Chemotherapy Drugs

Editors: Skeel, Roland T. Title: Handbook of Cancer Chemotherapy, 7th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Section II - Chemotherapeutic and Biotherapeutic Agents and Their Use > Chapter

4 - Antineoplastic Drugs and Biologic Response Modifiers: Classif ication, Use, and Toxicity of Clinically

Useful Agents

Chapter 4

Antineoplastic Drugs and Biologic Response Modifiers: Classification, Use, and Toxicity of Clinically Useful Agents

Rolando 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 hormonal agents, the name designates the physiologic behavior of the drug, and for natural products, the name reflects the source of the agents. The biologic response modifiers include agents that mimic, stimulate, enhance, inhibit, or otherwise alter host responses to the cancer. Several new agents have emerged that affect defined and putative abnormalities in the cancer cell and its environment and can best be classed as molecularly targeted agents. 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 4.1). As with the criteria for separating into classes, 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 manner is helpful in several respects. For example, because the antimetabolites interfere with purine and pyrimidine metabolism and the formation of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), they are all at least cell cyclespecific and in some instances primarily cell cycle phasespecific. The nitrosourea group of alkylating agents, on the other hand, contains drugs that are predominantly or entirely cell cyclenonspecific. 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.

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Table 4.1 Useful chemotherapeutic agents

Class and Type Agents

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Alkylating agents

Alkyl sulfonate Busulfan

Ethylenimine derivative Thiotepa (triethylenethiophosphoramide)

Metal salt Carboplatin, cisplatin, oxaliplatin

Nitrogen mustard Chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan

Nitrosourea Carmustine, lomustine, streptozocin

Triazene Dacarbazine, temozolamide

Antimetabolites

Antifolates Methotrexate, pemetrexed, raltitrexed, trimetrexate

Purine analogs Cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, pentostatin, thioguanine

Pyrimidine analogs Azacitidine, capecitabine, cytarabine, decitabine, floxuridine, fluorouracil, gemcitabine

Natural products

Antibiotics Bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, valrubicin

Enzyme Asparaginase

Microtubule polymer stabilizer

Docetaxel, paclitaxel



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Mitotic inhibitor Vinblastine, vincristine, vindesine, vinorelbine

Topoisomerase I inhibitors Irinotecan, topotecan

Topoisomerase II inhibitors Etoposide, teniposide

Hormones and hormone antagonists

Androgen Fluoxymesterone and others

Androgen antagonist Bicalutamide, flutamide, nilutamide

Aromatase inhibitor Aminoglutethimide, anastrozole, letrozole, exemestane

Corticosteroid Dexamethasone, prednisone

Estrogen Diethylstilbestrol

Estrogen antagonist (selective estrogen receptor modulator)

Fulvestrant, raloxifene, tamoxifen, toremifene

Luteinizing hormonereleasing hormone agonist

Goserelin, leuprolide, triptorelin

Polypeptide hormone release suppression

Octreotide

Progestin Megestrol acetate, medroxyprogesterone acetate

Thyroid hormones Levothyroxine, liothyronine

Molecularly targeted agents



Gene expression modulators Retinoids, rexinoids

Interleukin 2 receptor toxin Denileukin diftitox

Monoclonal antibody Alemtuzumab, cetuximab, gemtuzumab, ibritumomab tiuxetan, panitumumab, trastuzumab, rituximab, 131I-tositumomab

mTOR kinase inhibitor Temsirolimus

Proteosome inhibitor Bortezomib

Receptor tyrosine kinase inhibitors

Dasatinib, erlotinib, gefitinib, imatinib mesylate, lapatinib, semaxanib, sorafenib, sunitinib

Retinoic acid receptor expression modification

Tretinoin (ATRA)

Biologic response modifiers

Interferons Interferon -2a, interferon -2b

Interleukins Aldesleukin (interleukin 2), oprelvekin, denileukin diftitox

Myeloid- and erythroid-stimulating factors

Epoetin, filgrastim, sargramostim

Nonspecific immunomodulation

Thalidomide, lenalidomide

Miscellaneous agents

Adrenocortical suppressant Mitotane

Bisphosphonates Pamidronate, zoledronic acid



The classification scheme may also help predict cross-resistance between drugs. Tumors that are resistant to one of the nitrogen mustard types of alkylating agents would therefore 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., cisplatin). The classification system does not help in predicting multidrug resistance, which may have several phenotypes.

