 IV weekly for 6 weeks followed by 4 weeks of observation

2. 1 g/m2 IV on days 1 and 8 in combination with fluorouracil and mitomycin. Repeat every 4 weeks.

3. 500 mg/m2 IV on days 1 to 5 every 6 weeks.

Special precautions

1. A 30- to 60-minute infusion is recommended to reduce local pain and burning around the vein during treatment.

2. Avoid extravasation.

3. Have 50% glucose available to treat sudden hypoglycemia.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon and mild.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common and severe. May become progressively worse over 5-day course of therapy.

3. Mucocutaneous effects. Uncommon.

4. Miscellaneous effects:

a. Renaltoxicityis common. Althoughitis notclearlydose-related, it may limit continued drug use in individual patients. Proteinuria, glucosuria, azotemia, and hypophosphatemia, if persistent or severe, are indications to discontinue therapy. Hydration may ameliorate the problem.

b. Hypoglycemia: In patients with insulinoma, hypoglycemia may be severe (although transient), owing to a burst of insulin release.

c. Hyperglycemia is uncommon in normal or diabetic patients, as normal p cells are usually insensitive to the effects of streptozocin.

d. Transientmild hepatotoxicity is occasional.

e. Second malignancies are possible.

SUNITINIB

Other names. Sutent, Sunitinib malate.

Mechanism of action. Inhibition of multiple RTKs, including PDGF receptors, VEGF receptors, and several forms of the mutation-activated stem cell factor receptor (KIT), with consequent inhibition of tumor cells expressing dysregulated target RTKs and tumor angiogenesis. Metabolized primarily by the cytochrome P450 enzyme allele, CYP34A.

Primary indications

1. GIST that has shown progression during prior treatment with ima-tinib or in patients who are intolerant to imatinib

2. Advanced renal cell carcinoma

3. Neuroendocrine tumors of the pancreas

4. Angiosarcoma

5. Metastatic papillary, medullary, follicular, and Hurthle cell thyroid carcinoma.

Usual dosage and schedule. 50 mg by mouth daily for 4 weeks followed by a 2-week rest, with incremental dose reductions or increase (12.5 mg/day) based on tolerability.

Special precautions. Dose reduction should be considered when administered concurrently with strong CYP3A4 inhibitors. Dose increase should be considered when administered concurrently with strong CYP3A4 inducers. Prolonged QT intervals and torsade de pointes have been observed. Use with caution in patients at higher risk for developing QT interval prolongation.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression and lymphopenia are common, but it is uncommon to rare for them to be high grade (3 or 4). Bleeding is occasional, with possible tumor-related hemorrhage. Venous thromboembolic events are uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrhea, nausea, vomiting, anorexia, and abdominal pain are common. Rare fatal gastrointestinal complications, including perforation, have been seen. Hepatic and pancreatic enzyme elevations and other liver function abnormalities are occasional to common.

3. Mucocutaneous effects. Stomatitis is common. Skin discoloration is common. Rash and hand-foot syndrome are occasional. Alopecia is uncommon.

4. Miscellaneous effects:

a. Congestive heart failure with decrease in left ventricular ejection fraction to below the lower limit of normal is occasional (15%).

b. Hypertension is occasional, but severe hypertension is uncommon.

c. Adrenal insufficiencyis possible, based on animal studies.

d. Asthenia, headache, arthralgia, myalgia, oral pain, and back pain are occasional.

e. Cough and dyspnea are occasional.

f. Renal function abnormalities (low-grade) are occasional. Hypo-and hyperkalemia, hypo- and hypernatremia, and hypophos-phatemia are occasional.

g. Hypothyroidism is uncommon.

h. Edema is occasional.

TAMOXIFEN

Other name. Nolvadex.

Mechanism of action. Tamoxifen is a selective estrogen-receptor modulator that inhibits estrogen effects by competing with estrogen for binding on the cytosol estrogen-receptor protein in cancer cells. This complex is probably transported into the nucleus, where it affects nucleic acid function. It also has effects on cellular growth factors, epidermal growth factors, and TGF-α and TGF-β.

Primary indications

1. Breast carcinoma

a. Metastatic tumors in postmenopausal or premenopausal women with estrogen-receptor–positive (or unknown) tumors.

b. Adjuvant therapy in premenopausal women with estrogen-receptor–positive (or progesterone-receptor–positive) tumors after primary therapy. Optimal duration of therapy for most premenopausal women is 5 years. For postmenopausal women, aromatase inhibitors are substituted after 2 to 3 years of tamoxifen or given instead of tamoxifen.

c. Breast cancer prevention in very high-risk women, including women with carcinoma in situ of the breast after primary therapy.

Usual dosage and schedule. 20 mg by mouth as single daily dose.

Special precautions. Hypercalcemia may be seen during initial therapy. Use of selective serotonin reuptake inhibitors (except citalopram, escitalopram, and the serotonin-norepinephrine reuptake inhibitor venlafaxine) with tamoxifen decreases formation of endoxifen, the active metabolite of tamoxifen, by inhibition of CYP2D6, and should be avoided, if possible.

