4 - Antineoplastic Drugs and Biologic Response Modifiers

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: Classification, Use, and Toxicity of Clinically Useful Agents

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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 cycle specific and in some instances primarily cell cycle

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phase 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.

Table 4.1 Useful chemotherapeutic agents

Class and Type Agents
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
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 hormone releasing 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
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.

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

  • 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 cycle nonspecific.

  • Types of alkylating agents

    • 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.

    • 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.

    • 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.

    • Triazines. Dacarbazine, the only agent of this type, was originally thought to be an antimetabolite because of its resemblance to 5-aminoimidazole-4-carboxamide.

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

    • Nitrosoureas. 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).

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

B. Antimetabolites

  • General description. 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 the inhibition of DNA synthesis and ultimate cell death. Because of their primary effect on DNA synthesis, antimetabolites are most active in cells that are actively growing and are largely cell cycle phase specific.

  • Types of antimetabolites

    • Folic acid analogs. Methotrexate, the dominant member of this group, inhibits the enzyme dihydrofolate reductase. This inhibition blocks the production of reduced N-methylenetetrahydrofolate, 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. Ralitrexed (Tomudex) is a quinazoline antifolate that is an inhibitor of thymidylate synthase. Pemetrexed is a multitargeted pyrrolopyrimidine-based antifolate that, when polyglutamated, inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyl-transferase.

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

    • 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

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      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

  • 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.

  • Types of natural products

    • 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.

    • 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.

    • 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.

    • 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.

      • 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.

      • Bleomycins cause DNA strand scission. The resulting fragmentation is believed to underlie the cytotoxic activity of the drug.

      • Mitomycin causes cross-links between complementary strands of DNA that impair replication.

    • 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.

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D. Hormones and hormone antagonists

  • 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, 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 [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 pituitary regulating 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.

  • Types of hormones and hormone antagonists

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

    • Antiandrogens inhibit nuclear androgen binding.

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

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

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

    • 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.

    • 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

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      letrozole primarily block the conversion of adrenally generated androstenedione to estrone by aromatase in peripheral tissues without inhibition of progesterone or corticosteroid synthesis.

    • Hypothalamic hormone analogs, such as the luteinizing hormone releasing 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.

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

E. Molecularly targeted agents

  • 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.

  • 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 non small 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.

  • 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,

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    trastuzumab) or conjugated with radionuclides (ibritumomab tiuxetan, tositumomab) or another toxic moiety (gemtuzumab).

  • 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.

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, FDA National 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):

  • Universal (90% 100%)

  • Common (15% 90%)

  • Occasional (5% 15%)

  • Uncommon (1% 5%)

  • Rare (<1%)

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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

  • Philosophy. The optimal dose and schedule of a drug are those that give maximum benefit with tolerable toxicity. Most chemotherapeutic agents have a steep dose response 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:

    • 0 None

    • 1 Mild

    • 2 Moderate

    • 3 Severe

    • 4 Life threatening

  • Guidelines

    • Nonhematologic toxicity

      • 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. 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 (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

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        occur primarily on first or second doses of treatment and diminish with continued treatment.

      • 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.

    • 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

Degree of Suppression ANC (WBC)/ L on Day of Scheduled Treatmentb   Platelets/ Lon Day of Scheduled Treatment Dose as percentage of immediately preceding cycle
Minimal 1, 500( 3,500) and 100, 000 100
Mild 1,200 1,500 (3,000 3,500) or 75,000 100,000 75
Moderate 1,000 1,200 (2,500 3,000) or 50,000 75,000 50
Severe <1, 000 (<2, 500) or <50, 000 0 (delay 1 wk)
ANC, absolute neutrophil count; WBC, white blood cell count.
aIf the nadir of ANC is <1,000/ L and is associated with fever of >38.3 C (101F) or the nadir of platelets is <40,000/ L, decrease dose by 25% in subsequent cycles. If the dose is already to be reduced on the basis of the ANC or platelet count on the day of treatment as per this table, do not reduce further because of the nadir count.
bANC is the preferred parameter, if available. If counts are rising at the end of a treatment cycle, it is often appropriate to delay 1 wk and then treat according to the dose modification scheme shown here.

Table 4.3 Dose modifications for myelosuppressive drugsa with a nadir at 3 weeks or later

Point in Time ANC (WBC)/ L   Platelets/ L Dose as Percentage of Immediately P receding Cycle
I. On day of scheduled treatmentb 1,800( 3,500) and 100,000 Dose modified for nadir only
>1,800 (>3,500) or >100,000 0c
II. At last nadir >750 and >75,000 100
500 750 or 40,000 75,000 75
>500 or >40,000 50
III. After 2-wk delay 1,800 ( 3,500) and 100,000 Dose modified for nadir only
1,200 1,800 (2,500 3,500) or 75,000 100,000 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.

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- .

Primary indication.

  • Renal cell carcinoma.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects.

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

    • Transient liver function abnormalities, including hyperbilirubinemia, and hypoalbuminemia and elevation of the prothrombin time and partial thromboplastin time are common.

    • Colonic perforations are rare.

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

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  • Cardiovascular effects.

    • Arrhythmias are common and dose-related.

    • Hypotension is dose-related but is occasionally seen with lower-dose schedules.

    • Myocardial injury is seen primarily with higher-dose schedules.

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

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

  • Neuropsychiatric effects.

    • Changes in mental status are common, with dose-related severity.

    • Dizziness or light-headedness is common.

    • Blurry vision and other visual disturbances are occasional.

    • Seizures are uncommon to rare at lower-dose regimens.

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

  • Fever. With or without chills universal and may be severe.

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

  • Myalgias and arthralgias. Occasional to common.

  • Malaise and fatigue. Common and dose related.

Prophylaxis of acute toxicity

  • 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.

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

  • Antiemetics. Granisetron, ondansetron, or other 5HT3 antagonist, metoclopramide, and prochlorperazine may be used. Do not use dexamethasone.

  • 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.

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

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

  • 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,

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antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis.

Primary indications

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

  • T-cell prolymphocytic leukemia

  • Multiple myeloma

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

Usual dosage and schedule

(Malignant conditions only)

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

  • 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.

  • 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 any of its components.

Toxicity

  • 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 anti Pneumocystis carinii pneumonia (PCP) prophylaxis is recommended.1

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

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

  • Infusion-related events. Rigors, fever, nausea and vomiting, and rash including urticaria are common. Shortness of breath, hypotension, bronchospasm, headache, pruritus, and diarrhea are occasional. Angioedema is uncommon.

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  • Miscellaneous effects.

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

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

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

    • 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 acid binding 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.

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

  • Myelosuppression and other hematologic effects. None.

  • Nausea, vomiting, and other gastrointestinal effects. None

  • 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.

  • Miscellaneous effects.

    • Neurologic complaints of burning or pain are common.

    • 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

  • 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.

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  • 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.

Toxicity

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

  • 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.

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

  • Miscellaneous effects.

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

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

    • Decreased renal function is occasional.

    • Increased alkaline phosphatase level is occasional.

    • 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

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

  • 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

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

  • 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 (1.8 2.0 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.

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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

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

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

  • Mucocutaneous effects. Skin rash is rare.

  • Miscellaneous effects.

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

    • Flushing and feeling of warmth are occasional.

    • Chilling and feeling of coldness are occasional.

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

    • Allergic reactions are rare but have included anaphylactic reactions.

    • Hypocalcemia is rare.

    • 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.

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

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

  • Nausea, vomiting, and other gastrointestinal effects are occasional and usually mild.

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

  • Hormonal effects.

    • Adrenal insufficiency is common without replacement hydrocortisone in patients with normal adrenal glands.

    • Hypothyroidism is uncommon.

    • Masculinization is possible.

  • Neurologic effects.

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

    • Vertigo, nystagmus, and ataxia are occasional.

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  • Miscellaneous effects.

    • Facial flushing is uncommon.

    • Periorbital edema is uncommon.

    • Cholestatic jaundice is rare.

    • 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.

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)

  • 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.

  • Alternate dosing schedules:

    • Elderly. 0.5 mg PO daily; increase by 0.5 mg each week.

    • 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

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

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

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

  • Miscellaneous effects.

    • 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.

    • Neurologic. Headaches are common (44%) and are occasionally severe; they usually diminish in approximately

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      2 weeks. Weakness (asthenia) is common (22%). Dizziness is occasional.

    • Pulmonary. Infiltrates are rare but are a reason to stop anagrelide and treat with steroids.

    • 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

  • Carcinoma of the breast as adjuvant treatment in postmenopausal women with positive or unknown hormone receptors.

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

  • Carcinoma of the breast that is advanced or metastatic as 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

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

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

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

  • Miscellaneous effects.

    • Asthenia is common. Headache and dizziness are occasional.

    • Musculoskeletal pain is occasional. Arthralgia is occasional.

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

    • Dyspnea and cough are occasional.

    • Cataracts are occasional (6%).

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

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

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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

  • 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.

  • Maintenance of remission in acute promyelocytic leukemia.

Usual dosage and schedule

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

  • 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

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

Toxicity

  • 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.

  • 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.

  • 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.

  • Miscellaneous effects.

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

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    • 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.

    • 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.

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

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

    • 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 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.

  • 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.

  • L-asparaginase. 1,000 IU/kg/day (= 25 40 IU/m2) IV for 10 successive days beginning on day 22 of the treatment period.

  • 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

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had previous serious allergic reactions, such as generalized urticaria, bronchospasm, laryngeal edema, hypotension, or other unacceptable adverse reactions to prior pegaspargase therapy.

  • 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 as compared with the IV route of administration.

Toxicity

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

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

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

  • 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 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 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.

  • Miscellaneous effects.

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

    • 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.

    • Renal failure is rare.

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

    • CNS effects (depression, somnolence, fatigue, confusion, agitation, hallucinations, or coma) are seen occasionally.

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    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 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

  • 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.

  • Nausea and vomiting. Anorexia, nausea, vomiting, and diarrhea or constipation are common. Abdominal pain is occasional.

  • Mucocutaneous effects. Pharyngitis and stomatitis are occasional. Skin rash and urticaria are occasional. Pain at the injection site is common.

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

  • Miscellaneous effects.

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

    • Fever is common.

    • Fatigue and weakness are common.

    • Arthralgias and back pain are occasional.

    • 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

  • 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

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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 non small 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

  • 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.

  • 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.

  • 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.

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

  • Miscellaneous effects.

    • Fatigue, weakness, and headache are common

    • 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.

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

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

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.

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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

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Mild nausea, abdominal pain, and diarrhea are occasional. Vomiting and anorexia are uncommon.

  • 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.

  • Miscellaneous effects.

    • Cataracts and corneal ulcerations or opacities are uncommon.

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

    • 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.

    • Neurologic. Headache is common. Lethargy, fatigue, confusion, and mental depression are uncommon; pseudotumor cerebri is rare.

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

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

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

    • Peripheral edema is occasional.

    • 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.

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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

  • Myelosuppression and other hematologic effects. Uncommon.

  • Nausea, vomiting, and other gastrointestinal effects. Not expected.

  • 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).

  • Miscellaneous effects.

    • Hypertriglyceridemia is occasional.

    • Neurologic. Headache and paresthesias are occasional.

    • 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

  • Myelosuppression and other hematologic effects. No myelosuppression. May interact with warfarin, and increase international normalized ratio (INR).

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

  • Mucocutaneous effects. Mild skin rash is occasional.

  • Miscellaneous effects.

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

    • Elevated liver function tests are uncommon.

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

    • 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

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

  • Hodgkin's and non Hodgkin's lymphomas.

  • Pleural effusions used as sclerosing agent.

Usual dosage and schedule

  • 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.

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

Special precautions

  • 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.

  • Reduce dose for renal failure.

  • 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.

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

  • 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
2.5 4.0 25
4.0 6.0 20
6.0 10.0 10

Toxicity

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

  • Nausea, vomiting, and other gastrointestinal effects. Occasional and self-limiting.

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

  • Pulmonary effects.

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

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

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

  • Miscellaneous effects.

    • Lethargy, headache, and joint swelling are rare.

    • 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 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

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

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

Usual dosage and schedule

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

  • 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

  • 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).

  • 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.

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

  • Neurotoxicity. Peripheral neuropathy is common, and occasionally (7%) severe. This frequently manifests as paresthesias and dysesthesias. Headache is common.

  • Immunologic effects. Hypersensitivity reactions have been seen, including anaphylactic reactions and immune complex mediated hypersensitivity (rare).

  • Miscellaneous effects.

    • Fatigue and weakness are common.

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

    • Fever is common.

    • 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 flutter these

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      are probably uncommon to rare as a consequence of the drug.

    • Infiltrative pulmonary disease rare, but may be severe or fatal.

    • Hepatitis and pancreatitis have been observed 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

  • Standard doses. Chronic granulocytic (myelogenous) leukemia.

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

Usual dosage and schedule

  • 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.

  • High doses with stem cell rescue consult 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

  • 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).

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

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

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

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

  • Miscellaneous effects.

    • Secondary neoplasia is possible.

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

    • Seizures after high-dose therapy are occasional.

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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

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

  • Colorectal, stomach, pancreas, and biliary carcinomas.

  • 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.

  • 1,000 to 1,250 mg/m2 orally twice daily for 2 weeks as a single agent, followed by a 1-week rest, given as 3-week cycles.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

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  • Miscellaneous effects.

    • Fatigue is common.

    • Paresthesias are occasional.

    • Fever is occasional.

    • Headache or dizziness is occasional.

    • Cardiotoxicity is possible as with any fluorinated pyrimidine.

Carboplatin

Other names

Paraplatin, CBDCA.

Mechanism of action

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.

  • 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.

  • Higher doses up to 1,600 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. Reduced creatinine clearance reduces carboplatin clearance and increases toxicity.

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin administration. Infusion reactions may develop after several months of drug tolerance. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Toxicity

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

  • 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.

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

  • 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.

  • Miscellaneous effects.

    • Peripheral neuropathy or central neurotoxicity is uncommon.

    • Allergic reactions are uncommonly seen with rash, urticaria, pruritus, and rarely bronchospasm and hypotension as infusion reactions.

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    • Cardiovascular (cardiac failure, embolism, cerebrovascular accidents) effects are uncommon.

    • Hemolytic uremic syndrome is rare.

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

  • Systemic therapy.

    • Brain tumors.

    • Hodgkin's and non Hodgkin's lymphomas.

    • Melanoma.

  • Implantable carmustine-impregnated wafer.

    • Glioblastoma multiforme.

Usual dosage and schedule

  • Systemic therapy.

    • 200 to 240 mg/m2 IV as a 30- to 45-min infusion every 6 to 8 weeks. Dose is often divided and given over 2 to 3 days. Some recommend limiting the lifetime cumulative dose to 1,000 mg/m2 to limit pulmonary and renal toxicities.