A. Alkylating agents

1. General description 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 themselves or generate electrophiles in vivo to produce polarized molecules with positively charged regions. These polarized molecules can then 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

Cytoprotector (reactive species antagonists)

Amifostine, dexrazoxane, mesna

Methylhydrazine derivative Procarbazine

Photosensitizing agents Porfimer

Platelet-reducing agent Anagrelide

Salt Arsenic trioxide

Somatostatin analog Octreotide

Substituted melamine Altretamine (hexamethylmelamine)

Substituted urea Hydroxyurea

mTOR, mammalian target of rapamycin.



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cyclenonspecific.

2. Types of alkylating agents

a. Nitrogen mustards. These compounds produce highly reactive carbonium ionsthat react with the electron-rich areas of susceptible molecules. They vary inreactivity from mechlorethamine, which is highly unstable in aqueous form, tocyclophosphamide, which must be biochemically activated in the liver.

b. Ethylenimine derivatives. Triethylenethiophosphoramide (thiotepa) is the onlycompound in this group that has much clinical use. Ethylenimine derivatives arecapable 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, the only agent of this type, was originally thought tobe an antimetabolite because of its resemblance to 5-aminoimidazole-4-carboxamide.

Dacarbazine is now known to act as an alkylator after 5-aminoimidazole-4-carboxamide is cleaved from active diazomethane.

e. Nitrosoureas. Nitrosoureas undergo rapid, spontaneous activation in aqueoussolution to form products capable of alkylation and carbamoylation. They areunique among the alkylating agents with respect to not being cross-resistantwith other alkylating agents, being highly lipid soluble, and having delayedmyelosuppressive effects (6 to 8 weeks).

f. Metal salts. Cisplatin, carboplatin, and oxaliplatin inhibit DNA synthesisprobably through the formation of intrastrand cross-links in DNA and formationof DNA adducts. They also react with DNA through chelation or binding to thecell membrane.

B. Antimetabolites

1. General description. Antimetabolites are a group of low-molecular-weight compoundsthat exert their effect by virtue of their structural or functional similarity to naturallyoccurring metabolites involved in nucleic acid synthesis. Because they are mistaken bythe cell for normal metabolites, they either inhibit critical enzymes involved in nucleicacid synthesis or become incorporated into the nucleic acid and produce incorrectcodes. Both mechanisms result in the inhibition of DNA synthesis and ultimate celldeath. Because of their primary effect on DNA synthesis, antimetabolites are mostactive in cells that are actively growing and are largely cell cycle phasespecific.

2. Types of antimetabolites

a. Folic acid analogs. Methotrexate, the dominant member of this group, inhibitsthe enzyme dihydrofolate reductase. This inhibition blocks the production ofreduced N-methylenetetrahydrofolate, the coenzyme in the synthesis ofthymidylic acid. Other metabolic processes in which there is onecarbon unittransfer are also affected but are probably of less importance in the cytotoxicaction of methotrexate. Ralitrexed (Tomudex) is a quinazoline antifolate that isan inhibitor of thymidylate synthase. Pemetrexed is a multitargetedpyrrolopyrimidine-based antifolate that, when polyglutamated, inhibitsdihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide

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formyl-transferase.

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 not as well defined as for most pyrimidine analogs, although it is well demonstrated that they interfere with normal purine interconversions and therefore with DNA and RNA synthesis. Some of the analogs are also incorporated into the nucleic acids. The adenosine deaminase (ADA) inhibitor pentostatin increases the intracellular concentration of deoxyadenosine triphosphates in lymphoid cells and inhibits DNA synthesis, probably by blocking ribonucleotide reductase. Among the metabolic alterations is nicotinamide adenine dinucleotide (NAD) 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, NAD levels are also depleted.