Toxicity

1. Myelosuppression andotherhematologic effects. Myelosuppression is uncommon and mild. Thromboembolic phenomena are rare.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea occurs early in the course of therapy in up to 20% of patients but abates rapidly as therapy is continued. Diarrhea is occasional.

3. Mucocutaneous effects. Cataracts and other eye toxicities have been observed, but effects due to drug are uncommon. Skin rash and pruritus vulvae are uncommon. May cause increase or marked decrease in vaginal secretions and result in difficult or painful intercourse.

4. Miscellaneous effects:

a. Thromboembolism and strokes are rare but increased among women taking tamoxifen.

b. Hot flashes are common.

c. Vaginal bleeding and menstrual irregularity are uncommon to occasional.

d. Lassitude, headache, leg cramps, and dizziness are uncommon.

e. Peripheral edema is occasional.

f. Increased bone pain, tumor pain, and local disease flare (associated both with good tumor response as well as with tumor progression) are occasional.

g. Slowed progression of osteoporosis.

h. Reduction in serum cholesterol with favorable changes in lipid profile.

i. Liver function test abnormalities are occasional.

5. Uterine carcinomas are rare (two to four times the predicted incidence in adjuvant trials).

TEMOZOLOMIDE

Other name. Temodar.

Mechanism of action. Undergoes rapid conversion to the reactive substituted imidazole carboxamide, MTIC. This compound is believed to be active primarily through alkyation (methylation) of DNA at the O6 and N7 positions of guanine.

Primary indications

1. Glioblastoma, concurrently with radiotherapy and as maintenance after radiotherapy

2. Anaplastic astrocytoma that is refractory to nitrosoureas

3. Melanoma

4. Metastatic carcinomas to the brain.

Usual dosage and schedule

1. 150 to 200 mg/m2 by mouth on an empty stomach daily for 5 days every 28 days

2. 75 mg/m2 by mouth on an empty stomach daily during radiation therapy for up to 7 weeks.

Special precautions. Contraindicated in patients with a hypersensitivity to dacarbazine, since both drugs are metabolized to MTIC. Preventive treatment for Pneumocystis jiroveci pneumonia is required when temozolomide is administered with radiotherapy.

Toxicity

1. Myelosuppression and other hematologic effects. Myelosuppression with anemia, thrombocytopenia, and neutropenia is common and dose-dependent, but only occasionally is it severe.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and constipation are common, but usually not severe. Vomiting is occasional as is anorexia. Abdominal pain is uncommon.

3. Mucocutaneous effects. Rash and pruritis are occasional. Alopecia is common.

4. Miscellaneous effects:

a. Headache, fatigue, asthenia, and fever are common (20% to 65%).

b. Peripheral edema is occasional.

c. Neurologic symptoms are common on temozolomide, but it is difficult to distinguish whether the symptoms are from the drug or the disease. Common findings are convulsions, hemiparesis, dizziness, abnormal coordination, amnesia, or insomnia. Occasional findings are paresthesias, somnolence, paresis, incontinence, ataxia, dysphasia, gait abnormality, myalgias, and confusion. Diplopia or other visual abnormalities are occasional.

d. Anxiety and depression are occasional.

e. Upper respiratory and urinary tract infections are occasional.

f. MDS, acute leukemia, and other secondary malignancies have been observed.

TEMSIROLIMUS

Other names. Torisel, CCI-779.

Mechanism of action. After temsirolimus complexes with the immunophilin FKBP12, the complex inhibits mTOR kinase activity. mTOR, as a master regulator of cell physiology, is involved in regulation of cell growth and angiogenesis, and changes that are induced downstream from mTOR as a consequence of the temsirolimus inhibition lead to cell cycle arrest at the G1 phase.

Primary indication. Renal cell carcinoma.

Usual dosage and schedule

1. 25 mg IV over a 30- to 60-minute period weekly

2. Reduce dose to 12.5 mg/week if patients must be coadministered a strong CYP3A4 inhibitor

3. An increase from 25 mg/week up to 50 mg/week should be considered if patients must be coadministered a strong CYP3A4 inducer.

Special precautions. The concomitant use of strong CYP3A4 inhibitors or inducers should be avoided, if possible. Not recommended in combination with sunitinib. Avoid live vaccines.

Toxicity

1. Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are common. Venous thrombosis and embolism are uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, and vomiting are common. Diarrhea and abdominal pain are common. Bowel perforation may occur rarely.

3. Mucocutaneous effects. Mucositis is common. Maculopapular rash or acne are common. Nail disorders are common. Wound healing may be impaired.

4. Immunologic effects and infusion reactions. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have been observed are are occasional.

5. Miscellaneous effects:

a. Asthenia, edema, and fever are common.

b. Dyspneaandcougharecommon.

c. Increased liver transaminases and alkaline phosphatase is common; increased bilirubin is occasional.

d. Back pain, arthralgia, and myalagia are occasional.

e. Headache, chills, and chest pain are occasional.

f. Hyperglycemia is common and occasionally severe.

g. Hypophosphatemia is occasional and maybe severe.

h. Hypertriglyceridemiais common and maybe severe.

i. Interstitial lung disease is uncommon.

j. Creatinine is commonly increased, but renal failure is rare.

k. Taste perversion is common.