    • 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).

  • Implantable carmustine-impregnated wafer: up to 8 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 and other hematologic effects (3 to 6 weeks), do not administer the 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

  • Systemic therapy.

    • 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.

    • Nausea, vomiting, and other gastrointestinal effects. Are common, beginning 2 h after therapy and lasting 4 to 6 h.

    • Mucocutaneous effects.

      • 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.

      • Hyperpigmentation of skin after accidental contact is common.

    • Miscellaneous effects.

      • Hepatotoxicity is uncommon but can be severe.

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      • Pulmonary fibrosis is uncommon at low doses, but its frequency increases at cumulative doses higher than 1,000 mg/m2.

      • Secondary neoplasia is possible.

      • Renal toxicity is uncommon at cumulative doses of less than 1,000 mg/m2.

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

  • 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 placebo-treated 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

EGFR antibody, C225, Erbitux.

Mechanism of action

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

Primary indications

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

  • Colon cancer, usually in combination with irinotecan.

Usual dosage and schedule

400 mg/m2 IV loading dose administered over 2 h on day 1. Then 250 mg/m2 IV maintenance doses administered over 1 h weekly thereafter. May be administered in combination with other agents.

Special precautions

Severe anaphylactoid reactions that include cardiac arrest (2%) may occur. One hour of observation is recommended following a cetuximab infusion. Severe hypomagnesemia is seen in 10% to 15% of patients, and all patients should have magnesium levels monitored throughout the systemic persistence of cetuximab (8 weeks).

Toxicity

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

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

  • Mucocutaneous effects. Acne-like rash is common (76%). Stomatitis is occasional when used alone, but universal when used in combination with radiation therapy.

  • Miscellaneous effects.

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

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

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

    • Human antichimeric antibodies (HACAs) are uncommon.

    • 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

  • Chronic lymphocytic leukemia.

  • Low-grade non Hodgkin's lymphoma.

Usual dosage and schedule

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

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

Special precautions

Increased toxicity may occur with prior barbiturate use.

Toxicity

  • Myelosuppression and other hematologic effects. Dose limiting and may be prolonged.

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

  • Mucocutaneous effects. Rash is uncommon.

  • Miscellaneous effects.

    • Liver function abnormalities are rare.

    • Secondary neoplasia is possible.

    • Amenorrhea and azoospermia are common.

    • Drug fever is uncommon.

    • Pulmonary fibrosis is rare.

    • CNS effects including seizure and coma may be 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.

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

  • Soft tissue and bone sarcomas.

  • Non Hodgkin's lymphoma.

Usual dosage and schedule

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

  • 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

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with higher doses (>40 mg/m2) and with additional concurrent nephrotoxic drugs, such as aminoglycosides. At higher doses, diuresis with mannitol with or without furosemide plus vigorous hydration are mandatory.

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

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

    • After 1 h of infusion, give 12.5 g of mannitol by IV push.

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

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

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

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

    • After 1 h of infusion, give 25 g of mannitol by IV push.

    • Continue hydration.

    • After 2 h of hydration, if urinary output is at least 250 mL/h, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 to 2 h (1 mg/m2/min) through the sidearm of the IV, while continuing the hydration.

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

  • 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

  • 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 is often amenable to epoetin therapy.

  • Nausea, vomiting, and other gastrointestinal effects. Severe and often intractable vomiting regularly begins within 1 h of starting cisplatin and lasts for 8 to 12 h. 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 27).

  • Mucocutaneous effects. None.

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  • 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.

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

  • Severe electrolyte abnormalities. These abnormalities, for example, marked hyponatremia, hypomagnesemia, hypocalcemia, and hypokalemia, may be seen up to several days after treatment.

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

  • Miscellaneous effects.

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

    • Hyperuricemia is uncommon, and parallels renal failure.

    • 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 ADA. Accumulates in cells as triphosphate, is incorporated into DNA, and inhibits DNA repair enzymes and RNA synthesis. Also results in NAD depletion. Effect is independent of cell division.

Primary indication

Hairy-cell leukemia, chronic lymphocytic leukemia, Waldenstr m's macroglobulinemia, and possibly other lymphoid neoplasms.

Usual dosage and schedule

  • 0.09 mg/kg (3.33 mg/m2) IV daily as a continuous 7-day infusion.

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

  • 0.14 mg/kg (5.2 mg/m2) SC daily for 5 days.

Special precautions

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

Toxicity

  • Myelosuppression and other hematologic effects. Moderate granulocyte suppression is common. Marrow suppression with leukopenia and thrombocytopenia may be prolonged for more than a year. Serious infection is common. Profound suppression of CD4 and CD8 counts is common and often prolonged for more than 1 year. Opportunistic infections, including herpes, fungus, and pneumocystic infection, may occur and should be watched for. Some routinely use prolonged prophylaxis against one or more of these infections, to include acyclovir 400 mg b.i.d. and trimethoprim sulfamethoxazole, 1 double strength tablet twice daily on 2 or 3 days a week.

  • Nausea, vomiting, and other gastrointestinal effects. Mild nausea with decrease in appetite is common, but no vomiting is expected.

  • P.91


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

  • Miscellaneous effects.

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

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

    • Edema and tachycardia are occasional.

    • 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. Also inhibits DNA polymerases and DNA synthesis. Increases intracellular ara-CTP when used with cytarabine.

Primary indications

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

  • Acute lymphoblastic or acute myelogenous leukemia (AML) in adults.

Usual dosage and schedule

  • 52 mg/m2 IV over 2 h daily for 5 consecutive days; may be repeated in 2 to 6 weeks.

  • 40 mg/m2 IV over 1 h (days 2 6), followed in 4 h by cytarabine 1 g/m2 IV as a 2-h infusion (days 1 5) in AML in adults.

Special precautions

Capillary leak syndrome or systemic inflammatory response syndrome (SIRS) has been observed with clofarabine administration.

Toxicity

  • Myelosuppression and other hematologic effects. Pancytopenia is common. Febrile neutropenia and documented infections are common.

  • 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 4); jaundice is occasional. Anorexia is common.

  • Mucocutaneous effects. Nonspecific dermatitis and pruritus are common. Palmar-plantar erythrodysesthesia is occasional.

  • Miscellaneous effects.

    • Capillary leak syndrome and SIRS may occur following drug administration.

    • Arthralgia and back pain are occasional.

    • Creatinine elevations are uncommon to occasional.

    • Fatigue is common. Lethargy is occasional.

    • Flushing and hypotension are occasional to common. Left ventricular dysfunction is 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.

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Mediated in part by bcl-2 gene and promotion of apoptotic cell death.

Primary indications

  • Acute and chronic lymphocytic leukemia.

  • Hodgkin's and non Hodgkin's lymphomas.

  • Multiple myeloma.

  • Carcinoma of the breast.

  • Cerebral edema or spinal cord injury (compression).

  • Nausea and vomiting from chemotherapy.

Usual dosage and schedule

  • Prednisone. Dose varies with neoplasm and combination. Typical regimen, except for acute lymphocytic leukemia, is as follows.

    • 40 mg/m2 PO days 1 to 14 every 4 weeks or

    • 100 mg/m2 PO days 1 to 5 every 4 weeks.

  • Prednisone. For acute lymphocytic leukemia: 40 to 50 mg/m2 PO daily for 28 days.

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

Special precautions

Monitor for hyperglycemia.

Toxicity

  • Myelosuppression and other hematologic effects. None.

  • 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.

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

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

  • 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. Quadriceps weakness is common with prolonged dosing.

  • Miscellaneous effects.

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

    • Immunosuppression with increased susceptibility to infection is common.

    • 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

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metabolites. The primary effect of cyclophosphamide is probably on DNA.

Primary indications

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

  • Bone and soft tissue sarcomas.

  • Hodgkin's and non Hodgkin's lymphomas.

  • Acute and chronic lymphocytic leukemias.

  • Waldenstr m's macroglobulinemia.

  • Neuroblastoma and Wilms' tumor of childhood.

  • Gestational trophoblastic neoplasms.

  • Multiple myeloma.

Usual dosage and schedule

  • 1,000 to 1,500 mg/m2 IV every 3 to 4 weeks or

  • 400 mg/m2 PO days 1 to 5 every 3 to 4 weeks or

  • 60 to 120 mg/m2 PO daily.

  • High-dose regimens (4 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 the patient empty the bladder several times daily to diminish the likelihood of cystitis.

Toxicity

  • 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.

  • 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.

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

  • 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.

  • Miscellaneous effects.

    • Immunosuppression is common.

    • Amenorrhea and azoospermia are common.

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

    • Interstitial pulmonary fibrosis is rare.

    • Secondary neoplasia is possible.

    • Acute and potentially fatal cardiotoxicity occurs with high dose therapy. Abnormalities include pericardial effusion, congestive heart failure, decreased electrocardiographic (ECG) voltage, 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).

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Mechanism of action

A pyrimidine analog antimetabolite that, when phosphorylated to arabinosyl-cytosinetriphosphate (ara-CTP), is a competitive inhibitor of DNA polymerase.

Primary indications

  • Acute nonlymphocytic leukemia.

  • Meningeal lymphoma or leukemia.

Usual dosage and schedule

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

  • Maintenance. 100 mg/m2 SQ every 12 h for 4 or 5 days every 4 weeks (with other drugs).

  • Intrathecally.

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

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

  • High dose.

    • Induction. 2 to 3 g/m2 IV over 1 to 2 h every 12 h for up to 12 doses.

    • Consolidation. 3 g/m2 IV over 3 h every 12 h on days 1, 3, and 5.

Special precautions

None for standard doses. High dose, give in 1- to 3-h 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)

  • 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.

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

  • Mucocutaneous effects. Stomatitis is seen occasionally.

  • Miscellaneous effects.

    • Flu-like syndrome with fever, arthralgia, and sometimes a rash is occasional.

    • Transient mild hepatic dysfunction is occasional.

Toxicity (high dose)

  • Myelosuppression and other hematologic effects. Universal.

  • Nausea, vomiting, and other gastrointestinal effects. Common.

  • Mucocutaneous effects. Occasional to common mucositis.

  • 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.

  • Conjunctivitis. Hydrocortisone 2 drops OU q.i.d. for 10 days may ameliorate or prevent keratitis.

  • Hepatic toxicity with cholestatic jaundice. Uncommon.

  • Diarrhea. Common.

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.

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Primary indications

  • Melanoma.

  • All soft tissue sarcomas.

  • Hodgkin's lymphoma.

Usual dosage and schedule

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

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

  • 200 mg/m2 IV daily as a continuous 96-h infusion.

Special precautions

  • Administer cautiously to avoid extravasation, as tissue damage may occur.

  • 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 min rather than injecting rapidly. Ice application may also reduce pain.

Toxicity

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

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

  • Mucocutaneous effects.

    • Moderately severe tissue damage if extravasation occurs.

    • Alopecia is uncommon.

    • Erythematous or urticarial rash is uncommon.

  • Miscellaneous effects.

    • Flu-like syndrome with fever, myalgia, and malaise lasting several days is uncommon.

    • Hepatic toxicity is uncommon.

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

  • Gestational trophoblastic neoplasms.

  • Wilms' tumor, childhood rhabdomyosarcoma, and Ewing's sarcoma.

Usual dosage and schedule

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

  • Adults.

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

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

Special precautions

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

  • 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.

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Toxicity

  • Myelosuppression and other hematologic effects. May be dose limiting and severe. It begins within the first week of treatment, but the nadir may not be reached for 21 days.

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

  • 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.

  • Miscellaneous effects.

    • Mental depression is rare.

    • Hepatoveno-occlusive disease, worse with higher doses and shorter schedules, for example, single dose of 2.5 mg versus 5 days at 0.5 mg/day.

Darbepoetin

Other names

Aranesp, darbepoetin .

Mechanism of action

Darbepoetin is an erythropoiesis-stimulating protein, closely related to erythropoietin, which is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. It differs from recombinant human erythropoietin in that it contains five N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains three chains. It has the same biologic activity as endogenous erythropoietin, inducing erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells.

Primary indications

  • Anemia from chemotherapy in patients with nonmyeloid malignancies.

  • Anemia from cancer in patients with nonmyeloid malignancies.

  • Anemia associated with chronic renal failure.

Usual dosage and schedule

Patients with anemia from cancer or chemotherapy:

  • Starting dose of 2. 25 g/kg/week by SC injection, or

  • 500 g by SC injection every 3 weeks.

    Adult patients with chronic renal failure: starting dose of 0.45 g/kg/week by IV or SC injection.

    Dose adjustments of 25% to 40% upward or downward are recommended to keep the hemoglobin below 12.

Special precautions

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

  • Myelosuppression and other hematologic effects. Myelosuppression is not seen, except for rare cases of pure

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    red cell aplasia. Thromboembolic complications are uncommon.

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

  • Mucocutaneous effects. Uncommon rashes or urticaria. Pruritus is occasional.

  • Miscellaneous effects.

    • Cardiovascular. Hypertension may occasionally occur in association with a significant increase in hematocrit; the risk is greatest in patients with preexisting hypertension. Chest pain is uncommon and myocardial infarction is uncommon to rare. Edema is occasional.

    • Neurologic. Seizures, stroke, and transient ischemic attack are rare.

    • Musculoskeletal. Arthralgia and myalgia are occasional.

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

Dasatinib

Other name

SPRYCEL.

Mechanism of action

Inhibition of multiple RTKs, including BCR-ABL and the SRC family. Believed to bind to multiple conformations of the ABL kinase.

Primary indications

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

  • Acute lymphoblastic leukemia (ALL) that is Philadelphia chromosome positive and refractory to prior therapy.

Usual dosage and schedule

70 mg twice daily. Doses are adjusted up or down in 20-mg increments as needed.

Special precautions

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

Toxicity

  • Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common in all patients. Bleeding is common and is occasionally severe, but they are seen primarily in the accelerated or blastic phases. Febrile neutropenia is occasional.

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

  • Mucocutaneous effects. Stomatitis is occasional. Various skin maladies are uncommon.

  • Neurologic effects. Peripheral neuropathy is occasional.

  • Miscellaneous effects.

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

    • Respiratory. Dyspnea, cough, and upper respiratory infections are common.

    • Musculoskeletal pain is common.

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    • Fever and fatigue are common.

    • Hypophosphatemia and hypocalcemia are occasional. Abnormal transaminases or elevated bilirubin are uncommon.

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 indication

Acute nonlymphocytic leukemia, acute lymphocytic leukemia.

Usual dosage and schedule

  • 45 to 60 mg/m2 IV push on days 1, 2, and 3 as induction therapy for 1 or 2 cycles in combination with other drugs.