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 are 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 semisynthetic 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.

b. Podophyllum derivatives. Etoposide and teniposide, semisynthetic podophyllotoxins derived from the root of the May apple 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 (CPTs). These agents are analogs of CPT, a derivative of the Chinese tree Camptotheca accuminata. The primary target of the two clinically active agents, irinotecan and topotecan, 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 IIdependent DNA cleavage and intercalate with the DNA double helix.

2. Bleomycins cause DNA strand scission. The resulting fragmentation is

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believed to underlie the cytotoxic activity of the drug.

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 that is essential for 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, hypothalamicpituitary 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 [TGF]- and -). The relative roles of the various actions of hormones and hormone antagonists are only partially understood and probably vary among tumor types. For estrogen receptor antagonists 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 approximately 20 receptor-interacting proteins and 50 transcription-activating factors, as well as many response elements. Other effects aremediated through indirect effects on the hypothalamus and its anterior pituitaryregulating hormones. The final common pathway in most circumstances appears to lead to the malignant cell, which has retained 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 men 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. 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

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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 hormonereleasing hormone (LHRH) agonists leuprolide or goserelin, can inhibit luteinizing hormone and follicle-stimulating hormone (after initial stimulation) and the production of testosterone or estrogen by the gonads.

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

E. Molecularly targeted agents

1. General. This is a new classification 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 inhibitors. The first clinical example of this is the signal transduction inhibitor imatinib mesylate, which inactivates the constitutively active fusion product tyrosine kinase arising from the Philadelphia chromosome found in chronic myelogenous leukemia (CML), Bcr-Abl, as well as c-Kit kinase, which is overexpressed in gastrointestinal stromal tumors (GISTs). A second promising target is the epidermal growth factor receptor (EGFR)associated tyrosine kinase, because of its overexpression in a large variety of cancers. A number of small-molecule inhibitors of its enzymatic activity are in clinical use or are under development. One of these, erlotinib, which inhibits intracellular phosphorylation of the tyrosine kinase associated with EGFR, has demonstrated efficacy in nonsmall cell lung cancer and pancreatic cancer.

Other receptors such as the vascular endothelial growth factor (VEGF) receptor are stimulated by an increase in VEGF, which in turn is stimulated, among other things, by hypoxia and tumor cell products. The result is to increase angiogenesis and facilitate further tumor growth. Inhibitors of VEGF receptor tyrosine kinases (RTKs) (as well as other receptor tyrosine kinases), such as sunitinib, result in prolonged time to progression in gastrointestinal stromal tumors (GISTs) that have shown progression during prior treatment with imatinib or in patients who are intolerant to imatinib, and renal cell carcinoma.

3. Monoclonal antibodies. 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, 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-

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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.

F. Miscellaneous agents Miscellaneous agents are listed in Table 4.1. Descriptions of specific agents are found in Section III of this chapter.

II. Clinically useful chemotherapeutic and biologic agents Section III of this chapter contains an alphabetically arranged description of the chemotherapeutic and biologic 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, FDANational Cancer Institute (NCI) 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 fromthe 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 confirmand 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 the 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):

1. Universal (90%100%)

2. Common (15%90%)

3. Occasional (5%15%)

4. Uncommon (1%5%)

5. Rare (

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, and 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 chemotherapeutic agents have a steep doseresponse curve; therefore, if no toxicity is seen, as a rule, a higher dose 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 vs. no cure) and on the patient's physical and psychological tolerance for adverse effects.

The general grading scheme for all toxicity is as follows:

0None

1Mild

2Moderate

3Severe

4Life 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 (see Common Terminology Criteria for Adverse Events v3.0 (CTCAE) at http://ctep.cancer.gov/reporting/ctc.html for individual toxicities.) Occasionally, repeating a dose that caused intractable nausea and vomiting or a temperature higher than 40C (104F) is warranted, but for most other grade 3 or 4 toxicity, the subsequent doses should be reduced by 25% to 50%. 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. Nondose-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 (such as dexamethasone or diphenhydramine) or slowing the rate of infusion. For some biologic agents, such as trastuzumab, physiologic effects that look like hypersensitivity reactions occur primarily on first or second doses of treatment and diminish with continued treatment.