TENIPOSIDE

Other names. VM-26, Vumon.

Mechanism of action. Topoisomerase II-mediated double-strand DNA breaks. Causes cell cycle transit delay through S phase and arrest at late S/G2.

Primary indications

1. ALL

2. Neuroblastoma

3. Non-Hodgkin lymphomas.

Usual dosage and schedule

1. 165 mg/m2 IV over 30 to 60 minutes twice weekly for eight to nine doses (with cytarabine)

2. 250 mg/m2 IV over 30 to 60 minutes weekly for 4 to 8 weeks (with vincristine and prednisone).

Special precautions

1. Hypersensitivity reactions usually resolve with interruption of the infusion and often can be prevented with diphenhydramine and hydrocortisone pretreatment. Hypotension is alleviated by prolonging the infusion time. It is a possible vesicant.

2. See package insert for IV preparation and administration equipment requirements.

Toxicity

1. Myelosuppression and other hematologic effects. Common and dose-limiting.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common.

3. Mucocutaneous effects. Alopecia and mucositis are common.

4. Miscellaneous effects:

a. Hepatic and renal dysfunction is rare.

b. Hypersensitivity reactions with urticaria and flushing are occasional. Anaphylaxis is uncommon.

c. Hypotension is related to drug infusion rate but should be seen only occasionally at the recommended dose schedules.

d. Secondaryleukemiasareuncommon.

e. Chemical phlebitis is uncommon.

THALIDOMIDE

Other name. Thalomid.

Mechanism of action. Multiple potential mechanisms, including inhibition of VEGF, inhibition of TNF-α, direct inhibition of G1 growth and promotion of apoptosis, expansion of NK cells, and costimulation of T-cells.

Primary indications

1. Multiple myeloma

2. MDS

3. Primary myelofibrosis.

Usual dosage and schedule. A starting dose of 50 to 100 mg by mouth once daily in the evening. The dose is escalated weekly by 50 to 100 mg until the maximum dose specified, commonly 400 mg daily.

Special precautions. Severe and life-threatening birth defects, primarily phocomelia, can be caused by taking even a single 50-mg dose. For this reason, special precautions must be taken to assure that female patients are not pregnant when the drug is started, and that both female and male patients practice strict birth control measures. Prophylactic anticoagulation or aspirin may diminish frequency of thromboembolism.

Toxicity

1. Myelosuppression and other hematologic effects. Minimal myelosup-pression in most patients. Hypercoagulability with deep venous thrombosis is common (22%) in patients receiving the drug in combination with dexamethasone.

2. Nausea, vomiting, and other gastrointestinal effects. Constipation is common.

3. Mucocutaneous effects. Macular rash, usually involving the trunk, is common. Alopecia is uncommon. Severe or life-threatening epidermal damage is rare.

4. Miscellaneous effects:

a. Dose-dependent somnolence and dizziness is common. Tolerance usually develops to the sedative effects. Dizziness may be related to hypotension and can be minimized by adequate hydration and avoidance of rapid postural changes.

b. Peripheral neuropathy is common (25%) with chronic therapy. Occasional patients develop myalagia, tremor, or muscle spasms.

c. Fatigue is common.

d. Headache is occasional.

e. Edema is occasional to common.

f. Hypothyroidism is occasional.

g. Birth defects (see Specialprecautions).

THIOTEPA

Other names. Triethylenethiophosphoramide, Thioplex.

Mechanism of action. Alkylating agent similar to mechlorethamine.

Primary indications

1. Superficial papillary carcinoma of urinary bladder

2. Malignant peritoneal, pleural, or pericardial effusions

3. Neoplastic meningeal infiltrates.

Usual dosage and schedule

1. 30 to 60 mg in 40 to 50 mL water instilled into the bladder and retained for 1 hour. Dose is repeated weekly for 3 to 6 weeks, then every 3 weeks for five cycles.

2. 25 to 30 mg/m2 in 50 to 100 mL saline solution as a single intracavitary injection. Dose may be repeated as tolerated by blood counts.

3. 10 to 15 mg intrathecally.

Special precautions. Dose should be reduced in patients with impaired renal function, as the drug is primarily excreted in the urine.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-limiting. Pan-cytopenia and sepsis may follow intravesical or intracavitary administration. Nadir counts are reached in 1 to 2 weeks; recovery by 4 weeks is usual.

2. Nausea, vomiting, and other gastrointestinal effects. Uncommon.

3. Mucocutaneous effects. Uncommon. Thiotepa is not a vesicant. Hy-perpigmentation of skin occurs at high doses.

4. Miscellaneous effects:

a. Local pain, dizziness, headache, and fever are uncommon.

b. Secondaryneoplasms arepossible.

c. Amenorrhea and azoospermia are common.

TOPOTECAN

Other name. Hycamtin.