  • 45 mg/m2 IV push on days 1 and 2 every 4 weeks as consolidation therapy for 1 or 2 cycles in combination with other drugs.

Special precautions

  • Administer over severalminutes into the sidearm of a running IV infusion, taking precautions to avoid extravasation.

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

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

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

Serum bilirubin (mg/dL)   Serum creatinine (mg/dL) % of full dose
1.2 3.0 75
>3.0 or >3.0 50

Toxicity

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

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting occur on the day of administration in one half of patients.

  • 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.

  • 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 less than 45% or

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

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    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.

  • Miscellaneous effects.

    • Red urine caused by the drug and itsmetabolites is common.

    • Chemical phlebitis and phlebothrombosis of veins used for injection are 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 unprotected drug. The agent penetrates tumor tissue and releases the active ingredient daunorubicin. The active drug causes DNA strand breakage mediated by anthracycline effects on topoisomerase II; DNA intercalation; and DNA polymerase inhibition.

Primary indication

Kaposi's sarcoma, advanced, human immunodeficiency virus (HIV) associated.

Usual dosage and schedule

40 mg/m2 IV over 60 min every 2 weeks.

Special precautions

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

  • Do not give if the patient has significantly impaired cardiac function.

  • 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.

  • 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. 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 doxorubicin 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.

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

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

  • Mucocutaneous effects. Alopecia is occasional. Stomatitis is occasional.

  • Miscellaneous effects.

    • Cardiac events, including cardiomyopathy or congestive heart failure may occur and are dose dependent (see Special precautions).

    • Infusion reactions. Acute infusion-associated reactions with back pain, flushing, and tightness in the chest and throat,

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      alone or in combination, have occurred in approximately 14% 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.

    • Generally occur during the first 5 min 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.

    • Fatigue is common.

    • Fever is common.

    • Pain at the injection site is likely after extravasation.

Decitabine

Other name

Dacogen.

Mechanism of action. Pyrimidine analog that inhibits methyl-transferase, 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

  • Myelodysplastic syndromes.

  • Acute myelogenous leukemia in the elderly.

Usual dosage and schedule

15 mg/m2 continuous IV infusion over 3 h, repeated every 8 h for 3 days. This cycle is repeated every 6 weeks for a minimum of four cycles. Therapy may be continued so long as the patient improves from the drug.

Toxicity

  • Myelosuppression?. Neutropenia, thrombocytopenia, and anemia are common. Febrile neutropenia is five times as common as in patients receiving supportive care.

  • Nausea and vomiting. Nausea, vomiting, and diarrhea or constipation occur in approximately one third of patients.

  • Abdominal pain may be associated.

  • Mucocutaneous effects. Stomatitis is occasional. Skin rash is occasional, alopecia is occasional, and urticaria is uncommon.

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

  • Miscellaneous effects.

    • Pulmonary edema is uncommon.

    • Blurred vision is uncommon.

    • Fever is common; infections are occasional.

    • Arthralgias and back pain are occasional.

    • Hypomagnesemia and hypokalemia occur in approximately 25% of patients.

    • Abnormal liver function tests are uncommon.

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.

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Primary indication

Persistent or recurrent CTCL that expresses the CD25 component of IL-2 receptor.

Usual dosage and schedule

9 or 18 g/kg/day (350-700 mg/ m2/day) IV over at least 15 min for 5 consecutive days every 21 days.

Special precautions

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

Toxicity

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

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

  • Mucocutaneous effects. Rashes including generalized macro-papular, petechial, vesicular bullous, urticarial, and eczematous ones may be seen, with both acute and delayed onset.

  • Miscellaneous effects.

    • Severe infections are common.

    • Acute hypersensitivity reactions occur commonly, including hypotension, back pain, dyspnea, vasodilation, rash, chest pain or tightness, and tachycardia. Syncope is uncommon; anaphylaxis is rare.

    • Cardiovascular effects, including hypotension, vasodilation, fluid retention, and tachycardia are common. Hypertension and arrhythmias are occasional.

    • Respiratory reactions of dyspnea, increase in cough, and pharyngitis are common.

    • Vascular leak syndrome is common.

    • Metabolic changes that include hypoalbuminemia, transaminase increase and hypocalcemia are common. Hypokalemia, albuminuria, and increase in creatinine are occasional.

    • Arterial and venous thromboses are uncommon.

    • Flu-like symptoms with chills, fever, headache, and weakness are common. Myalgias and arthralgias are occasional.

    • Loss of visual acuity, usually resulting in permanent visual impairment, uncertain frequency, probably rare to 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 anthracycline-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, for example, 600 mg/m2 of dexrazoxane for

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60 mg/m2 of doxorubicin. Repeat whenever doxorubicin is to be repeated. Administered as a slow injection or rapid infusion over 15 to 30 min.

Special precautions

None.

Toxicity

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

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

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

  • Mucocutaneous effects. No increase observed.

  • Miscellaneous effects.

    • Pain at the injection site is occasional.

    • Hepatic toxicity is possible.

Docetaxel

Other name.

Taxotere.

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 indication

Carcinomas of the breast, stomach, lung, ovary, and prostate.

Usual dosage and schedule

  • 60 to 100 mg/m2 as a 1-h infusion every 3 weeks. Dexamethasone, 8 mg PO b.i.d. 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:

  • 35 mg/m2 as a 1-h infusion weekly. Dexamethasone, 8 mg PO b.i.d. 1 day before and 10 mg IV 30 min before should be given before weeks 1 and 2 of docetaxel to limit the frequency and severity of hypersensitivity reactions. If there are no hypersensitivity reactions in the first 2 weeks, the oral doses given the day before docetaxel may be eliminated.

Special precautions

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

Toxicity

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

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

  • Mucocutaneous effects. Mild mucositis is common; severe mucositis is uncommon. Alopecia is common. Mild-to-moderate cutaneous reactions such as maculopapular eruptions are

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    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.

  • Hypersensitivity reactions. Mild-to-moderate hypersensitivity reactions with flushing, hypotension (or rarely hypertension) with or without dyspnea, and drug fever are occasional; use of the prophylactic regimen recommended. Severe hypersensitivity reactions are uncommon.

  • Miscellaneous effects.

    • 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.

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

    • Hepatic. Reversible increases in transaminase, alkaline phosphatase, and bilirubin.

    • Local reactions. Reversible peripheral phlebitis.

    • Mild diarrhea is common; severe diarrhea is rare.

    • 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

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

  • Bone and soft tissue sarcomas.

  • Hodgkin's and non Hodgkin's lymphomas.

  • Multiple myeloma.

  • Acute lymphocytic and acute nonlymphocytic leukemias.

  • Wilms' tumor, neuroblastoma, and rhabdomyosarcoma of childhood.

Usual dosage and schedule

  • 60 to 75 mg/m2 IV every 3 weeks. (Or as 96-h continuous infusion.)

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

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

  • 15 to 20 mg/m2 IV weekly.

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

Special precautions

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

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

  • Do not exceed a lifetime cumulative dose of 550 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.

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

    • For serum bilirubin of 1. 2 to 3.0 mg/dL, give one half the normal dose.

    • For serum bilirubin of more than 3. 0mg/dL, give one fourth the normal dose.

Toxicity

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Mild to moderate in approximately one half of patients.

  • 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 the veins used for drug injection in which chemical phlebitis has occurred is common.

  • 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 550mg/m2. This limit is lower (450 mg/m2) if the patient has received prior chest radiotherapy or is taking cyclophosphamide concomitantly. Weekly schedule and 96-h 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 less than 45% or

    • To 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 usually not serious.

  • Miscellaneous effects.

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

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

  • Fever, chills, and urticaria are uncommon.

Doxorubicin, liposomal

Other name

Doxil.

Mechanism of action

Doxorubicin, liposomal, 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. The active drug causes DNA strand breakage mediated by anthracycline effects on topoisomerase II, DNA intercalation, and DNA polymerase inhibition.

Primary indications

  • Kaposi's sarcoma, advanced, HIV associated.

  • Ovarian and breast carcinomas.

  • Multiple myeloma.

Usual dosage and schedule

  • 20 mg/m2 IV infusion at a rate of 1 mg/min for the first dose, then over 30 min for subsequent doses every 3 weeks for Kaposi's sarcoma.

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

  • 40 mg/m2 IV infusion at a rate of 1 mg/min for the first dose, then over 1 h every 4 weeks for multiple myeloma, together with vincristine and dexamethasone.

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 may cause marrow or other toxicity.

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

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

  • 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.

  • Miscellaneous effects.

    • 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.

    • 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

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      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.

    • Asthenia is occasional.

    • Fever is occasional.

    • 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

  • Carcinomas of the breast, esophagus, lung, ovary, and stomach.

  • Hodgkin's and non Hodgkin's lymphoma.

  • Soft tissue sarcomas.

Usual dosage and schedule

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

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

Special precautions

  • Take care to avoid extravasation.

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

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

    • For serum bilirubin of 1. 2 to 3.0 mg/dL, give half the normal dose.

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

Toxicity

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

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

  • Mucocutaneous effects.

    • Stomatitis that is dose dependent.

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

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

    • Severe local tissue damage possibly progressing to skin ulceration and necrosis is common if subcutaneous extravasation occurs.

  • 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 patient has received prior chest radiotherapy or prior anthracycline or anthracenedione therapy.

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    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.

  • Miscellaneous effects.

    • Red-orange urine for 24 h after injection owing to the drug and its metabolites is common.

    • 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.

Epoetin

Other names

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

Mechanism of action

Epoetin- 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 erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells.

Primary indications

  • Anemia from chemotherapy in patients with nonmyeloid malignancies.

  • Anemia associated with malignancy.

  • Anemia associated with chronic renal failure.

  • Anemia associated with zidovudine therapy in 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 there is no response to this dose, it should be discontinued.

Responders may do well with alternate schedules, such as 80,000 units every other week.

Special precautions

  • Iron supplementation is beneficial if there is any question of body iron stores. If at any time the hematocrit rises above 40%, hold epoetin injections until the hematocrit falls to 36% or less and reinitiate at a lower dose or a longer interval.

  • Contraindicated in patients with uncontrolled hypertension or known hypersensitivity to albumin or mammalian cell-derived products. Pure red cell aplasia may occur.

Toxicity

  • Myelosuppression. None. Therapeutic effect is an increase in hemoglobin.

  • Nausea and vomiting. None.

  • Mucocutaneous effects. Rare rashes or hives.

  • Miscellaneous effects.

    • Improved energy level, activity level, and self-rated quality of life scores occur in patients receiving therapy.

    • Edema is occasional.

    • Diarrhea is occasional.

    • A rise in blood pressure occurs in approximately 25% of patients. Hypertensionmay rarely occur in association with a significant increase in hematocrit; the risk is greatest

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      in patients with preexisting hypertension. Chest pain is uncommon; edema is occasional.

    • Seizures are rare.

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

    • Thrombotic complications are uncommon.

    • Pure red cell aplasia is rare.

Erlotinib

Other name

Tarceva.

Mechanism of action

Inhibits intracellular phosphorylation of the tyrosine kinase associated with EGFR.

Primary indications

  • Non small cell lung cancer, as monotherapy.

  • Pancreatic cancer (with gemcitabine).

Usual dosage and schedule

  • 150 mg PO daily, at least 1 h before or 2 h after food. Give with caution if liver impairment is present.

  • 200 mg PO daily when given with gemcitabine or other cytotoxic agents.

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. 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.

Toxicity

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

  • 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.

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

  • Miscellaneous effects.

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

    • Bone pain and myalgia are common.

    • Dyspnea is common, cough is occasional.

    • Anxiety and neuropathy are occasional.

Estrogens

Other names

Diethylstilbestrol (DES), chlorotrianisene (TACE), DES diphosphate (Stilphostrol), and others.

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Mechanism of action

Suppression of testosterone production through negative feedback on hypothalamus.

Primary indication

Prostate carcinoma.

Usual dosage and schedule

  • DES, 1 to 3 mg PO daily.

  • TACE, 12 to 25 mg PO daily.

Special precautions

  • Acute fluid retention and pulmonary edema are possible, particularly with high-dose IV therapy (rarely used now).

  • Hypercalcemia may occur with initial therapy.

Toxicity

  • Myelosuppression and other hematologic effects. None.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea with possible vomiting is common at the beginning of therapy but diminishes or stops with continued treatment. Severity may be lessened by beginning treatment with doses lower than those recommended. Diarrhea is uncommon.

  • Mucocutaneous effects. Darkening of nipples is common.

  • Miscellaneous effects.

    • Peripheral edema due to sodium retention is common, but congestive heart failure occurs in fewer than 5%of patients.

    • Any patient on estrogens may be at a higher risk than normal for thromboemboli. An increase in cardiovascular deaths has been seen in male patients given DES at 5 mg daily for prostate carcinoma.

    • Increased bone pain, tumor pain, and local disease flare are associated with both good tumor response and tumor progression.

    • Feminization with gynecomastia occurs in male patients.

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

  • Small cell anaplastic and non small cell lung carcinomas.

  • Stomach carcinoma.

  • Germ cell cancers.

  • Lymphomas.

  • Acute leukemia.

  • Neuroblastoma.

Usual dosage and schedule

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

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

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

  • 50 mg/m2 PO daily for 21 days. Repeat after 1 to 2 weeks' rest.

  • High-dose therapy (750 to 2,400 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

  • Administer etoposide as a 30- to 60-min infusion to avoid severe hypotension. Monitor blood pressure during infusion.

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    Etoposide phosphate may be administered as a 5-min bolus infusion.

  • Take care to avoid extravasation.

  • 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.

  • Decrease dose by 50% for bilirubin levels of 1. 5 to 3 mg/dL; decrease by 75% for bilirubin levels of 3 to 5mg/dL; discontinue drug if bilirubin level is more than 5 mg/dL.

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

Toxicity

  • 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.

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

  • Mucocutaneous effects.

    • Alopecia is common.

    • Stomatitis is uncommonwith standard doses; common with high-dose therapy.

    • Painful rash may occur with high-dose therapy.

    • Chemical phlebitis is occasional.

  • Miscellaneous effects.

    • Hepatotoxicity is rare.

    • Peripheral neurotoxicity is rare.

    • Allergic reaction is rare.

    • Hemorrhagic cystitis may occur with high-dose therapy.

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

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

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

Usual dosage and schedule

25 mg PO once daily after meal.

Special Precautions

Potential hazard to fetus if given during pregnancy.

Toxicity

  • Myelosuppression and other hematologic effects. No doserelated effect. Thromboembolic events are uncommon to rare.

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

  • Mucocutaneous effects. Rash is uncommon.

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  • Miscellaneous effects.

    • Fatigue is occasional.

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

    • Headache is occasional.

    • Peripheral edema, weight gain is occasional.