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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 myelosuppression, 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 4.2 and 4.3 can serve as a guide to reasonable dose changes for drugs whose major toxicity is myelosuppression. Separate schemes are given for the nitrosoureas and for drugs that have more prolonged myelosuppression.

III. Data for clinically useful chemotherapeutic and biologic agents Note: Although every effort has been made to ensure that the drug dosage and schedules herein are accurate and in accord with published standards, users are advised to check the product information sheet included in the package of each FDA-approved drug and FDA-NCI guidelines for drugs that are not yet approved for general use to verify recommended dosages, contraindications, and precautions.

Agents that have not yet been approved by the FDA are included because they either have some demonstrated usefulness or are widely used in investigational studies. 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.

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Table 4.2 Dose modifications for myelosuppressive drugs with a nadira at less than 3 weeks

Dose as



Degree of Suppression

ANC (WBC)/L on Day of Scheduled Treatmentb

Platelets/Lon Day of Scheduled

Treatment

percentage of

immediately preceding

cycle

Minimal 1, 500(3,500)

and 100, 000 100

Mild 1,2001,500 (3,0003,500)

or 75,000100,000 75

Moderate 1,0001,200 (2,5003,000)

or 50,00075,000 50

Severe

Aldesleukin

Other name 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-.

of scheduled treatmentb

3,500) modified for nadir only

>1,800 (>3,500)

or >100,000 0c

II. At last nadir

>750 and >75,000 100

500750 or 40,00075,000 75

>500 or >40,000 50

III. After 2-wk delay

1,800 (3,500)

and 100,000 Dose modified for nadir only

1,2001,800 (2,5003,500)

or 75,000100,000 75

>1,200 or >75,000 Continue to hold

ANC, absolute neutrophil count; WBC, white blood cell count.

aNitrosoureas or other agents with prolonged nadir.

bANC is the preferred parameter to use. cWithhold treatment and repeat count in 2 wk. At 2 wk, treat on basis of lowest dose indicated by nadir (II) or delay (III) section of table.



Primary indication.

1. Renal cell carcinoma.

2. Melanoma.

Usual dosage and schedule A wide range of doses and routes (IV or 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 x 106 IU/m2) as a 15-min IV infusion every 8 h for up to 14 doses on days 1 to 5. Repeat on days 15 to 19. Repeat cycle in 6 to 12 weeks if the disease is stable or is responding.

2. 18 x 106 IU/m2/24 h as a continuous IV infusion daily for up to 5 days. Repeat in 4 weeks. Repeat cycle in 4 to 6 weeks if the disease is stable or is responding.

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

4. 9 x 106 IU/m2 daily by continuous IV infusion on days 1 to 4 (96 h), together with chemotherapy (cisplatin, vinblastine, dacarbazine) and interferon in melanoma. Schedules 1, 2, and 4 require hospitalization. Schedule 3 can be given in an outpatient setting but may require several hours of observation after treatment.

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 h, 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. Intensive care, controlled volume replacement, and intubation may be required. The lower doses can be given in an outpatient setting.

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 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 with lower-dose schedules.

c. Myocardial injury is seen primarily with 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. Neuropsychiatric effects.

a. Changes in mental status 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 chillsuniversal 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 PO before therapy and every 6 h for one or two doses for outpatient IL-2 dosing; every 6 h for 3 doses for inpatient IL-2 regimens.

2. Cimetidine, 800 mg PO, 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 PO 1.5 h before chills are predicated to start, based on the first treatment.

5. Hydromorphone 0. 5 to 1mg IV, may be substituted for meperidine in patients who tolerate the latter drug poorly.

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

7. Hydroxyzine, 25 to 50 mg every 6 h for itching.

Alemtuzumab

Other names Campath, Campath-1H

Mechanism of action Alemtuzumab is a chimeric (murine and human) monoclonal antibody directed against the CD52 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, and some other somatic cells. Cellular cytotoxicity is mediated through complement-mediated lysis, antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis.

Primary indications

1. B-cell chronic lymphocytic leukemia that has previously been treated with alkylating agents and has failed fludarabine therapy.