Mechanism of action. Topotecan, a semisynthetic derivative of campto-thecin, is a potent inhibitor of topoisomerase I, an enzyme essential for effective replication and transcription. It binds to the topoisomerase I-DNA cleavable complex, preventing religation after cleavage by topoi-somerase I.

Primary indications

1. Ovarian carcinoma

2. Carcinoma of the cervix

3. Small-cell and non-small-cell carcinoma of the lung.

Usual dosage and schedule

1. Asa single agent, 1.5 mg/m2 IV as a 30-minute infusion daily times five every 3 weeks.

2. In combination with cisplatin, 0.75 mg/m2 IV as a 30-minute infusion daily times three every 3 weeks.

Special precautions. None.

Toxicity

1. Myelosuppression and other hematologic effects. Leukopenia is universal and dose-limiting. Anemia and thrombocytopenia are common and occasionally severe. Febrile neutropenia is occasional to common.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common but usually mild. Other gastrointestinal symptoms, including constipation and abdominal pain, occur occasionally.

3. Mucocutaneous effects. Alopecia is common; stomatitis is occasional but usually mild; skin rash is rare.

4. Miscellaneous effects:

a. Fever, headache, fatigue, and weakness are common (15% to 25%) but rarely severe.

b. Microscopic hematuria is occasional.

c. Dyspnea occurs occasionally, but it is uncommon for it to be severe.

d. Infection as a consequence of severe leukopenia is common.

TOREMIFENE

Other name. Fareston.

Mechanism of action. A selective estrogen-receptor modulator that inhibits estrogen effects by competing with estrogen for binding on the cytosol estrogen-receptor protein in cancer cells. The receptor-hormone complex ultimately controls the promoter region of genes that affect cell growth.

Primary indication. Metastatic carcinoma of the breast in postmenopausal women with estrogen-receptor–positive (or unknown) tumors.

Usual dosage and schedule. 60 mg by mouth daily.

Special precautions. Uncertain whether it has any carcinogenic effect on endometrium, as has been observed with tamoxifen. May result in increased PT in patients taking warfarin (Coumadin). Cytochrome P450 3A4 enzyme inhibitors, such as phenobarbital, phenytoin, and carbamazepine, increase the rate of toremifene metabolism, lowering the concentration in the serum.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon and mild. Thromboembolic phenomena are rare.

2. Nausea, vomiting, and other gastrointestinal effects. Minimalnausea is common early in treatment; vomiting is uncommon.

3. Mucocutaneous effects. Dry eyes and cataracts are rare. May cause an increase or decrease in vaginal secretions, which may result in difficult or painful intercourse.

4. Miscellaneous effects:

a. Hot flashes are common.

b. Dizziness is occasional.

c. Sweating is occasional.

d. Vaginal discharge, bleeding, and menstrual irregularity are occasional.

e. Hypercalcemia is uncommon.

f. Occasional elevation of liver function tests.

TOSITUMOMAB, IODINE-131

Other name. Bexxar.

Mechanism of action. I-131 tositumomab is a murine Ig2a monoclonal anti-CD20 antibody radiolabeled with I-131, an emitter of both beta and gamma radiation. The mechanism of action includes antibody-mediated cytotoxicity and cellularly targeted radiotherapy (radioimmunotherapy).

Primary indication. Non-Hodgkin lymphoma, chemotherapy-refractory, CD20-positive, low-grade or transformed low-grade.

Usual dosage and schedule

1. Before dosimetric and therapeutic doses, patients are premedicated with acetaminophen 650 mg and diphenhydramine 50 mg. A saturated solution of potassium iodide, two to three drops orally three times daily, is given beginning 24 hours before the dosimetric dose and continuing for 14 days after the therapeutic dose to prevent uptake of I-131 by the thyroid.

2. Dosimetric dose of 450 mg of unlabeled tositumomab is given as a 1-hour infusion followed by a 20-minute infusion of 5 mCi (35 mg) of I-131 tositumomab to determine the patient-specific activity (millicuries) of radiolabeled tositumomab to deliver a therapeutic dose of 65 to 75 cGy 7 to 15 days later.

3. Assessment ofbiodistribution ofI-131 tositumomab: Do not administer therapeutic step if biodistribution is altered.

4. Therapeutic dose: 450 mg of unlabeled tositumomab is given as a 1-hour infusion followed by a 20-minute infusion of calculated patient-specific (in millicuries) activity labeled to 35 mg of tositumomab (median 90 mCi, range is approximately 50 to 200 mCi).

Special precautions. Use with caution in patients with at least 25% marrow involvement with lymphoma, prior external beam radiotherapy to at least 25% of the bone marrow, or a history of HAMAs or HACAs. A saturated solution of potassium iodide, two to three drops orally three times daily, is given beginning 24 hours before the dosimetric dose and continuing for 14 days after the therapeutic dose to prevent uptake of I-131 by the thyroid.

1. Myelosuppression andotherhematologic effects. Myelosuppression is universal, with about 35% to 65% of patients having grade 3 or 4 thrombocytopenia or neutropenia. The nadir counts occur at a median of 4 to 7 weeks and last 3 weeks, with recovery to baseline by 10 to 12 weeks after drug administration. Febrile neutropenia is common in previously treated patients but not when used as initial therapy.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea is common; vomiting, abdominal pain, and anorexia are occasional.