    • Dyspnea and cough are uncommon to occasional.

    • Hot flashes are occasional.

    • Decreased bone mineral density with osteoporosis is occasional and there is increased risk for fractures.

    • 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

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

  • Treatment of granulocytopenia secondary to chemotherapy.

  • Granulocytopenia from primary marrow disorders, such as idiopathic neutropenia and aplastic anemia, and myelodysplastic syndrome.

  • Granulocytopenia associated with acquired immunodeficiency syndrome (AIDS) and its therapy.

Usual dosage and schedule

  • Adjunct to chemotherapy. Commonly 200 to 400 g/m2 (5-10 g/kg) SQ daily, starting no sooner than 24 h and no later than 4 days after the last dose of chemotherapy, for 10 to 20 days until the neutrophil count exceeds 10,000/ L 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 g daily and patients weighing more than 75 kg with 480 g daily.

  • Other purposes. 40 to 500 g/m2 SQ, 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, because it may promote growth of leukemic cells.

Toxicity

  • Myelosuppression. None (leukocytosis).

  • Nausea and vomiting. Rare.

  • Mucocutaneous effects. Exacerbation of preexisting dermatologic conditions are occasional; pyoderma gangrenosum is rare.

  • Miscellaneous effects. Usually mild and short lived.

    • Bone pain, musculoskeletal symptoms such as cramps, and back or leg pain is common.

    • Splenomegaly with prolonged use.

    • Exacerbation of preexisting inflammatory or autoimmune disorders is rare.

    • Mild elevation of LDH and alkaline phosphatase.

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Floxuridine

Other name

FUDR

Mechanism of action

A pyrimidine antimetabolite that, when converted to the active nucleotide, inhibits the enzyme thymidylate synthetase.

Primary indication

Hepatic metastasis of gastrointestinal carcinoma, primary hepatic carcinoma.

Usual dosage and schedule

4.0 to 6.0 mg/m2 as a continuous infusion into the hepatic artery daily for 2 weeks, then off for 2 weeks. Administered through continuous infusion pump.

Special precautions

  • Reduce dose in patients with compromised liver function.

  • Ulcer-like pain or other significant gastrointestinal symptoms are indications to discontinue intra-arterial therapy, as hemorrhage or perforation may occur.

Toxicity

  • Myelosuppression and other hematologic effects. Uncommon.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are uncommon unless the hepatic artery catheter has become displaced and the stomach and duodenum are being infused. Abdominal cramps and pain are common if the catheter is displaced and the stomach and duodenum are being infused. Can progress to frank gastritis or duodenal ulcer. Esophagitis, proctitis, and diarrhea may also occur.

  • Mucocutaneous effects.

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

    • Partial alopecia is uncommon.

    • Hyperpigmentation of skin over face, hands, and the vein used for the infusion is occasional.

    • Maculopapular rash is uncommon.

    • Sun exposure tends to increase skin reactions.

  • Miscellaneous effects.

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

    • Increased lacrimation is uncommon.

    • Liver function abnormalities and jaundice are common when given by hepatic arterial infusion. Dose should be reduced during subsequent cycle.

    • Sclerosing cholangitis when given by hepatic artery infusion is uncommon.

Fludarabine

Other names

FAMP, Fludara.

Mechanism of action

Inhibition of DNA polymerase , ribonucleotide reductase, and DNA primase.

Primary indications

  • Chronic lymphocytic leukemia (B cell).

  • Macroglobulinemia.

  • Indolent lymphomas.

  • Acute leukemia (in combination).

Usual dosage and schedule

25 mg/m2 IV as a 30-min infusion daily for 5 days. Other dose schedules, usually less intensive,

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have been used, often in combinations with other drugs. Repeat every 4 weeks.

Special precautions

If there is the potential for tumor lysis syndrome, administer allopurinol and ensure good hydration and close clinical monitoring. Transfusion-associated graft-versushost disease may be seen. Therefore, prior irradiation of blood products for transfusion in patients at risk is recommended. Sometimes 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 chronic lymphocytic leukemia. Not recommended for use in combination with pentostatin because of the 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

  • Myelosuppression and other hematologic effects. Granulocytopenia and thrombocytopenia are common but appear to become less common in patients whose disease is responding. Infection, particularly pneumonia, is common during initial courses and uncommon after the sixth course. Autoimmune hemolytic anemia.

  • Nausea and vomiting. Common (30%) but not usually severe.

  • Mucocutaneous effects. Occasional mucositis, rash, no alopecia.

  • 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.

  • Immune suppression. Common. Usually seen as a depression in CD4 and CD8 lymphocyte counts. Opportunistic infections may result, and many recommend pneumocystis pneumonia prophylaxis until the CD4 lymphopenia resolves.

  • Miscellaneous effects.

    • Abnormal liver or renal function is rare.

    • Allergic pneumonitis is occasional to uncommon.

    • Edema is occasional.

    • Diarrhea is occasional.

    • Tumor lysis syndrome is rare.

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

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

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

Usual dosage and schedule

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

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

    • 450 to 600 mg/m2 IV weekly.

    • 200 to 400 mg/m2 daily as a continuous intravenous infusion.

    • 1,000 mg/m2 daily for 4 days as a continuous IV infusion every 3 to 4 weeks.

    • Leucovorin 20 mg/m2 IV is followed by fluorouracil 425 mg/m2 IV. The combination is given daily for 5 days.

    • Courses are repeated every 4 weeks.

  • Intracavitary. 500 to 1,000 mg for pericardial effusion; 2,000 to 3,000 mg for pleural or peritoneal effusions.

  • Topically. Apply solution or cream twice daily. Use only 5% strength for carcinomas.

Special precautions

  • Reduce dose in patients with compromised liver function.

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

Toxicity

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

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

  • Mucocutaneous effects.

    • 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.

    • Partial alopecia is uncommon.

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

    • Maculopapular rash is uncommon.

    • Sun exposure tends to increase skin reactions.

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

  • Miscellaneous effects.

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

    • Increased lacrimation is uncommon.

    • 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 the prostate cancer cells.

Primary indication

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

Usual dosage and schedule

250 mg PO every 8 h.

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Special precautions

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

Toxicity

  • Myelosuppression and other hematologic effects. None.

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

  • Mucocutaneous effects. Mild skin rash is occasional.

  • Miscellaneous effects.

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

    • Elevated liver function tests are uncommon; liver failure is rare, but may be preceded by flu-like symptoms or right upper quadrant pain and tenderness.

    • Hypertension is occasional.

    • 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 down regulates the estrogen receptor protein in human breast cancer cells. In vitro, there is reversible inhibition of the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines.

Primary indications

  • Hormone receptor positive metastatic breast cancer in post-menopausal women with disease progression following antiestrogen therapy. (There are no efficacy data for premenopausal women with advanced breast cancer.)

  • Hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following therapy with a third-generation aromatase inhibitor.

Usual dosage and schedule

250 mg IM (into the buttock[s]) as either a single 5-mL injection or two concurrent 2.5-mL injections, repeated once monthly.

Special precautions

Safety has not been evaluated in patients with moderate-to-severe hepatic impairment.

Toxicity

  • Myelosuppression and other hematologic effects. Anemia is rare.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea is common; vomiting, constipation, diarrhea, and anorexia are occasional.

  • Mucocutaneous effects. Rash and increased sweating are occasional.

  • Miscellaneous effects.

    • For the body as a whole, headache, back pain, abdominal pain, injection site pain, and pelvic pain are occasional.

    • Occasional patients also experience a flu-like syndrome or fever.

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    • Vasodilation is occasional (18%).

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

    • 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 thereby blocks growth signals within the cell.

Primary indication

Carcinoma of the lung.

Usual dosage and schedule

  • 250 to 500 mg daily. Special precautions. Diarrhea may be dose limiting and may require discontinuation of the drug.

Toxicity

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

  • 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.

  • Mucocutaneous effects. Acne-like 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.

  • Miscellaneous effects.

    • Dyspnea is occasional to common.

    • Asthenia is common.

    • Headache is occasional.

    • Somnolence is occasional.

    • Elevated hepatic transaminases are occasional but may be 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

  • Carcinoma of the pancreas, locally advanced or metastatic.

  • Non small cell carcinomas of the lung.

  • Carcinomas of breast, biliary tract, bladder, and ovary.

  • Non Hodgkin's lymphoma.

  • Soft tissue sarcoma.

Usual dosage and schedule

  • 1,000 mg/m2 IV over 30 min once weekly for up to 7 weeks when used as a single agent. After 1 week of rest, subsequent

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    cycles are given once weekly for 3 consecutive weeks out of 4.

  • 1,000 to 1,250 mg/m2 IV over 30 min once weekly for 2 or 3 successive weeks during each 3- to 4-week cycle, when used in combination regimens.

Special precautions

Prolongation of infusion time beyond 60 min increases toxicity.

Toxicity

  • Myelosuppression and other hematologic effects. Dose related and common.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but only occasionally severe.

  • Diarrhea and constipation are occasional to common.

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

  • Miscellaneous effects.

    • Transient elevations of serum transaminases and alkaline phosphatase are common.

    • Mild proteinuria and hematuria are common.

    • Hemolytic uremic syndrome is rare (0. 25%).

    • Fever without documented infection is common.

    • Neurotoxicity: mild paresthesias are occasional.

    • 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 indications

Patients with CD33-positive acute nonlymphocytic (myeloid) leukemia in first relapse who are older than 60 and are not considered candidates for other cytotoxic chemotherapy.

Usual dosage and schedule

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

Special precautions

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

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

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

  • Tumor lysis syndrome may occur, particularly when the WBC count is higher than 30,000/ L.

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Toxicity

  • Myelosuppression and other hematologic effects. Severe-tolife-threatening granulocytopenia and thrombocytopenia are universal. Severe or worse anemia is common.

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

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

  • Miscellaneous effects.

    • Infusion-related events: chills, fever, headache, nausea, and vomiting are common. Hypotension, hypertension, hyperglycemia, and dyspnea are occasional. Hypoxia is uncommon (~5%).

    • 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.

    • Severe or life-threatening infections are common. These include sepsis, pneumonia, and opportunistic infections.

    • Hypertension, hypotension, and tachycardia are occasional.

    • 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 test values.

Hydroxyurea

Other names

Hydrea, Droxia.

Mechanism of action

Interferes with DNA synthesis, at least in part by inhibiting the enzymatic conversion of ribonucleotides to deoxyribonucleotides.

Primary indications

  • Head and neck carcinomas.

  • Chronic granulocytic (myelogenous) leukemia; acute lymphocytic and acute nonlymphocytic leukemia with high blast counts.

  • Essential thrombocythemia.

  • Polycythemia rubra vera.

  • Prevention of retinoic acid syndrome in acute promyelocytic leukemia.

  • Sickle cell anemia with frequent painful crises.

Usual dosage and schedule

  • 800 to 2,000 mg/m2 PO as a single or divided daily dose or

  • 3,200 mg/m2 PO as a single dose every third day (not for leukemias).

  • Starting dose in sickle cell anemia is 15 mg/kg/day, with increments of 5 mg/kg every 12 weeks, so long as the absolute neutrophil count (ANC) is more than 2,000 cells/ l and platelets more than 80,000/ l.

Special precautions

The daily dose must be adjusted for blood count trends. Be careful not to change the dose too often,

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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 more in patients with impaired renal function, such as may be seen in elderly patients.

Toxicity

  • Myelosuppression and other hematologic effects. Occurs at doses of more than 1,600 mg/m2 daily by day 10. Recovery is usually prompt. Increased red cell mean corpuscular volume (MCV) is common.

  • 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.

  • Mucocutaneous effects. Stomatitis is rare. Maculopapular rash may be seen. Inflammation of mucous membranes caused by radiation may be exaggerated.

  • Miscellaneous effects.

    • Temporary renal function impairment or dysuria is uncommon.

    • CNS disturbances are rare.

    • May be 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 -emitting yttrium 90 (90Y). The mechanism of action includes antibody-mediated cytotoxicity and cellularly targeted radiotherapy (Radioimmunotherapy [RIT]).

Primary indications

  • Non Hodgkin's lymphoma, follicular B cell, CD-20 positive.

  • Rituximab refractory.

  • Relapsed or refractory to other agents, but not rituximab refractory (experimental).

Usual dosage and schedule

Rituximab, 250 mg/m2 is given days 1 and 8, and 90Y-ibritumomab tiuxetan 0.3 to 0.4 mCi/kg IV on day 8. The maximum dose is 32 mCi.

Special precautions

Use with caution in patients with greater than or equal to 25% marrow involvement with lymphoma, prior external beam radiotherapy to greater than or equal to 25% of the bone marrow, or a history of human antimouse antibodies (HAMA) or HACA. Because the drug does not emit radiation, hospitalization is not required.

Toxicity

  • Myelosuppression and other hematologic effects. Neutropenia 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/ l.

  • Nausea, vomiting, and other gastrointestinal effects. Low-grade nausea and vomiting are common.

  • Mucocutaneous effects. Urticaria and pruritus are occasional.

  • Miscellaneous effects.

    • Immunologic. HAMA or HACA may develop.

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    • Infusion-related fever, chills, dizziness, asthenia, headache, back pain, arthralgia, and hypotension are occasional.

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

  • Acute nonlymphocytic leukemia.

  • Blast crisis of chronic granulocytic (myelogenous) leukemia.

  • Acute lymphocytic leukemia.

Usual dosage and schedule

12 to 13 mg/m2 IV daily for 3 days (usually in 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 of more than 150 mg/m2 have been associated with decreased cardiac ejection fraction.

Toxicity

  • Myelosuppression and other hematologic effects. Universal and dose limiting.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and anorexia are common. Diarrhea is occasional to common.

  • Mucocutaneous effects. Alopecia is common;mucositis is common but usually not severe.

  • Hepatic dysfunction. Common but usually not severe and not clearly due to the idarubicin.

  • Renal effects. Common but usually not clinically significant.

  • Cardiac effects. Uncommon during induction and consolidation (1%-5%).

  • Tissue damage. is probable if infiltration occurs.

  • Neurologic effects. 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

  • Testicular and lung cancers.

  • Bone and soft tissue sarcomas.

  • Lymphoma.

Usual dosage and schedule

  • 1.2 g/m2 IV over 30min 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 1,200 mg/m2 as a daily continuous infusion is given until 16 h after the last dose of ifosfamide.

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  • 3.6 g/m2 IV daily as a 4-h infusion for 2 consecutive days, usually with other agents. Mesna is given at a dose of 750 mg/m2 IV just before and at 4 and 8 h 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 before (or mixed with) the ifosfamide dose and again at 4 and 8 h 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 min.

Toxicity

  • Myelosuppression and other hematologic effects. 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.