2. T-cell prolymphocytic leukemia

3. Multiple myeloma

4. Nonmalignant conditions, including rheumatoid arthritis and graft-versus-host disease

Usual dosage and schedule (Malignant conditions only)

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

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

3. Maintenance. 30 mg as a 2-h IV infusion three times a week on alternate days for 12 weeks.

Infusion-related events (see following text) 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 more than 30 mg and cumulative doses of more 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

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any of its components.

Toxicity

1. Myelosuppression and other hematologic effects. Lymphopenia is universal. Neutropenia, anemia, and thrombocytopenia are common and are 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%2%). Pancytopenia and marrow hypoplasia are uncommon, but may require permanent discontinuation of therapy. Because of the high incidence of opportunistic infections, antiherpes and antiPneumocystis carinii pneumonia (PCP) prophylaxis is recommended.1

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

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

4. Infusion-related events. Rigors, fever, nausea and vomiting, and rashincluding urticariaare common. Shortness of breath, hypotension, bronchospasm, headache, pruritus, and diarrhea are occasional. Angioedema is uncommon.

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, dysesthesias, dizziness, and tremor are occasional.

Alitretinoin

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

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

Primary indication AIDS-related cutaneous Kaposi's sarcoma.

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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 min 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. Pruritus, exfoliative dermatitis, or other erosive or draining skin lesions are occasional.


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, persistent or recurrent after first-line therapy.

Usual dosage and schedule

1. 260 mg/m2 PO 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 PO 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 (MAO) inhibitor class may cause severe orthostatic hypotension. Cimetidine may increase toxicity.

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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-tomoderate nausea, vomiting, and other gastrointestinal effects occur in approximately 30% of patients and are rarely severe. Tolerance may develop.

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


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

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

c. Decreased renal function is occasional.

d. Increased alkaline phosphatase level is occasional.

e. Diarrhea is occasional.

AMIFOSTINE

Other name Ethyol.

Mechanism of action The prodrug, amifostine, is dephosphorylated to an active free thiol metabolite that can reduce the toxic effects of cisplatin. The differential activity between normal and cancer tissues 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.


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



2. For reduction of xerostomia from radiation of the head and neck. 200 mg/m2 administered once daily as a 3-min IV infusion, starting 15 to 30 min before standard-fraction radiation therapy (1.82.0 Gy).

Special precautions To minimize hypotension during the infusion, patients should be adequately hydrated before the amifostine infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 min 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. Skin rash is rare.


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 name 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 indication Adrenocortical carcinoma, ectopic Cushing's syndrome.

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Usual dosage and schedule 1,000 mg PO daily in four divided doses.

Special precautions Hydrocortisone must be given concomitantly to prevent adrenal insufficiency, particularly if used in breast cancer. Suggested dose is 100 mg PO daily in divided doses for 2 weeks, and then 40 mg PO daily in divided doses.

Toxicity

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

2. Nausea, vomiting, and other gastrointestinal effects are occasional and 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. Hormonal effects.

a. Adrenal insufficiency is common without replacement hydrocortisone 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.


a. Facial flushing is uncommon.

b. Periorbital edema is uncommon.

c. Cholestatic jaundice is rare.

d. Fever is uncommon.

Anagrelide

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

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

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

Usual dosage and schedule (Supplied as 0.5- and 1-mg capsules)

1. 0.5 mg PO q.i.d. or 1 mg PO b.i.d. Increase by 0.5 mg/day 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 PO daily; increase by 0.5 mg each week.

b. Abnormal renal or hepatic function. 0.5 mg PO b.i.d.

Special precautions Contraindicated in pregnancy. 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 h before and after anagrelide is taken. Use other drugs that inhibit platelet aggregation (such as nonsteroidal anti-inflammatory drugs) with caution. Monitor platelet count every few days during first week, and then weekly until the maintenance dose is reached.

Toxicity

1. Myelosuppression. No White cell count suppression. Anemia is common (36%) but mild. Thrombocytopenic hemorrhage is uncommon (2%).