3. Mucocutaneous effects. Pruritis, rash, and sweating are occasional.

4. Miscellaneous effects:

a. Immunologic: HAMAs or HACAs are common and associated with influenza-like syndrome. Hypersensitivity reactions are occasional and may range from mild allergic reactions or injection site reactions to anaphylaxis and serum sickness.

b. Infusion-related fever, chills, dizziness, asthenia, wheezing or coughing, nasal congestion, headache, back pain, arthralgia, and hypotension are common, more with dosimetric than therapeutic dose. Most commonly, these are self-limited and mild to moderate in severity.

c. Fatigue or asthenia is common.

d. Cardiorespiratory: Cough, dyspnea, and edema are occasional; hypotension and vasodilatation are uncommon.

e. Thyroid suppression is occasional despite prophylaxis with potassium iodide.

f. Myelodysplasia and secondary leukemia are uncommon.

TRASTUZUMAB

Other names. Humanized anti-HER2 antibody, Herceptin.

Mechanism of action. A recombinant humanized monoclonal antibody that targets the extracellular domain of the human EGFR protein, HER2 (p185 HER2).

Primary indications

1. Carcinoma of the breast that has overexpression of HER2 (c-erbB-2), either in advanced disease or as adjuvant therapy

2. Metastatic gastric or gastroesophageal junction adenocarcinoma and other carcinomas that exhibit overexpression of HER2.

Usual dosage and schedule

1. Initial dose of 4 mg/kg IV over 90 minutes, then 2 mg/kg IV over 30 minutes weekly

2. Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks for 52 weeks (adjuvant breast cancer) until disease progression or intolerable toxicity (advanced breast cancer or other cancers).

Special precautions

1. During the first infusion, and occasionally during later infusions, a systemic symptom complex similar to that seen with other human monoclonal antibodies is common. Severe hypersensitivity reactions and pulmonary adverse events have been reported but are uncommon to rare. These events include anaphylaxis, angioedema, bronchospasm, hypotension, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, and acute respiratory distress syndrome. A more common symptom complex consists of mild to moderate chills, fever, asthenia, pain, nausea, vomiting, and headache. These latter symptoms are generally well managed by temporary slowing or interruption of the infusion and administration of acetaminophen, diphenhydramine, and meperidine.

2. Cardiac dysfunction (cardiac symptoms or an asymptomatic decrease in ejection fraction of 10% or greater) occurs in about 7% of patients treated with trastuzumab alone but in 28% of patients treated with trastuzumab plus anthracycline and in 11% of patients treated with trastuzumab plus paclitaxel. In most cases, this improves with symptomatic therapy. Severe disability or death from cardiac dysfunction occurs in about 1% of patients. Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common with the first infusion. Diarrhea is also common.

3. Mucocutaneous effects. A rash is occasional to common and may be associated with urticaria or pruritus.

4. Miscellaneous effects:

a. Mild to moderate chills, fever, asthenia, pain, and headache are common, primarily during the first infusion.

b. Cardiac dysfunction occurs in about 7% of patients treated with trastuzumab alone, but in 28% of patients treated with trastu-zumab plus anthracycline and in 11% of patients treated with trastuzumab plus paclitaxel. In most cases, this improves with symptomatic therapy.

c. Chest pain, back pain, dyspnea, and cough are occasional to common.

d. Peripheral edema is occasional.

TRETINOIN

Other names. All-trans-retinoic acid, t-RNA, ATRA, Vesanoid, Retin-A.

Mechanism of action. Binds to cytoplasmic retinoic acid-binding proteins and then is transported to the nucleus where it interacts with nuclear RARs. These then affect expression of the genes that control cell growth and differentiation. In acute promyelocytic leukemia, which characteristically has a chromosomal translocation, t(15:17), abnormal mRNA transcripts are seen for RAR-a, the gene for which is on chromosome 17.

Primary indication. Acute promyelocytic leukemia for induction of remission.

Usual dosage and schedule. 45 mg/m2 by mouth daily (divided into two doses in the morning and 6 hours later) until 30 days after complete remission is documented, up to a maximum of 90 days. Therapy usually initiated concurrently with anthracycline.

Special precautions. Avoid use in pregnant women because of marked teratogenic potential. Advise patients to avoid pregnancy by using two reliable contraceptive methods simultaneously. Retinoic acid acute pro-myelocytic (RA-APL) syndrome (see subsequent discussion) may require mechanical ventilation and dexamethasone 10 mg every 12 hours at the first signs of fever with respiratory distress until resolution of the acute symptoms (often several days). Continuation of retinoid therapy is controversial.

Toxicity

1. Myelosuppression andotherhematologic effects. Myelosuppression is rare. Forty percent of patients develop leukocytosis, which increases the risk of RA-APL syndrome. Disseminated intravascular coagulation is common (26%).