  • Nausea, vomiting, and other gastrointestinal effects. Common without standard antiemetics.

  • Mucocutaneous effects. Alopecia is common; mucositis is rarely seen at standard doses; dermatitis is rare.

  • 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.

  • Miscellaneous effects.

    • CNS toxicity (somnolence, confusion, depressive psychosis, hallucinations, disorientation, and uncommonly, seizures, cranial nerve dysfunction, or coma) is occasional with doses in lower range, more common with larger doses.

    • Infertility is common in men and women, as with other alkylating agents.

    • Renal impairment is occasional to common. Fanconi syndrome dependent on dose. May be severe acidosis.

    • Liver dysfunction is uncommon.

    • Phlebitis is uncommon.

    • Fever is rare.

    • Peripheral neuropathy with high-dose therapy is uncommon.

Imatinib Mesylate

Other names

Gleevec, STI-571 (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

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transforming function and excess proliferation seen in CML.

It also inhibits platelet-derived growth factor receptor (PDGFR) tyrosine kinase and c-Kit tyrosine kinase, the latter being activated in gastrointestinal stromal tumors (GISTs).

Primary indications

  • CML in chronic phase, accelerated or blast phase of the disease.

  • ALL, Philadelphia chromosome positive.

  • GIST.

  • Dermatofibrosarcoma protuberans (DFSP)

  • Other rare hematologic disorders with susceptible mutations.

Usual dosage and schedule

  • 400 to 600 mg PO daily in the chronic phase of CML, ALL, GISTs, and other susceptible hematologic disorders.

  • 600 to 800 mg PO daily in the accelerated phase or blast crisis and DFSP.

Toxicity

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, abdominal pain, and diarrhea are common, but it is uncommon that they are severe.

  • Mucocutaneous effects. Skin rash is common; pruritus and petechiae are occasional.

  • Miscellaneous effects.

    • Fluid retention and edema are common. Pleural effusion and ascites are occasional.

    • Musculoskeletal pain or cramps, arthralgia, headache, fever, and fatigue are common, but it is uncommon that they are severe or life threatening.

    • Dyspnea and cough are occasional.

    • Elevated liver function tests or serum creatinine are uncommon to rare. Rare cases of severe hepatotoxicity have been seen.

    • Congestive heart failure is rare. It may be related to imatinib inhibition of Abl, which in turn may be related to mitochondrial function in the heart.

Interferon

Other names

Roferon-A (interferon -2a, recombinant -A interferon), Intron A (interferon -2b, recombinant -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

  • Melanoma (both as adjuvant and metastatic disease therapy).

  • Renal cell carcinoma.

  • Multiple myeloma.

  • Kaposi's sarcoma, HIV associated.

  • CML.

  • Non Hodgkin's lymphoma (low grade), mycosis fungoides.

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  • Condyloma acuminatum (intralesional).

  • Chronic hepatitis B and C.

Usual dosage and schedule

  • 3 to 10 million IU IM or SQ in various schedules. Daily dosing is often used for several weeks or months, followed by 3 times a week dosing.

  • As adjuvant therapy for high-risk melanoma, 20 million IU/m2 IV 5 consecutive days weekly for 4 weeks, then 10 million IU/m2 SQ three times weekly for 48 weeks.

  • For HIV-related Kaposi's sarcoma, 30 million IU/m2 SC or IM three times weekly, with dose modifications based on toxicity. 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

  • Myelosuppression and other hematologic effects. Common but usually 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/ L and consequent increased risk for infection.

  • Nausea and 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.

  • Mucocutaneous effects. Rash, dryness, or inflammation of the oropharynx, dry skin or pruritus, and partial alopecia is occasional to common.

  • Flu-like 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.

  • Neurologic effects.

    • Peripheral nervous system: occasional paresthesias or numbness.

    • 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.

  • General systemic effects. Fatigue, anorexia, and weight loss are common with chronic administration.

    • Cardiovascular effects. Mild hypotension is common but rarely symptomatic. Rarely to uncommonly seen are hypertension, chest pain, arrhythmias, or other cardiovascular disorders.

    • Respiratory effects. Dyspnea and cough are occasional at higher doses.

  • Infectious effects. Exacerbation of herpetic eruptions and nonherpetic cold sores is uncommon.

  • Miscellaneous effects. Leg cramps, insomnia, urticaria, hot flashes, coagulation disorders are uncommon. Visual problems, including blurring, diplopia, dry eyes, nystagmus, and photophobia are uncommon.

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  • Metabolic effects and laboratory abnormalities.

    • Elevated liver enzymes are common.

    • Mild proteinuria; increase in serum creatinine is occasional.

    • Hypercalcemia is occasional.

    • Hypothyroidism and hyperthyroidism with or without antithyroid antibodies.

    • Hypertriglyceridemia is rare.

  • Antibody development (binding and neutralizing) occurs more readily with interferon -2a than with interferon -2b. The significance of this is not clear, though it may be associated with the development of clinical resistance in some patients.

Irinotecan

Other names

Camptosar, CPT-11.

Mechanism of action

Irinotecan, a semisynthetic water-soluble derivative of CPT, is a prodrug for the lipophilic metabolite SN-38, 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

  • Carcinoma of the colon or rectum, esophagus, or stomach.

  • Carcinoma of the lung.

Usual dosage and schedule

  • 80 to 125 mg/m2 IV over 90 min 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.

  • 180 mg/m2 IV over 90 min every 2 weeks when used with leucovorin (over 2 h) plus bolus fluorouracil followed by a 22-h infusion of fluorouracil.

For severe or worse diarrhea ( 7 stools over pretreatment), doses should be held. When the diarrhea has improved ( 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 seven to nine times per day, and by 50 to 60 mg/m2 if there was an increase in stools of 10 times or more. Doses are also held during treatment and reduced in the same and subsequent cycles for severe neutropenia (ANC <1,000).

Special precautions

  • Both early and late diarrhea may occur. That which occurs within 24 h (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 h until the patient is diarrhea-free for 12 h) and prompt fluid and electrolyte replacement as indicated, if the diarrhea becomes severe (increase of 7 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

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    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 glucuronosyltransferase gene and its corresponding enzyme (UGT1A1) that 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 (Third Wave Technologies).

Toxicity

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting 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 10%). Severe diarrhea may be more common if homozygous for UGT1A1*28. Abdominal cramping is common, occasionally severe. Anorexia is common. Constipation and dyspepsia are occasional. Ileus, colitis, or toxic megacolon are seen rarely.

  • Mucocutaneous effects. Alopecia and mucositis are common. Rash and sweating occur occasionally.

  • Miscellaneous effects.

    • Fever is common, rarely severe.

    • Headache, back pain, chills, and edema are occasional.

    • Grade 1 to 2 increases in liver function test values are common; it is uncommon for liver function abnormalities to be severe, except in patients with known liver metastasis.

    • Dyspnea, cough, or rhinitis is occasional to common, but usually not severe.

    • Insomnia or dizziness is occasional.

    • Flushing is occasional.

    • Anaphylactic reactions are rare.

Lapatinib

Other name

Tykerb.

Mechanism of action

Lapatinib is a dual tyrosine kinase inhibitor with specificity for epidermal growth factor (ErbB1) receptor (EGFR) and ErbB2 (Her2/neu).

Primary indication

Carcinoma of breast that overexpresses the HER2 protein.

Usual dosage and schedule

  • 1,500 mg PO daily.

  • 1250 mg PO daily with other agents such as capecitabine.

Special precautions

The drug being a new agent, unanticipated adverse effects may emerge with further experience.

Toxicity

  • Myelosuppression and other hematologic effects. Myelosuppression is not an effect of lapatinib. Other EGFR inhibitors may potentiate warfarin and cause unexpected rise in INR.

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  • Nausea, vomiting, and other gastrointestinal effects. Nausea and diarrhea are common; vomiting dyspepsia, and anorexia are occasional. Other EGFR inhibitors are associated with transaminase elevations and occasionally with increased bilirubin.

  • Mucocutaneous effects. Rash is common.

  • Miscellaneous effects.

    • Left ventricular ejection fraction decrease is rare and generally asymptomatic.

    • Fatigue is common.

Lenalidomide

Other name

Revlimid.

Mechanism of action

Multiple potential mechanisms, including immunomodulatory and antiangiogenic effects. Precise mechanism not delineated.

Primary malignancy indications

  • Myelodysplastic syndrome, low or intermediate-1 risk, associated with deletion of 5q31 (del 5q).

  • Multiple myeloma.

Usual dosage and schedule

  • 10 mg PO daily, with dosing interruptions and subsequent dose reduction to 5 mg daily as determined by cytopenias or other toxicity. Renal insufficiency is associated with decreased clearance.

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

  • 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%), have been seen in patients treated with lenalidomide combination therapy uncommon to occasional. Relative benefit of prophylactic anticoagulation or antiplatelet therapy is uncertain, but some form of prophylaxis is generally recommended, particularly in patients with myeloma or in others receiving corticosteroids.

  • Nausea, vomiting, and other gastrointestinal effects. Diarrhea is common; constipation is common but less frequent than diarrhea. Nausea is common, but vomiting is only occasional. Abdominal pain is occasional.

  • Mucocutaneous effects. Macular rash, dryness of the skin, increased sweating, and pruritus are common. Urticaria is occasional.

  • Miscellaneous effects.

    • Cough, nasopharyngitis, dyspnea, and bronchitis are occasional.

    • Myalgia, arthralgia, muscle cramps, or limb pain are occasional.

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    • Fatigue and fever are common, but rigors are uncommon.

    • Headache and dizziness are occasional. Peripheral neuropathy is uncommon (5%). Insomnia and depression are occasional.

    • Hypothyroidism is occasional.

    • Palpitations, hypertension, chest pain, and peripheral edema are occasional.

    • Hypokalemia and hypomagnesemia are occasional.

    • Birth defects. (See Special precautions in the preceding text.)

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

  • 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.

  • Carcinoma of the breast as adjuvant therapy in hormone receptor positive postmenopausal women.

Usual dosage and schedule

2.5 mg PO daily.

Special precautions

Potential hazard to fetus if given during pregnancy. Because of the potential fracture risk, bone density testing and treatment with calcium and Vitamin D with or without bisphosphonates are often used.

Toxicity

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

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

  • Mucocutaneous effects. Rash is uncommon.

  • Miscellaneous effects.

    • Thromboembolic events are uncommon (1. 2%) and less than with tamoxifen.

    • Hot flashes are common and night sweats are occasional.

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

    • Weight increase is occasional.

    • Fatigue is occasional.

    • Osteoporosis (occasional) is accelerated, with increase in fracture risk (uncommon).

    • Headache is uncommon.

    • Peripheral edema, weight gain is occasional (lower than with megestrol).

    • Dyspnea and cough are uncommon to occasional.

    • Hypercalcemia is rare.

    • Endometrial cancer is rare (0. 2%) and less likely than with tamoxifen.

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Lomustine

Other name

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 enters the brain easily.

Primary indication. Malignant brain tumors.

Usual dosage and schedule

100 to 130 mg/m2 PO once every 6 to 8 weeks (lower dose used for patients with compromised bone marrow function). Some recommend restricting cumulative dose to 1,000 mg/m2 to limit pulmonary and renal toxicity.

Special precautions

Because of delayed myelosuppression (3 6 weeks), do not treat more often than every 6 weeks. Await a return of normal platelet and granulocyte counts before repeating therapy.

Toxicity

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting may begin 3 to 6 h after therapy and last up to 24 h.

  • Mucocutaneous effects. Stomatitis and alopecia are rare.

  • Miscellaneous effects.

    • Confusion, lethargy, and ataxia are rare.

    • Mild hepatotoxicity is infrequent.

    • Secondary neoplasia is possible.

    • Pulmonary fibrosis is uncommon at doses of less than 1,000 mg/m2.

    • Renal toxicity is uncommon at doses of less than 1,000 mg/m2.

Luteinizing Hormone releasing Hormone (Lhrh) Analogs

Other names

Leuprolide (Lupron, Lupron depot, Viadur), goserelin (Zoladex depot), triptorelin pamoate (Trelstar depot).

Mechanism of action

Initial release of follicle-stimulating hormone and luteinizing hormone 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

  • Metastatic prostate carcinoma.

  • Breast carcinoma in premenopausal and perimenopausal women with metastatic disease (goserelin).

Usual dosage and schedule

  • Leuprolide depot, 7. 5 mg IM monthly, 22.5 mg IM every 3 months, or 30 mg IM every 4 months.

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  • Goserelin depot, 3. 6 mg SC every 4 weeks or 10.8 mg SC every 12 weeks. Use only 3.6-mg implant for breast carcinoma.

  • Triptorelin depot 3. 75 mg IM monthly.

Special precautions

Worsening of symptoms may occur during the first few weeks.

Toxicity

  • Myelosuppression and other hematologic effects. Rare, if at all.

  • Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and constipation are uncommon.

  • Mucocutaneous effects. Erythema and ecchymosis at the injection site, rash, hair loss, and itching are uncommon.

  • Cardiovascular effects. Congestive heart failure, hypertension, and thrombotic episodes are uncommon. Peripheral edema is occasional.

  • Miscellaneous effects.

    • CNS: dizziness, pain, headache, and paresthesias are uncommon.

    • Endocrine: hot flashes are common; decreased libido is common; gynecomastia with or without tenderness is uncommon; impotence is occasional to common.

    • 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.

    • Hypersensitivity reactions with rare angioneurotic edema and anaphylaxis have been reported.

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

  • Hodgkin's lymphoma.

  • Malignant pleural and, less commonly, peritoneal or pericardial effusions.

  • CTCLs (topically).

Usual dosage and schedule

  • 6 mg/m2 IV on days 1 and 8 every 4 weeks (in MOPP regimen for Hodgkin's disease).

  • 8 to 16 mg/m2 by intracavitary injection.

  • 10 mg in 60 mL of tap water applied to entire body surface (avoid eyes).

Special precautions

  • Administer over several minutes into the sidearm of a running IV infusion, taking care to avoid extravasation.

  • 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,

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    irrigate the affected part immediately with water for at least 15 min and follow by 2.6% sodium thiosulfate solution (1/6 M).

  • Mechlorethamine should be used soon after preparation (15 30 min) as it decomposes on standing. It must not be mixed in the same syringe with any other drug.

Toxicity

  • Myelosuppression and other hematologic effects. Dose-limiting, with the nadir at approximately 1 week and recovery by 3 weeks.

  • Nausea, vomiting, and other gastrointestinal effects. Universal. They usually begin within the first 3 h and last 4 to 8 h.

  • Mucocutaneous effects. Severe painful inflammation and necrosis are likely if extravasation occurs. May be ameliorated if 2.6% thiosulfate solution (1/6 M) is instilled into the area to neutralize active drug, and ice packs are applied locally for 6 to 12 h. Maculopapular rash is uncommon.