2. Nausea and vomiting. Nausea is occasional (15%), and vomiting is uncommon.

3. Mucocutaneous effects. Rash, including urticaria is occasional (8%). Hyperpigmentation is rare. Sun sensitivity is possible.


a. Cardiovascular. Palpitations (26%), forceful heart beat, and tachycardia are common. Congestive heart failure is uncommon, but fluid retention or edema is common (21%). Tachyarrhythmias (including atrial fibrillation and premature atrial beats) are occasional. Angina, cardiomyopathy, or other severe cardiovascular effects are rare, although there are a few 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 (44%) and are occasionally severe; they usually diminish in approximately 2 weeks. Weakness (asthenia) is common (22%). Dizziness is occasional.

c. Pulmonary. Infiltrates are rare but are a reason to stop anagrelide and treat

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with steroids.

d. Other gastrointestinal. Diarrhea (26%), 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.

Anastrozole

Other name Arimidex.

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

Primary indications

1. Carcinoma of the breastas adjuvant treatment in postmenopausal women with positive or unknown hormone receptors.

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

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

Usual dosage and schedule 1 mg PO daily.

Special precautions Potential hazard to fetus if given during pregnancy. Consider obtaining bone mineral density test and treating with calcium and vitamin D, with or without bisphosphonates as clinically indicated.

Toxicity

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

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

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


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



b. Musculoskeletal pain is occasional. Arthralgia is 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 name 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 .

Primary indications

1. Remission induction therapy of acute promyelocytic leukemia that is refractory to retinoid and anthracycline therapy and has t(15;17) translocation or PML/RAR gene expression.

2. Maintenance of remission in acute promyelocytic leukemia.


1. Induction. 0.15 mg/kg IV over 1 to 2 hours daily until marrow remission. Maximum of 60 doses.

2. Consolidation. 0.15 mg/kg IV daily for 25 doses over a period of up to 5 weeks. Consolidation is started 3 to 6 weeks after completion of induction therapy.

Special precautions

1. Cardiovascular. 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 before initiation of therapy and patients with prolonged QT intervals should have measures taken to reduce this prolongation before treatment with arsenic trioxide. A QT value greater than 500 millisecond 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

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prolongation of the QT.

2. 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 b.i.d.) should be started at the first signs of this syndrome and continued until it subsides.

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 types of abdominal distress are occasional.

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


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%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 auscultatory findings are occasional to common (8%20%).

f. Renal. Renal failure is occasional.

Asparaginase

Other names

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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 approximately 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 6,000 IU/m2 of body surface area IM on days 4, 7, 10, 13, 16, 19, 22, 25, and 28 of the treatment period.

2. L-asparaginase. 1,000 IU/kg/day (= 2540 IU/m2) IV for 10 successive days beginning on day 22 of the treatment period.

3. Pegaspargase. 2,500 IU/m2 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 asparaginase. For IM use, limit volume at single injection site to 2 mL. For IV administration, give over 1 to 2 h in saline or D5W.

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 therapy.

1. Be prepared to treat anaphylaxis at each administration of the drug. Epinephrine, antihistamines, corticosteroids, and life-support equipment should be readily available.

2. Giving concurrently with or immediately before vincristine may increase vincristine toxicity.

3. The IM route is preferred for pegaspargase, because of a lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and renal disorders as compared with the IV route of administration.

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Toxicity

1. Myelosuppression and other hematologic effects. Occasional myelosuppression. CNS thrombosis and other coagulopathy are uncommon.

2. Nausea, vomiting, and other gastrointestinal effects. Occasional and usually mild. (See the following text for liver and pancreas effects.)

3. Mucocutaneous effects. No toxicity occurs except as a sign of hypersensitivity.

4. Anaphylaxis. Mild to severe hypersensitivity reactions, including anaphylaxis, 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 coliderived 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 IM, 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 Lasparaginase 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.


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 glutamicoxaloacetic 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, occurs occasionally. 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

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thereby, 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

Usual dosage and schedule 75 mg/m2 SC 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 so long as the patient improves from the drug.

Toxicity

1. Myelosuppression. 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 and vomiting. 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. Pain at the injection site is common.