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting, abdominal pain, diarrhea, anorexia, and constipation are common but usually not severe. Gastrointestinal hemorrhage is occasional to common and may be severe. Inflammatory bowel disease is rare.

3. Mucocutaneous effects. Universal, particularly at doses at higher end of range. They include redness, dryness, and pruritus of the skin and mucous membranes; increased sweating; possible vesicle formation; peeling of the skin of the palms and soles; cheilitis; and conjunctivitis. There also may be increased skin photosensitivity (e.g., to sun) and the nails may become brittle. Alopecia is uncommon.

4. Retinoic acidsyndrome. High fever, respiratorydistress, weight gain, diffuse pulmonary infiltrates, pleural or pericardial effusions with the possibility of impaired myocardial contractility, and hypotension, with or without concomitant leukocytosis, are common in patients with acute promyelocytic leukemia (25%; see Chapter 18).

5. Miscellaneous effects:

a. Cardiovascular: Arrythmias, flushing, hypotension, hypertension, and phlebitis are occasional. Cardiac failure, cardiac arrest, pulmonary hypertension, and other more severe cardiovascular problems are uncommon.

b. Cataracts and corneal ulcerations or opacities are uncommon.

c. Musculoskeletal: Arthralgias, bone pain, and muscle aches are occasional to common; skeletal hyperostosis is common at higher doses (80 mg/m2/day).

d. Hypertriglyceridemia: Mild to moderate elevations are common; marked elevations (more than five times normal) are uncommon; hypercholesterolemia occurs to lesser degree.

e. Neurologic: Headache is common; paresthesias, dizziness, and visual disturbances are occasional; lethargy, fatigue, and mental depression are uncommon; pseudotumor cerebri is rare.

f. Hepatotoxicity with increased LDH, SGOT, SGPT, GGTP, and alkaline phosphatase is common.

g. Hyperhistaminemia with shock is rare.

h. Renal insufficiency is occasional.

i. Fever, malaise, shivering, and edema are common.

VALRUBICIN

Other name. Valstar.

Mechanism of action. Valrubicin, a semisynthetic analog of doxorubicin, penetrates into cells where its metabolites inhibit the incorporation of nucleosides into nucleic acids, cause chromosomal damage, and arrest cell cycle in G2. A principal mechanism of valrubicin metabolites is DNA-strand breakage mediated by anthracycline effects on topoi-somerase II.

Primary indication. Intravesical therapy of BCG-refractory carcinoma in situ of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

Usual dosage and schedule. 800 mg, diluted in 75 mL of normal saline, intravesically once a week for 6 weeks. Retain in bladder for 2 hours before voiding.

Special precautions. Should not be administered if there is any question about perforation of the bladder or integrity of bladder mucosa.

Toxicity

1. Myelosuppression and other hematologic effects. Uncommon, unless bladder rupture or perforation occurs, in which case severe neutropenia can be expected 2 weeks after administration.

2. Nausea, vomiting, and other gastrointestinal effects. Uncommon.

3. Mucocutaneous effects. Rash is uncommon.

4. Miscellaneous effects:

a. Local reactions: Frequency, dysuria, urgency, bladder spasm, hematuria, and bladder pain are common. Urinary incontinency and cystitis are occasional. Local burning symptoms associated with the procedure, urethral pain, pelvic pain, and gross hematuria are uncommon to rare.

b. Body as a whole: Abdominal pain, asthenia, back pain, chest pain, fever, headache, and malaise are uncommon.

VANDETANIB

Other names. Zactima, ZD6474.

Mechanism of action. An oral multitargeted RTK inhibitor of EGFR and VEGF receptor, and the RET proto-oncogene RTK, which is associated with both hereditary and sporadic medullary thyroid cancer, blocking both tumor growth and inhibiting tumor angiogenesis.

Primary indications

1. Non–small-cell carcinoma of the lung

2. Medullary thyroid carcinoma.

Usual dosage and schedule. 300 mg by mouth daily.

Special precautions. Do not use in patients with hypokalemia, hypomag-nesemia, or long QT syndrome. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter. Do not give if QTc is greater than 480 msec.

Toxicity

1. Myelosuppression and other hematologic effects. None reported.

2. Nausea, vomiting, and other gastrointestinal effects. Diarrheais common and occasionally grade 3 to 4. Nausea is common, but vomiting is only occasional and usually not severe. Constipation is occasional to common. Anorexia is common, but usually only grade 1 to 2.

3. Mucocutaneous effects. Rash is common, but high-grade dermatologic abnormalities are uncommon.

4. Miscellaneous effects:

a. Fatigue is common and occasionally grade 3 to 4. Weight loss is occasional.

b. Headache is common.

c. QTc interval prolongation is occasional (about 15%).

d. Hypertension is occasional and may be high-grade (rise of >30 mm Hg systolic) but usually easily controlled.

e. Dyspnea is common in patients receiving vandetanib for lung cancer.

VINBLASTINE

Other names. VLB, Velban.

Mechanism of action. Mitotic inhibition with reversible metaphase arrest due to action on microtubular and spindle contractile proteins.