  • Miscellaneous effects.

    • Phlebitis, thrombosis, or both of the vein used for the injection are common.

    • Amenorrhea and azoospermia are common.

    • Hyperuricemia with rapid tumor destruction.

    • Weakness, sleepiness, and headache are uncommon.

    • Severe allergic reactions, including anaphylaxis, are rare.

    • Secondary neoplasms, including myelodysplasia, acute leukemia, and carcinomas are possible.

Melphalan

Other names

Phenylalanine mustard, L-sarcolysin, L-PAM, Alkeran.

Mechanism 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

  • Multiple myeloma.

  • Stem cell preparative regimens.

Usual dosage and schedule

  • 8 mg/m2 PO on days 1 to 4 every 4 weeks or

  • 10 mg/m2 PO on days 1 to 4 every 6 weeks or

  • to 4 mg/m2 PO daily for 2 to 3 weeks, and then 1 to 2 mg/m2 PO daily for maintenance.

  • High-dose regimens of 140 to 200 mg/m2 IV have been used, followed by stem cell rescue (e. g., bone marrow transplantation).

  • 16 mg/m2 IV every 2 weeks x4, then every 4 weeks.

Special precautions

  • Myelosuppression and other hematologic effects may be delayed and prolonged to 4 to 6 weeks. Reduce IV dose by 50% for creatinine more than 1.5 times normal.

  • Use in early myeloma may preclude harvest of sufficient numbers of peripheral stem cells for autologous transplantation.

Toxicity

  • Myelosuppression and other hematologic effects. Dose limiting; nadir at days 14 to 21.

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  • Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are uncommon at standard doses, but common with high-dose regimens.

  • Mucocutaneous effects. Alopecia, dermatitis, and stomatitis are uncommon at standard doses; alopecia and mucositis are common with high-dose regimens.

  • Miscellaneous effects.

    • Acute nonlymphocytic leukemia and myelodysplasia are rare but well documented.

    • Pulmonary fibrosis is 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

Acute lymphocytic leukemia.

Usual dosage and schedule

  • 100 mg/m2 PO daily if used alone.

  • 50 to 90 mg/m2 PO daily if used with methotrexate.

Special precautions

  • Decrease dose by 75% when used concurrently with allopurinol.

  • Increase interval between doses or reduce dose in patients with renal failure.

Toxicity

  • Myelosuppression and other hematologic effects. Common but mild at recommended doses.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are uncommon. Diarrhea is rare.

  • Mucocutaneous effects. Stomatitis may be seen with very large doses. Dry, scaling rash is uncommon.

  • Miscellaneous effects.

    • Intrahepatic cholestasis and mild focal centrolobular necrosis with jaundice are uncommon.

    • Hyperuricemia with rapid leukemia cell lysis is common.

    • 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 cyclophosphamide)-induced hemorrhagic cystitis.

Usual dosage and schedule

Mesna dose is at least 20% of the ifosfamide dose (on a weight [mg] basis), administered just before (or mixed with) the ifosfamide dose and again at 4 and 8 h 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.

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

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cystitis. Neither mesna nor its only metabolite, mesna disulfide, affects ifosfamide, cyclophosphamide, or the antineoplastic metabolites.

Toxicity

  • Myelosuppression and other hematologic effects. None.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are occasional. Nausea and vomiting are more commonly from ifosfamide.

  • Mucocutaneous effects. Bad taste in the mouth is common.

  • Miscellaneous effects.

    • Headache, fatigue, and limb pain are occasional.

    • Hypotension or allergic reactions are uncommon to rare.

    • 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

  • Bladder, breast, head and neck, gastrointestinal, lung, and gestational trophoblastic carcinomas.

  • Osteosarcomas (high-dose methotrexate).

  • Acute lymphocytic leukemia.

  • Meningeal leukemia or carcinomatosis.

  • Non Hodgkin's lymphoma.

Usual dosage and schedule

  • Gestational trophoblastic carcinoma. 15 to 30mg PO or IMon days 1 to 5 every 2 weeks.

  • Other carcinomas. 40 to 80 mg/m2 IV or PO two to four times monthly with a 7- to 14-day interval between doses.

  • Acute lymphocytic leukemia. 15 to 20 mg/m2 PO or IV weekly (together with mercaptopurine).

  • Osteogenic sarcoma. Up to 12 g/m2 with leucovorin rescue (high-dose methotrexate). This usage requires on-site monitoring of methotrexate levels and a high degree of expertise to administer safely.

  • Intrathecally. 12mg/m2 (not >20 mg) twice weekly.

Special precautions

  • 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.

  • Intrathecal methotrexate must be mixed in buffered physiologic solution containing no preservative.

  • Avoid aspirin, sulfonamides, tetracycline, phenytoin, and other protein-bound drugs that may displace methotrexate and cause an increase in free drug.

  • Oral anticoagulants, e. g., warfarin, may be potentiated by methotrexate; therefore prothrombin times should be followed carefully.

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  • Oral antibiotics may decrease methotrexate absorption; penicillin and nonsteroidal anti-inflammatory drug (NSAIDs) decrease clearance of methotrexate.

  • Monitor use with theophylline.

  • In patients with renal insufficiency, it may be necessary to markedly reduce the dose or discontinue methotrexate therapy.

  • Do not give if patient has an effusion, because of reservoir effect.

Toxicity

  • Myelosuppression and other hematologic effects. Occurs commonly, with nadir at 6 to 10 days after a single IV dose. Recovery is rapid.

  • Nausea, vomiting, and other gastrointestinal effects. Occasional at standard doses.

  • Mucocutaneous effects.

    • Mild stomatitis is common and a sign that a maximum tolerated dose has been reached. Higher doses may result in confluent or hemorrhagic stomal ulcers and bloody diarrhea.

    • Erythematous rashes, urticaria, and skin pigment changes are uncommon.

    • Mild alopecia is frequent.

  • Miscellaneous effects.

    • Acute hepatocellular injury is uncommon at standard doses.

    • Hepatic fibrosis is uncommon but seen at low chronic doses.

    • Pneumonitis is rare.

    • Polyserositis is rare.

    • Renal tubular necrosis is rare at standard doses.

    • Convulsions and a Guillain-Barr like syndrome following intrathecal therapy are uncommon.

Mitomycin

Other names

Mitomycin C, Mutamycin.

Mechanism of action

Alkylation and cross-linking by mitomycin metabolites interfere with structure and function of DNA.

Primary indication. Bladder (intravesical), esophagus, stomach, anal, and pancreas carcinomas.

Usual dosage and schedule

  • 20 mg/m2 IV on day 1 every 4 to 6 weeks or

  • 2 mg/m2 IV on days 1 to 5 and 8 to 12 every 4 to 6 weeks.

  • 10 mg/m2 IV on day 1 every 8 weeks in combination with fluorouracil and doxorubicin for stomach and pancreatic carcinomas.

  • 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

  • Myelosuppression and other hematologic effects.

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    • 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, may be poorly responsive to plasmapheresis and other therapies.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common at higher doses, but severity is usually mild to moderate.

  • Mucocutaneous effects.

    • Stomatitis and alopecia are common.

    • Cellulitis is common at injection site if extravasation occurs.

  • Miscellaneous effects.

    • Renal toxicity is uncommon.

    • Pulmonary toxicity is uncommon but may be severe.

    • Fever is uncommon.

    • 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 indication

Adrenocortical carcinoma.

Usual dosage and schedule

Begin with 2 to 6 g PO daily in 3 or 4 divided doses and build to a maximum tolerated daily dose that is usually 8 to 10 gm, although it may range from 2 to 16 gm. Glucocorticoid and mineralocorticoid replacements during mitotane therapy are necessary to prevent hypoadrenalism.

Cortisone acetate (25 mg PO in the morning and 12.5 mg PO in the evening) and fludrocortisone acetate (0.1 mg PO in the a.m.) 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

  • Myelosuppression and other hematologic effects. None.

  • Nausea, vomiting, and other gastrointestinal effects. Common and may be dose limiting.

  • Mucocutaneous effects. Skin rash occurs occasionally.

  • CNS effects. Lethargy, sedation, vertigo, or dizziness in up to 40% of patients; may be dose limiting.

  • 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 the effects of anthracenedione on topoisomerase II.

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Primary indications

  • Acute nonlymphocytic leukemia.

  • Carcinoma of the breast or ovary.

  • Non Hodgkin's and Hodgkin's lymphoma.

Usual dosage and schedule

  • 12 to 14 mg/m2 IV as a 5- to 30-min infusion once every 3 weeks for solid tumors.

  • 12 mg/m2 IV as a 5- to 30-min infusion daily for 3 days for acute nonlymphocytic leukemia.

Special precautions

Rarely causes extravasation injury if infiltrated. Cardiotoxicity is probably less than that with doxorubicin; but prior anthracycline, chest irradiation, or underlying cardiac disease increases the risk.

Toxicity

  • Myelosuppression and other hematologic effects. Universal.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common but less frequent and less severe than with doxorubicin. Diarrhea is uncommon.

  • Mucocutaneous effects. Alopecia is common, but its frequency and severity are less than with doxorubicin. Mucositis is occasional.

  • 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.

  • Miscellaneous effects.

    • Local erythema and swelling with transient blue discoloration if extravasated, but rarely leads to severe skin damage.

    • Green or blue discoloration of urine.

    • 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 triphosphorylated ara-G, it is incorporated into DNA (preferentially into T cells), inducing fragmentation and apoptosis.

Primary indication

T-cell ALL and T-cell lymphoblastic lymphoma that have relapsed or are refractory to at least two prior chemotherapeutic regimens.

Usual dosage and schedule

  • Adults 1,500 mg/m2 IV over 2 h on days 1, 3, and 5, repeated every 21 days.

  • Children 650 mg/m2 IV over 1 h daily for 5 consecutive days, repeated every 21 days.

Special precautions

Closemonitoring for neurologic events is recommended, owing to the possibility of severe neurologic complications of therapy. Prophylaxis against tumor lysis syndrome is recommended.

Toxicity

  • Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common. Febrile neutropenia is occasional.

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

  • Mucocutaneous effects. Stomatitis is occasional.

  • Neurologic effects.

    • Headache is occasional.

    • Somnolence and confusion are occasional.

    • Peripheral neuropathy is occasional. May range from numbness and paresthesias to motor weakness and paralysis.

    • Ataxia is occasional.

    • Insomnia is occasional.

    • Convulsions and coma are rare.

    • Leukoencephalopathy and demyelination and ascending peripheral neuropathy are rare.

  • Immune effects and infusion reactions.

  • Miscellaneous effect.

    • Fatigue, weakness, and fever (occasionally with rigors) are common.

    • Cough, dyspnea, and pleural effusion are common to occasional.

    • Abnormal liver function test results are occasional.

    • Hypokalemia, hypomagnesemia, hypocalcemia, and increased creatinine are occasional.

    • Edema is occasional.

    • Sinus tachycardia is occasional.

    • Musculoskeletal pain is occasional.

Nilotinib

Other names

Tasigna, AMN107.

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 chronic myelogenous leukemia (CML). In vitro, nilotinib is active against many Bcr-Abl mutations associated with imatinib resistance.

Primary indications

  • CML in chronic, accelerated, or blastic phase and Philadelphia chromosome positive acute lymphocytic leukemia in patients resistant or intolerant to imatinib.

Usual dosage and schedule

600 mg PO daily or 400 mg PO twice daily.

Toxicity

  • Myelosuppression and other hematologic effects. Thrombocytopenia is common. Neutropenia and anemia are occasional.

  • Nausea, vomiting and other gastrointestinal effects. Nausea and vomiting are occasional.

  • Mucocutaneous effects. Skin rash is common; alopecia, dry skin, and pruritus are occasional.

  • Miscellaneous effects.

    • Abnormal liver function tests, including elevations in bilirubin (primarily unconjugated) are occasional.

    • Increase in the corrected QT interval by 5 to 15 msec has been seen.

    • Increase in lipase and amylase are uncommon.

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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 PO once daily for 30 days, followed by 150 mg PO 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 preexisting dyspnea.

Inhibits activity of liver cytochrome P-450 isoenzymes and may delay elimination of drugs such as warfarin, phenytoin, and theophylline.

Toxicity

  • Myelosuppression and other hematologic effects. None.

  • Nausea, vomiting, and other gastrointestinal effects. Occasional nausea. Constipation is uncommon.

  • Mucocutaneous effects. Rash, dry skin, and sweating are uncommon.

  • Miscellaneous effects.

    • Hepatitis is rare (1%).

    • Interstitial pneumonitis with dyspnea is uncommon (2%). May be higher in patients with Asian ancestry.

    • Inhibits activity of liver cytochrome P-450 isoenzymes and may delay elimination of drugs such as warfarin, phenytoin, and theophylline.

    • Hot flashes are common.

    • Increased liver function test values are uncommon.

    • Impaired adaptation to darkness is common.

Octreotide

Other name

Sandostatin, Sandostatin LAR depot.

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

  • Carcinoid tumors.

  • Vasoactive intestinal peptide tumors and other amine precursor uptake and decarboxylation tumors.

  • Chemotherapy-induced diarrhea.

  • Acromegaly.

Usual dosage and schedule

100 to 1, 500 g/day SC, 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, 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.

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Special precautions

Lower doses indicated if there is severe renal dysfunction (creatinine >5 mg/dL).

Toxicity

  • Myelosuppression and other hematologic effects. None.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea abdominal discomfort, bloating, and diarrhea are common, particularly early in early therapy. Vomiting is only occasionally seen. Decreased gall bladder 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.

  • Mucocutaneous effects. Local site reactions are occasional; other effects are rare.

  • Endocrine effects. Hypoglycemia or hyperglycemia is uncommon; hypothalamic pituitary dysfunction is rare.

  • Bradycardia and other conduction abnormalities occur in up to 25% of patients with acromegaly who are treated with octreotide.

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.

Usual dosage and schedule

  • 50 g/kg SQ once daily, starting 6 to 24 h after completion of chemotherapy. Continue until the postnadir count is 50, 000/ L. (Treatment for more than 21 days in a row is not recommended.) 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. Severe allergic reactions, including anaphylaxis, may be seen.

Toxicity

  • Myelosuppression and other hematologic effects. None. Mild decrease in hemoglobin concentration, predominantly due to increase in plasma volume.

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

  • Mucocutaneous effects. Occasional rash, particularly at injection site.

  • Miscellaneous effects.

    • Cardiovascular. Atrial arrhythmia (flutter or fibrillation) and palpitations are occasional (~10%), but usually transient. Ventricular arrythmias have been seen (rare).

    • Syncope is occasional. (Anaphylactic reactions have been observed rarely.)