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


a. Cardiorespiratory. Cough and dyspnea are common. Pulmonary edemauncommon. Edema is occasional. Tachycardia or other more serious cardiac disordersuncommon.

b. Fever is common.

c. Fatigue and weakness are common.

d. Arthralgias and back pain are occasional.

e. Hypokalemia is occasional.

Bevacizumab

Other name Avastin.

Mechanism of action Binds VEGF and prevents its interaction 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 indication



1. Carcinomas of the colon, rectum, breast, and lung.

Usual dosage and schedule Five mg/kg IV once every 2 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 every 2-week dosing) and the half-life of approximately 20 days. Serious, and in some cases fatal, hemoptysis has occurred in nonsmall cell lung cancer, with the highest risk appearing in patients with squamous cell histology. Blood pressure monitoring is recommended every 2 to 3 weeks because of the risk of hypertension. Urinary protein should be evaluated before each treatment with a urine dipstick, and if the value is 2+ or greater, the patient should undergo further assessment to rule out severe proteinuria.

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, except for hemoptysis in patients with squamous cell carcinomas of the lung. Thromboembolic events are occasional.

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. Nasal septum perforation is rare.

4. Immunologic effects and infusion reactions. Infusion reactions with wheezing and stridor are uncommon.


a. Fatigue, weakness, and headache are common

b. Cardiovascular and respiratory. Hypertension is common and occasionally is severe (>200/110 mm Hg). Hypotension is occasional. Dyspnea is occasional. Congestive heart failure is uncommon, but risk with anthracyclines is increased (14%). Venous thromboembolic events are increased by approximately 15% compared with chemotherapy not containing bevacizumab.

c. Neurologic. Dizziness is common. Reversible posterior leukoencephalopathy syndrome is rare.

d. Metabolic. Hypokalemia is occasional. Proteinuria is common, but severe proteinuria (>3.5 g/24 h) is uncommon and rarely leads to nephrotic syndrome.

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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 they 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 but good tolerability after 8 weeks of treatment. Treatment may be continued for up to 2 years.

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

Toxicity

1. Myelosuppression and other hematologic effects. Mild-tomoderate 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.

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 may also be increased skin photosensitivity (e.g., to sun) and the nails may become brittle. Alopecia is uncommon.


a. Cataracts and corneal ulcerations or opacities are uncommon.

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

c. Hypertriglyceridemia (80%) and hypercholesterolemia (35%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, confusion, and mental

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depression are uncommon; pseudotumor cerebri is rare.

e. Gastrointestinal. Inflammatory bowel disease and pancreatitis (associated with hypertriglyceridemia) are rare.

f. Hepatotoxicity with increased lactate dehydrogenase (LDH), SGOT, serum glutamic-pyruvic transaminase (SGPT), gamma glutamyl transpeptidase (GGTP), and alkaline phosphatase is occasional.

g. Hypothyroidism is common, with decreased T4 and thyroidstimulating hormone (TSH).

h. Peripheral edema is occasional.

i. Hypernatremia is rare.

Bexarotene (GEL)

Other name Targretin gel (1%).

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 they 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 (Stage IA and IB) 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. Not expected.

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

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a. Hypertriglyceridemia is occasional.

b. Neurologic. Headache and paresthesias are occasional.

c. Peripheral edema. 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, often in combination with LHRH agonist.

Usual dosage and schedule 50 mg PO daily, in the morning or evening.

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.


a. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot flashes (49%), impotence, and loss of libido are common but reversible after cessation of therapy.

b. Elevated liver function tests are uncommon.

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

d. Dizziness or vertigo is occasional.

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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

1. Testis, head and neck, penis, cervix, vulva, anus, and skin carcinomas.

2. Hodgkin's and nonHodgkin's lymphomas.

3. Pleural effusionsused as sclerosing agent.


1. 10 to 20 units/m2 IV or IM once or twice a week or 2. 30 units IV push weekly for 9 to 12 weeks in combination with other drugs for testis cancer.

2. 60 units in 50 mL of normal saline instilled intrapleurally.

Special precautions

1. In patients with lymphoma, a test dose of 1 or 2 units should be given IM before the first dose of bleomycin because of the possibility of anaphylactoid, acute pulmonary or severe hyperpyretic responses. If no acute reaction occurs within 4 h, regular dosing may begin.