Primary indications

1. Hodgkin and non-Hodgkin lymphomas

2. Testicular, gestational trophoblastic carcinomas.

Usual dosage and schedule

1. 6 mg/m2 IV on days 1 and 15 in combination with doxorubicin, bleomycin, and dacarbazine for lymphomas

2. 4 to 18 mg/m2 IVweekly.

Special precautions. Administer as a slow push, taking care to avoid extravasation.

Toxicity

1. Myelosuppression and other hematologic effects. Dose-related leukopenia occurs with a nadir at 4 to 10 days and recovery in 7 to 10 days. Severe thrombocytopenia is uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Common but not usually severe.

3. Mucocutaneous effects. Extravasation maylead to severe inflammation, pain, and tissue damage. Local infiltration with 1 to 6 mL of hyaluronidase (150 units/mL) may help (see Table 26.1). Mild alopecia is common. Stomatitis is occasionally severe.

4. Miscellaneous effects:

a. Neurotoxicity manifested by (1) constipation, adynamic ileus, and abdominal pain if very high doses are used; or (2) paresthesias, peripheral neuropathy, and jaw pain with lower doses. Neurotoxicity is less frequent with vinblastine than with vincristine.

b. Transient hepatitis is uncommon.

c. Depression, headache, convulsions, and orthostatic hypotension are rare.

VINCRISTINE

Other names. VCR, Oncovin, Vincasar.

Mechanism of action. Mitotic inhibition with reversible metaphase arrest due to drug action on microtubular and spindle contractile proteins.

Primary indications

1. Hodgkin and non-Hodgkin lymphomas

2. ALL

3. Multiple myeloma

4. Wilms tumor, neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma of childhood.

Usual dosage and schedule

1. 1 to 2 mg/m2 (maximum 2.0 to 2.4 mg, except in Hodgkin lymphoma) IV weekly

2. 0.4 mg/day as a continuous IV infusion on days 1 to 4.

Special precautions

1. Administer as a slow IV push, taking care to avoid extravasation.

2. Because neurotoxicity is cumulative, neurologic evaluation should be done before each dose and therapy withheld if severe paresthesias, motor weakness, or other severe abnormalities occur. Underlying neurologic problems accentuate the effect of vincristine.

3. Reduce dose ifliver disease is significant.

4. Stool softeners or high-fiber or bulk diets may avert severe constipation.

Toxicity

1. Myelosuppression and other hematologic effects. Mild and rarely of clinical significance.

2. Nausea, vomiting, and other gastrointestinal effects. Nauseaandvomiting are not seen unless paralytic ileus occurs. Constipation is common.

3. Mucocutaneous effects. Severe local inflammation if extravasation occurs. Alopecia is common.

4. Miscellaneous effects:

a. Neurotoxicity: Dose-dependent and dose-limiting. Mild paresthesias and decreased deep tendon reflexes are to be expected. More extensive peripheral neuropathies, severe constipation, or ileus are indications to reduce or hold therapy. Autonomic dysfunction with orthostatic hypotension or urinary retention may be seen.

b. Uric acid nephropathy due to rapid tumor cell lysis and release of uric acid is always a potential problem when therapy is first given.

c. Syndrome of inappropriate antidiuretic hormone is rare.

d. Jawpain is uncommon.

VINORELBINE

Other name. Navelbine.

Mechanism of action. Binds to tubulin, depolymerizes microtubules causing mitotic inhibition, similar to other vinca alkaloids. Lower affinity for axonal microtubules associated with lower neurotoxicity.

Primary indications

1. Metastatic carcinoma of the breast

2. Non–small-cell carcinoma of the lung.

Usual dosage and schedule

1. 30 mg/m2 IV as 6- to 10-minute rapid infusion weekly when used with a single agent or with cisplatin

2. 20 to 25 mg/m2 IV as a 6- to 10-minute rapid infusion in various schedules, when used with other myelotoxic agents.

Special precautions. Administer infusion through the side arm of a freely flowing IV, taking care to avoid extravasation. Reduce dose by 50% for serum bilirubin levels of 2.1 to 3 mg/dL; by 75% for bilirubin levels of more than 3 mg/dL.

Toxicity

1. Myelosuppression and other hematologic effects. Granulocytopenia is common and dose-limiting, with nadir at 7 to 10 days. Thrombo-cytopenia is uncommon. Anemia is occasional to common.

2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common but usually mild to moderate. Diarrhea occurs occasionally.

3. Mucocutaneous effects. Alopecia, mild diarrhea, and stomatitis are occasional. Severe local inflammation can occur with extravasation.

4. Miscellaneous effects:

a. Neurotoxicity: Cumulative but reversible constipation and decreased deep tendon reflexes are occasional; paresthesias are uncommon.

b. Erythema, pain, and skin discoloration at injection site are common; phlebitis at injection site is occasional.

VORINOSTAT

Other name. Zolinza.

Mechanism of action. Inhibits HDACs, which are overexpressed in some cancer cells. Accumulation of acetylated histones following vorinostat exposure induces cell cycle arrest or apoptosis in some transformed cells in vitro.