    • Fluid retention with edema (renal sodium and water retention) or dyspnea on exertion is common, but usually mild to moderate. Renal failure is rare. May be associated with capillary leak syndrome.

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    • Conjunctival injection and mild visual blurring are occasional. Papilledema is rare, but may be more common in children. Caution should be exerted in patients with preexisting papilledema or tumors of the CNS.

    • Asthenia is occasional.

    • Dizziness and insomnia are 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

  • Carcinoma of the colon and rectum.

  • Carcinoma of the stomach.

  • Non small cell lung cancer.

Usual dosage and schedule

  • Single agent. 130 mg/m2 as a 2-h infusion every 3 weeks or 85 mg/m2 as a 3-h infusion every 2 weeks.

  • Combination therapy. 85 to 100 mg/m2 as a 2-h infusion every 2 weeks in combination with fluorouracil (often as a continuous infusion).

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.

Toxicity

  • Myelosuppression and other hematologic effects. Low grade myelosuppression is common, but grade 3 or 4 granulocytopenia, thrombocytopenia, or anemia is uncommon (~5%). Hemolytic anemia is rare.

  • 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.

  • Mucocutaneous effects. Alopecia is uncommon. Stomatitis is increased when used with fluorouracil.

  • Miscellaneous effects.

    • Neurotoxicity, consisting of paresthesias and cold-induced dysesthesias in the stocking glove or perioral distribution are common as acute transient changes that begin with the infusion and last for less than one 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.

    • Laryngospasm may develop during or within 2 h of the infusion and can last up to 5 days. Cold temperatures may induce the spasm, and warm liquids or a hot-pack may ameliorate.

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    • Nephrotoxicity is uncommon.

    • Ototoxicity is rare.

    • Anaphylaxis is rare.

Paclitaxel

Other name

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

  • Carcinomas of the ovary, breast, lung, head and neck, bladder, and cervix.

  • Melanoma.

  • Kaposi's sarcoma, AIDS related.

Usual dosage and schedule

  • 135 to 225 mg/m2 as a 3-h infusion every 3 weeks.

  • 135 to 200 mg/m2 as a 24-h infusion every 3 weeks.

  • 100 mg/m2 as a 3-h infusion every 2 weeks for the treatment of AIDS-related Kaposi's sarcoma.

  • 80 to 100 mg/m2 as a 1-h weekly infusion.

  • 30 50 mg/m2 as a 1-h infusion weekly as a radiosensitizer.

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 Cremophor vehicle required to make paclitaxel water soluble. Such a reaction is minimized but not totally prevented by pretreatment with antihistamines and corticosteroids and by prolonging the infusion rate (to 24 h). Paclitaxel must be filtered with a 0.2-micron in-line filter.

Standard pretreatment regimen

  • Dexamethasone, 20 mg IV for doses more than 100 mg/m2 and 10 mg IV for doses less than 100 mg/m2, 30 to 60 min before treatment.

  • Diphenhydramine, 50 mg IV 30 to 60 min before treatment.

  • Histamine H2-receptor antagonist, IV 30 to 60 min before treatment (e. g., Cimetidine, 300 mg).

Toxicity

  • Myelosuppression and other hematologic effects. Granulocytopenia is universal and dose limiting; thrombocytopenia is common; anemia is occasional.

  • Nausea, vomiting, and other gastrointestinal effects. Common, but usually not severe.

  • Mucocutaneous effects. Alopecia is universal; mucositis is occasional at recommended doses.

  • Hypersensitivity reactions. Dyspnea, hypotension (or occasionally hypertension), bronchospasm, urticaria, and erythematous rashes are occasionally seen, despite precautions.

  • Miscellaneous effects.

    • Sensory neuropathy is common (30% 35%), and may be progressively worse with time. Recovery may take months to years.

    • Hepatic dysfunction is uncommon.

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    • Diarrhea is occasional and mild.

    • Myalgias and arthralgias are common (25%).

    • Seizures are rare.

  • Abnormal electrocardiogram is occasional. If there is clinically significant bradycardia, stop the 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 Cremophor vehicle for paclitaxel and its associated toxicity, and exploits albumin receptor mediated endothelial transport. As with parent compound, intratumor paclitaxel results in 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

  • Metastatic carcinoma of the breast, non small cell carcinomas of the lung, head and neck, and ovary.

  • Melanoma.

Usual dosage and schedule

  • 260 mg/m2 IV over 30 min every 3 weeks.

Special precautions

Hypersensitivity reactions may occur during the infusion of nab-paclitaxel, but are rare. Premedication, as is used with paclitaxel with Cremophor, is not required.

Toxicity

  • Myelosuppression and other hematologic effects. Granulocytopenia is common and dose limiting; anemia is common as well, but rarely severe. Thrombocytopenia is uncommon. Febrile neutropenia is rare.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are occasional to common, but usually not severe. Diarrhea is common, but rarely severe.

  • Mucocutaneous effects. Alopecia is universal; mucositis is occasional.

  • Hypersensitivity reactions. Uncommon and rarely severe.

  • Miscellaneous effects.

    • 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.

    • Sensory neuropathy is common and may be progressively worse with time. Recovery may take months to years.

    • Asthenia is common.

    • Ocular or visual disturbances are occasional.

    • Cough and dyspnea are occasional.

    • Abnormal liver function tests are common, and occasionally severe.

    • Myalgias and arthralgias are common.

    • Seizures are rare.

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Pamidronate

Other name

Aredia.

Mechanism of action

A bisphosphonate that inhibits osteoclastic resorption of bone and calcium release induced by tumor cytokines.

Primary indications

  • Hypercalcemia associated with malignancy.

  • Osteolytic bone metastases of breast cancer.

  • Osteolytic and osteoporotic bone lesions of multiple myeloma.

  • Paget's disease.

Usual dosage and schedule

  • Multiple myeloma: 90 mg IV as a 4-h infusion every month.

  • Breast cancer: 90 mg IV as a 2-h infusion every 3 to 4 weeks.

  • Hypercalcemia of malignancy: 60 to 90 mg IV as a 4- to 24-h infusion. May be repeated every 1 to 8 weeks, as needed.

  • Paget's disease: 30 mg IV daily as a 4-h infusion on 3 consecutive days.

Special precautions

  • 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.

  • 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

  • Myelosuppression and other hematologic effects. Rare.

  • Nausea, vomiting, and other gastrointestinal effects. Abdominal pain, anorexia, constipation, nausea, vomiting are uncommon to occasional.

  • Mucocutaneous effects. Infusion site reaction is occasional.

  • Miscellaneous effects.

    • Fatigue is occasional.

    • Abnormal laboratory reports are occasional (hypocalcemia, hypokalemia, hypomagnesemia, and hypophosphatemia, particularly at the 90-mg dose).

    • Uveitis, iritis, scleritis, and episcleritis are rare.

    • Bone pain or generalized pain is occasional.

    • Osteonecrosis of the jaw is uncommon to rare.

Panitumumab

Other names

Vectibix Epidermal growth factor receptor (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 to be potentially most useful in those tumors that overexpress EGFR, but correlation with percentage of positive cells or intensity of EGFR expression is lacking.

Primary indication

Colon cancer expressing EGFR.

Usual dosage and schedule

6 mg/kg (220 mg/m2) IV over 60 min every 2 weeks.

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Special precautions

Anti-panitumumab antibodies have not been seen, but are possible. Severe hypomagnesemia may be seen, and all patients should have magnesium levels monitored throughout the persistent use of cetuximab (8 weeks).

Toxicity

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

  • Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea are occasional. Other chemotherapy-induced diarrhea may be exacerbated. Abdominal pain is common.

  • Mucocutaneous effects. Acne-like rash is universal and may be severe. Other skin, mucous membrane, and conjunctival reactions are occasional to common.

  • Miscellaneous effects.

    • Fatigue, headache, and back pain are occasional.

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

    • Infusion reactions with allergic or hypersensitivity reactions, fever, chills, or dyspnea are occasional but only rarely severe.

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

    • Pulmonary fibrosis is rare.

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 approximately 3.5 to approximately 15 to 80 h 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 and 24 h after each chemotherapy cycle.

Special precautions

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

  • The fixed-dose formulation should not be used in infants, children, and others weighing less than 45 kg.

Toxicity

  • Myelosuppression and other hematologic effects. None (leukocytosis with immature forms in the peripheral blood is common).

  • Nausea, vomiting, and other gastrointestinal effects. Rare to uncommon.

  • Mucocutaneous effects. Exacerbation of preexisting dermatologic conditions is occasional; pyoderma gangrenosum is possible.

  • Miscellaneous effects. Usually mild and short lived.

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    • Bone pain, musculoskeletal symptoms such as cramps, and back or leg pain are common, somewhat more frequent than in placebo-treated patients and may be severe.

    • Splenomegaly with prolonged use is possible. Splenic rupture is rare.

    • Exacerbation of preexisting inflammatory or autoimmune disorders is rare.

    • Mild elevation of LDH and alkaline phosphatase.

    • Allergic-type reactions may occur, including anaphylaxis (rare).

    • Adult respiratory distress syndrome has been reported in neutropenic patients receiving filgrastim and is possible with pegfilgrastim.

Pemetrexed

Other name

Alimta Mechanism 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

  • Malignant pleural mesothelioma that is unresectable or not amenable to curative surgery. Given in combination with cisplatin.

  • Non small cell lung cancer after prior chemotherapy.

Usual dosage and schedule

  • 500 mg/m2 IV over 10 min on day 1 of each 21-day cycle. For mesothelioma, it is followed in 30 min by cisplatin 75 mg/m2 over 2 h.

Special precautions

  • Folic acid, 400 to 1, 000 g PO 5 times daily, starting 7 days before pemetrexed and continuing for 21 days after the last dose; and 1, 000 g of vitamin B12 IM during the week before pemetrexed and every three cycles thereafter must be taken as a prophylactic measure to reduce treatment-related hematologic and GI Toxicity.

  • Dexamethasone 4 mg PO twice daily the day before, on the day of, and the day after pemetrexed should be given to reduce skin rash.

  • If creatinine clearance is less than 45 mL/min, give with caution and avoid NSAIDs.

Toxicity

  • Myelosuppression. Anemia is common. Neutropenia and thrombocytopenia are occasional.

  • Gastrointestinal effects. Anorexia, nausea, vomiting, and constipation or diarrhea are common. Liver function abnormalities are occasional.

  • Mucocutaneous effects. Rash is occasional to common. Stomatitis and pharyngitis are common. Alopecia is occasional.

  • Neurotoxicity. Fatigue is common.

  • Immune suppression.

  • Miscellaneous effects.

    • Fever is common.

    • Serum creatinine elevation is uncommon; renal failure is rare.

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    • Myalgia and arthralgia are occasional.

    • Dyspnea and chest pain are common, but may be secondary to underlying condition.

    • Hypersensitivity reactions are occasional, but rarely severe.

    • Thrombosis, embolism, and cardiac ischemia are each uncommon.

Pentostatin

Other names

2_-Deoxycoformycin, Nipent.

Mechanism of action

Inhibition of ADA, particularly in the presence of adenosine or deoxyadenosine leads to cyto

Toxicity

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, chronic lymphocytic leukemia, CTCL (mycosis fungoides), other lymphoid neoplasms.

Usual dosage and schedule

  • 4 mg/m2 IV push over 1 to 2 min or diluted in a larger volume over 20 to 30 min. Patients should be given hydration with 500 to 1,000 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.

  • 2 mg/m2 IV every three weeks when used in combination with cyclophosphamide or other agents.

Special precautions

  • Hydration required to ensure urine output of 2 L daily on the day pentostatin is administered. Patients are often hospitalized for the first drug administration. Allopurinol 300 mg b.i.d. 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 is needed for renal impairment (creatinine clearance <50 mL/min).

  • Should not be used in combination with fludarabine because of a high probability of severe or fatal pulmonary toxicity.

Toxicity

  • Myelosuppression. Common but severity variable.

  • 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.

  • Mucocutaneous effects. Mucositis is rare; skin rashes and pruritus are occasional to common.

  • Pulmonary. Cough is common and dyspnea is occasional. Higher doses or use in combination of fludarabine may lead to severe pulmonary Toxicity.

  • Miscellaneous effects.

    • Fatigue is common.

    • Chills and fever are common.

    • Infections, probably related both to myelosuppression and lymphocytopenia are occasional.

    • Renal insufficiency is rare at usual doses.

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    • Neuropsychiatric effects. High doses may cause serious neurologic and psychiatric symptoms, including seizures, mental confusion, irritability, and coma.

    • Cough or other respiratory problems are occasional.

Procarbazine

Other names

Matulane, Natulan.

Mechanism of action

Uncertain but appears to affect preformed DNA, RNA, and protein.

Primary indications

  • Hodgkin's and non Hodgkin's lymphomas.

  • Brain tumors.

  • Melanoma.

Usual dosage and schedule

60 to 100 mg/m2 PO 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.

Drug or food Possible result
Ethanol Disulfiram-like reactions: nausea, vomiting, visual disturbances, headache
Sympathomimetics, tricyclic antidepressants, tyramine-rich foods (cheese, wine, bananas) Hypertensive crisis, tremors, excitation, angina, cardiac palpitations
CNS depressants Additive depression

Toxicity

  • Myelosuppression and other hematologic effects. Pancytopenia is dose limiting. Recovery may be delayed.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea is frequent during first few days until tolerance develops. Diarrhea is uncommon.

  • Mucocutaneous effects.

    • Stomatitis is uncommon.

    • Alopecia, pruritus, and drug rash are uncommon.

  • CNS effects. Paresthesias, neuropathies, headache, dizziness, depression, apprehension, nervousness, insomnia, nightmares, hallucinations, ataxia, confusion, convulsions, and coma have been reported with varying frequency.

  • Miscellaneous effects.

    • Secondary neoplasia is possible.

    • Visual disturbances are rare.

    • Postural hypotension is rare.

    • Hypersensitivity reactions are rare.

    • There is a strong potential for teratogenesis.

Progestins

Other names

Medroxyprogesterone acetate (Provera, Depo-Provera), hydroxyprogesterone caproate (Delalutin), megestrol acetate (Megace).

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Mechanism of action

Mechanisms of antitumor effects or for appetite stimulation are not clear.

Primary indications

  • Appetite stimulation.

  • Endometrial carcinoma.

Usual dosage and schedule

  • As appetite stimulant. Megestrol acetate 800 mg PO daily.

  • As antineoplastic.

    • Megestrol acetate 80 to 320 mg PO daily.

    • Medroxyprogesterone acetate 1,000 to 1,500 mg IM weekly or 400 to 800 mg PO twice weekly.

    • Hydroxyprogesterone caproate 1,000 to 1,500 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

  • Myelosuppression and other hematologic effects. None.