2. Reduce dose for renal failure.

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 preexisting 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 FIo2 (fraction of inspired oxygen) (such as might be used during surgery) should be avoided as it exacerbates lung injury, sometimes acutely.

Serum creatinine % of full dose



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. Occasional and self-limiting.

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

4. Pulmonary effects.

a. Acute anaphylactoid or pulmonary edemalike response is occasional in patients with lymphoma (see Special precautions, in the preceding text).

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.


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

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

Bortezomib

Other name Velcade.

2.54.0 25

4.06.0 20

6.010.0 10

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Mechanism of action A reversible inhibitor of the chymotrypsin-like activity of the 26S proteosome, which mediates protein degradation and plays an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis.

Primary indications

1. Multiple myeloma in patients with at least one prior therapy.

2. Mantle cell lymphoma in patients with at least one prior therapy.


1. 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11, every 3 weeks.

2. After eight cycles, may use 1.3 mg/m2 IV bolus weekly x 4, every 5 weeks.

Special precautions Cardiogenic shock, congestive heart failure, and respiratory insufficiency have been rarely observed. Anaphylaxis has also been observed. Patients with hepatic or renal impairment should be monitored closely.

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 and vomiting. 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 frequently manifests as paresthesias and dysesthesias. Headache is common.

5. Immunologic effects. Hypersensitivity reactions have been seen, including anaphylactic reactions and immune complexmediated hypersensitivity (rare).


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 be orthostatic or not. Peripheral edema is common. Other cardiovascular events during treatment have included severe congestive heart failure, AV block,



angina, atrial fibrillation, and flutterthese are probably uncommon to rare as a consequence of the drug.

e. Infiltrative pulmonary diseaserare, but may be severe or fatal.

f. Hepatitis and pancreatitis have been observedprobably 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. Chronic granulocytic (myelogenous) leukemia.

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


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

2. High doses with stem cell rescueconsult specific protocols. Not recommended outside research setting. Typical dose is 1 mg/kg PO q6h for 4 consecutive days. Alternative dosing of intravenous form (Busulfex) is 0.8 mg/kg of ideal body weight (or actual if lower) as a 2-h infusion through a central catheter every 6 h for 4 days (16 doses). 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/L, 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

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stem cell rescue (e.g., bone marrow transplantation).

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

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

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

5. Metabolic effects. Adrenal insufficiency syndrome is rare. Hyperuricemia may occur when the leukemia cell count is rapidly reduced. Ovarian suppression and amenorrhea are common.


a. Secondary neoplasia is possible.

b. Fatal hepatoveno-occlusive disease with high-dose therapy is occasional.

c. Seizures after high-dose therapy 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 chemotherapeutic regimens. May also be used in patients in whom anthracyclines are contraindicated.

2. Colorectal, stomach, pancreas, and biliary carcinomas.

3. As a radiosensitizer in lieu of fluorouracil.

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

1. 1,000 to 1,250 mg/m2 orally twice daily for 2 weeks as a single agent, followed by a 1-

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week rest, given as 3-week cycles.

2. 800 to 1,250 mg/m2 orally twice daily for 2 weeks when used in combination with other drugs, followed by 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 Patients with moderate renal impairment (CCr 30 to 50 mL/min) require a 25% dosage reduction: diarrhea may be severe and necessitate 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. Increase in prothrombin time (PT) and INR may be seen in patients previously stable on oral anticoagulants. Monitor PT/INR more frequently when patient is on capecitabine.

Toxicity

1. Myelosuppression and other hematologic effects. Common, but when used as a single agent, these are usually 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-and-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.


a. Fatigue is common.

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

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Covalent binding to DNA.

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

Usual dosage and schedule AUC(area-under-the-curve) 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) x ([creatinine clearance] +25). Administration dose is given by IV infusion over 15 to 60 min, and repeated every 4 weeks.

2. Higher doses up to 1,600 mg/m2 divided over several days have been used followed by stem cell rescue (e.g., bone marrow transplantatio

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Chemotherapy Drugs