Primary indication. CTCL with progressive, persistent, or recurrent skin disease after two other systemic therapies.

Usual dosage and schedule. 400 mg by mouth daily with food. May be reduced to 300 mg daily or 5 days weekly if the higher dose is not tolerated.

Special precautions. Patients should drink at least 2 L offluid daily to prevent dehydration from vomiting and diarrhea. Deep venous thrombosis and pulmonary embolism (5%) have been reported. Serum chemistries (including potassium, magnesium, calcium, glucose, and creatinine) and platelets should be monitored every 2 weeks during the first 2 months of treatment. Severe thrombocytopenia and gastrointestinal bleeding may occur with concomitant use with other HDAC inhibitors, such as valproic acid.

Toxicity

1. Myelosuppression and other hematologic effects. Thrombocytopenia is common; anemia and neutropenia are occasional. Increased PT and INR may be seen with concomitant use of warfarin with vorinostat.

2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, and diarrhea are common. Vomiting, constipation, and weight loss are occasional.

3. Mucocutaneous effects. Alopecia is occasional to common.

4. Miscellaneous effects:

a. Blood chemistry abnormalities: Hypercholesterolemia, hyper-triglyceridemia, hyperglycemia, and increased creatinine are common and may be severe (grade 3 or higher).

b. Cardiovascular: QTc prolongation on the electrocardiogram is uncommon. Pulmonary embolism and deep venous thrombosis are uncommon.

c. Edema is occasional.

d. Neuromuscular: Fatigue is common. Headache, muscle spasms, and dizziness are occasional.

e. Neoplastic: Squamous cell carcinoma is uncommon.

ZOLEDRONIC ACID

Other name. Zometa.

Mechanism of action. A bisphosphonate that inhibits osteoclastic resorption of bone and calcium release induced by tumor cytokines.

Primary indications

1. Hypercalcemia associated with malignancy

2. Bone metastases, breast cancer, prostate cancer (after progression on hormonal therapy), and from other solid tumors in conjunction with standard antineoplastic therapy

3. Osteolytic and osteoporotic bone lesions of multiple myeloma.

Usual dosage and schedule

1. Hypercalcemia of malignancy: 4 mg IV as a 15-minute infusion. May be repeated every 1 to 8 weeks, as needed.

2. Multiple myeloma or metastatic bone lesions: 4 mg IV as a 15-min-ute infusion every 3 to 4 weeks.

Special precautions. Do not infuse over less than 15 minutes. Potential for renal tubular damage, particularly if infused more rapidly. The risk of adverse reactions, particularly renal adverse reactions, may be greater in patients with impaired renal function. Dose adjustments are not necessary when treating for hypercalcemia, as long as serum creatinine is less than 4.5 mg/dL. In patients with multiple myeloma or metastatic bone lesions of solid tumors, the dose should be progressively reduced for baseline creatinine clearance of 30 to 60 mL/min. Do not give if clearance less than 30 mL/min. Hold therapy if creatinine increases during therapy. Use caution when administered concurrently with aminoglyco-sides. Serum creatinine should be monitored before each treatment.

Osteonecrosis of the jaw has been reported, primarily in association with dental procedures such as tooth extraction; such procedures should be avoided during and following bisphosphonate treatment, if possible.

Toxicity

1. Myelosuppression and other hematologic effects. Rare.

2. Nausea, vomiting, and other gastrointestinal effects. Abdominal pain, anorexia, constipation, nausea, and vomiting are uncommon to occasional.

3. Mucocutaneous effects. Infusion site reaction is occasional.

4. Miscellaneous effects:

a. Flulike syndrome with fever, chills, skeletal aches, and pains is occasional.

b. Hypocalcemia and hypomagnesemia are occasional, but grade 3 or 4 abnormalities are uncommon to rare.

c. Increase of the serum creatinine of 0.5 mg/dL above baseline is occasional, but elevation to greater than three times ULN is uncommon.

d. Hypophosphatemia less than 2 mg/dL is occasional but does not appear to have serious consequences or require treatment.

e. Osteonecrosis of the jaw is uncommon to rare.

f. Conjunctivitis or other ocular abnormalities are rare.

g. There is potential for bronchoconstriction in aspirin-sensitive patients.

Selected Readings

Chabner B, Longo DL. Cancer Chemotherapy and Biotherapy: Principles and Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.

Dorr RT, Van Hoff DD, eds. Cancer Chemotherapy Handbook. Norwalk: Appleton & Lange; 1994.

National Cancer Institute Cancer Therapy Evaluation Program. Common terminology criteria for adverse events v4.0. Retrieved from http://ctep.cancer.gov/reporting/ctc.html.

Perry MC. The Chemotherapy Source Book. Philadelphia: Lippincott Williams & Wilkins; 2008.

Rosner GL, Hargis JB, Hollis DR, et al. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. J Clin Oncol. 1996;14:3000-3008.

Sparreboom A, Wolff AC, Mathijssen RH, et al. Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol. 2007;25: 4707–4713.

Tannock IF, Hill RP, eds. The Basic Science of Oncology. New York: McGraw-Hill; 1998.