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

  • Mucocutaneous effects. Mild alopecia or skin rash is uncommon.

  • Miscellaneous effects.

    • Mild fluid retention is occasional to common.

    • Mild liver function abnormalities is occasional; intrahepatic cholestasis may occur.

    • Menstrual irregularities are common.

    • Increased appetite and weight gain are common.

Raloxifene

Other name

Evista.

Mechanism 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

  • Prevention of osteoporosis in postmenopausal women.

  • 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 PO 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

  • Myelosuppression and other hematologic effects. Uncommon and mild.

  • Nausea, vomiting, and other gastrointestinal effects. Uncommon.

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  • Mucocutaneous effects. Rash, sweating, and vaginitis are uncommon.

  • Miscellaneous effects.

    • Thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis, are rare. Lower risk than with tamoxifen.

    • Leg cramps are uncommon to occasional.

    • Hot flashes are common.

    • Lowers total cholesterol and low-density lipoprotein cholesterol.

  • Carcinogenesis. Risk for endometrial carcinoma is rare (0.5%) and lower than with tamoxifen (0.75%).

Raltitrexed

Other name

Tomudex.

Mechanism of action

Raltitrexed is a quinazoline antifolate that is a direct specific inhibitor of thymidylate synthase, which thereby blocks the conversion of uridylate to thymidylate and consequent DNA synthesis.

Primary indication

Advanced colorectal carcinoma in patients in whom fluorouracil regimens are not tolerated or are inappropriate.

Usual dosage and schedule

3 mg/m2 IV over 15 min every 3 weeks.

Special precautions

Dose must be reduced for renal insufficiency. For creatinine clearance of 55 to 65 mL/min, give 75% dose; for 25 to 54 mL/min, give 50% dose; for <25 mL/min, give no raltitrexed.

Toxicity

  • Myelosuppression and other hematologic effects. Common, but severe or worse less than 5% of the time.

  • Nausea, vomiting, and other gastrointestinal effects.

    • Nausea, vomiting, and diarrhea are common and occasionally severe.

    • Asymptomatic increases in hepatic transaminases are occasional.

    • Abdominal pain is common.

  • Mucocutaneous effects. Mucositis is occasional and rarely severe. Skin rash is occasional

  • Miscellaneous effects.

    • Asthenia and fever are common, but usually mild to moderate, although a more severe flu-like syndrome is occasional.

    • Weight loss and dehydration are occasional.

    • Arthralgia is uncommon.

    • Headache is occasional.

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's lymphomas,

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and the Fc domain recruits immune effect or functions to mediate B-cell lysis.

Primary indications

  • Non Hodgkin's B-cell lymphoma that is low grade or follicular, CD20 positive, as a single agent or in combination or sequence with cytotoxic chemotherapy.

  • Non Hodgkin's lymphoma, diffuse large B-cell, CD20 positive, in combination or sequence with cytotoxic chemotherapy.

  • Other B-cell non Hodgkin's lymphomas.

  • Chronic lymphocytic leukemia, usually in combination or sequence with cytotoxic chemotherapy.

Usual dosage and schedule

  • 375 mg/m2 given as a slow IV infusion, initially at a rate of 50 mg/h. If hypersensitivity or other infusion-related events do not occur, escalate in 50-mg/h increments to a maximum of 400 mg/h. Usually takes 4 to 6 h to infuse initial therapy. Interrupt or slow down 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.

Special precautions

  • 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 swelling in tongue or throat, 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 min of starting the infusion.

  • Most will resolve with slowing down 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 bronchodilators and may preclude additional treatment with rituximab.

  • The rate of infusion events decreases from 80% during the first infusion to 40% during subsequent infusions.

  • Abdominal pain, bowel obstruction, and perforation have been seen in patients receiving rituximab in combination with chemotherapy.

  • Hepatitis B reactivation with related fulminant hepatitis and other viral infections has been reported.

Toxicity

  • 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 approximately 30% of patients treated with rituximab, but only uncommonly are they severe.

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  • Nausea, vomiting, and other gastrointestinal effects. Nausea is common (23%) but rarely severe. Vomiting and diarrhea are occasional. Bowel obstruction and perforation are rare.

  • 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.

  • Miscellaneous effects.

    • Infusion-related hypersensitivity 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 in the preceding text.

    • Myalgia and arthralgia are occasional. Rarely, a serum sickness like reaction may be seen that requires corticosteroid therapy.

    • Hypotension is occasional but rarely severe. Chest pain, bronchospasm, tachycardia, increased cough, edema, and postural hypotension are uncommon. Severe though potentially fatal cardiac events, including angioedema, arrhythmia, and angina are rare.

    • Renal failure, possibly requiring dialysis, has been seen, particularly in association with tumor lysis syndrome in patients with high tumor cell burden. May also be seen if used in combination with cisplatin.

    • Hepatitis B reactivation with related fulminant hepatitis is rare.

    • Dizziness and anxiety are occasional.

    • Progressive multifocal leukoencephalopathy is rare.

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

  • Myeloid reconstitution after peripheral blood or bone marrow progenitor cell transplantation.

  • Neutrophil recovery following chemotherapy in acute myelogenous leukemia.

  • Mobilization of peripheral blood progenitor cells (PBPC).

  • Granulocytopenia from primary marrow disorders, such as myelodysplastic syndrome or aplastic anemia.

  • Granulocytopenia associated with AIDS and its therapy.

Usual dosage and schedule

  • Myeloid reconstitution after autologous stem cell transplantation. 250 g/m2 IV daily as a 2-h infusion beginning 2 to 4 h after the autologous stem cell infusion and not less than 24 h after the last dose of chemotherapy or less than 12 h after the

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    last dose of radiotherapy. Continue for 21 days or until the absolute neutrophil count reaches 20,000/ L.

  • Bone marrow transplantation failure or engraftment delay. 250 g/m2 daily for 14 days as a 2-h IV infusion. If there is no marrow recovery, may be repeated in 7 days at same or higher dose (500 g/m2). Dose and duration are dependent on the response.

  • Mobilization of PBPC. The recommended dose is 250 g/m2/ day administered IV over 24 h or SC once daily. Dosing should continue at the same dose through the period of PBPC collection.

  • Neutrophil recovery following chemotherapy in acute myelogenous leukemia. 250 /m2/day administered intravenously over a 4-h period starting 4 days following the completion of induction chemotherapy and continuing until the ANC is more than 1,500 cells/ L for 3 consecutive days or a maximum of 42 days.

  • Aplastic anemia, myelodysplastic syndrome, and AIDS. Doses may be much lower (50 100 g/m2 SQ 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 h; longer infusion may help.

Toxicity

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

  • Nausea, vomiting, and other gastrointestinal effects. Occasional.

  • Mucocutaneous effects. Rash is uncommon; exacerbation of preexisting dermatologic conditions is occasional; mild local reactions at injection site is common.

  • Miscellaneous effects. Usually mild and short lived at standard doses, but with increasing dose, may be more severe.

    • Bone pain, musculoskeletal symptoms such as cramps, and back or leg pain are common.

    • Pericarditis, fluid retention, and venous thrombosis are dose related and uncommon at standard doses.

    • Flu-like symptoms (fever, chills, aches, headache) are occasional at standard doses, but common at higher doses.

Sorafenib

Other names

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 indication

Renal cell carcinoma.

Usual dosage and schedule

  • 400 mg PO 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 prothrombin time and INR, resulting in increased risk of bleeding.

Toxicity

  • Myelosuppression and other hematologic effects. Lymphopenia is common; anemia, neutropenia, and thrombocytopenia

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    are occasional; various bleeding events (including epistaxis, gastrointestinal hemorrhage, respiratory tract hemorrhage, hematomas) are common but only rarely life threatening.

  • Nausea, vomiting, and other gastrointestinal effects. Diarrhea is common (33%); nausea and vomiting are occasional to common (10% 20%); anorexia and constipation are occasional.

  • Increased amylase and lipase are common and transient increases in transaminases are occasional. Clinical pancreatitis is uncommon.

  • Mucocutaneous effects. Hand foot skin reaction is common (30%). Alopecia is common (27%). Pruritus is occasional to common (19%). Other skin changes are rare to uncommon.

  • Miscellaneous effects.

    • Hypertension, usually mild to moderate, is occasional. Hypertensive crisis is rare.

    • Fatigue is common.

    • Sensory neuropathy is occasional (13%).

    • Hypophosphatemia is common (45%) (unknown etiology).

Streptozocin

Other names

Streptozotocin, 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 myelo toxicity.

Primary indications

  • Pancreatic islet cell and pancreatic exocrine carcinomas.

  • Carcinoid tumors.

Usual dosage and schedule

  • 1.0 to 1.5 g/m2 IV weekly for 6 weeks followed by 4 weeks of observation.

  • 1.0 g/m2 IV on days 1 and 8 in combination with fluorouracil and mitomycin. Repeat every 4 weeks.

  • 500 mg/m2 IV on days 1 to 5 every 6 weeks.

Special precautions

  • A 30- to 60-min infusion is recommended to reduce local pain and burning around the vein during treatment.

  • Avoid extravasation.

  • Have 50% glucose available to treat sudden hypoglycemia.

Toxicity

  • Myelosuppression and other hematologic effects. Uncommon and mild.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common and severe. May become progressively worse over a 5-day course of therapy.

  • Mucocutaneous effects. Uncommon.

  • Nephrotoxicity. Renal toxicity is common. Although it is not clearly dose 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.

  • Miscellaneous effects.

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    • Hypoglycemia: in patients with insulinoma, hypoglycemia may be severe (although transient) owing to a burst of insulin release.

    • Hyperglycemia is uncommon in healthy persons or diabetic patients, as normal cells are usually insensitive to streptozocin's effect.

    • Transient mild hepatotoxicity is occasional.

    • Second malignancies are possible.

Sunitinib

Other names

Sutent, Sunitinib malate.

Mechanism of action

Inhibition of multiple RTKs, including PDGF-Rs, 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 P-450 enzyme allele, CYP3A4.

Primary indications

  • GIST that has shown progression during prior treatment with imatinib or in patients who are intolerant to imatinib.

  • Renal cell carcinoma.

Usual dosage and schedule

50 mg PO 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.

Toxicity

  • Myelosuppression and other hematologic effects. Myelosuppression and lymphopenia are common, but it is uncommon to rare for them to be of high grade (3 or 4). Bleeding is occasional, with possible tumor-related hemorrhage. Venous thromboembolic events are uncommon.

  • Nausea, vomiting, and other gastrointestinal effects. Diarrhea, nausea, vomiting, dyspepsia, 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.

  • Mucocutaneous effects. Stomatitis and altered taste are common. Skin discoloration is common. Rash and hand-foot syndrome are occasional. Alopecia is uncommon.

  • Miscellaneous effects.

    • Congestive heart failure with decrease in left ventricular ejection fraction to below the lower limit of normal is occasional.

    • Hypertension is common, but severe hypertension is uncommon.

    • Adrenal insufficiency is possible, based on animal studies.

    • Fatigue is common. Asthenia, headache, arthralgia, myalgia, oral pain, and back pain are occasional.

    • Cough and dyspnea are occasional.

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    • Renal function abnormalities (low grade) are occasional. Hypo- and hyperkalemia, hypo- and hypernatremia, and hypophosphatemia are occasional.

    • Hypothyroidism is uncommon.

    • Edema is occasional.

Tamoxifen

Other name

Nolvadex.

Mechanism 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- and TGF- .

Primary indications

  • Breast carcinoma.

    • Metastatic tumors in postmenopausal or premenopausal women with estrogen receptor positive (or unknown) tumors.

    • Adjuvant therapy in women with estrogen receptor positive (or progesterone receptor positive) tumors after primary therapy. Optimal duration of therapy for most women is probably limited to 5 years.

    • Breast cancer prevention in very high risk women.

  • Melanoma, in combination with other drugs (controversial).

Usual dosage and schedule

20 mg PO as single daily dose.

Special precautions

Hypercalcemia may be seen during initial therapy.

Toxicity

  • Myelosuppression and other hematologic effects. Uncommon and mild.

  • 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.

  • 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.

  • Miscellaneous effects.

    • Hot flashes are common.

    • Vaginal bleeding and menstrual irregularity are uncommon to occasional.

    • Lassitude, headache, leg cramps, and dizziness are uncommon.

    • Peripheral edema is occasional.

    • Increased bone pain, tumor pain, and local disease flare (associated both with good tumor response as well as with tumor progression) are occasional.

    • Slowed progression of osteoporosis.

    • Reduction in serum cholesterol with favorable changes in lipid profile.

    • Thromboembolic phenomena are rare.

    • Liver function test abnormalities are occasional.

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  • Carcinogenesis. 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 alkylation (methylation) of DNA at the O6 and N7 positions of guanine.

Primary indication

  • Glioblastoma, concurrently with radiotherapy and as maintenance after radiotherapy.

  • Anaplastic astrocytoma that is refractory to nitrosoureas.

  • Melanoma.

  • Metastatic carcinomas to the brain.

Usual dosage and schedule

  • 150 to 200 mg/m2 PO on an empty stomach daily for 5 days every 28 days.

  • 75 mg/m2 PO on an empty stomach daily during radiation therapy for up to 7 weeks.

Special precautions

Contraindicated in patients with a hypersensitivity to dacarbazine (DTIC), because both drugs are metabolized to MTIC. Preventive treatment for pneumocystis jiroveci pneumonia (PCP) is required when temozolomide is administered with radiotherapy.

Toxicity

  • Myelosuppression and other hematologic effects. Myelosuppression with anemia, thrombocytopenia, and neutropenia, is common and dose dependent, but only occasionally is it severe.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and constipation are occasional to common, but usually not severe. Vomiting is occasional as is anorexia. Abdominal pain is uncommon.

  • Mucocutaneous effects. Rash and pruritus are occasional. Alopecia is common.

  • Miscellaneous effects.

    • Headache, fatigue, asthenia, and fever are common (20 65%).

    • Peripheral edema is occasional.

    • 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.

  • Anxiety and depression are occasional.

Temsirolimus

Other names

TEMSR, CCI-779.

Mechanism of action

After temsirolimus complexes with the immunophilin FKBP12, the complex inhibits mTOR (mammalian target of rapamycin) kinase activity. mTOR, as a master regulator of cell physiology, is involved in regulation of cell growth and

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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 indications

Renal cell carcinoma.

Usual dosage and schedule

25 mg IV weekly.

Toxicity

  • Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are common.

  • Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, and vomiting are common. Diarrhea is common.

  • Mucocutaneous effects. Mucositis is common. Maculopapular rash or acne are common. Nail disorders are common.

  • Immune effects and infusion reactions.

  • Miscellaneous effects.

    • Asthenia is common.

    • Hyperglycemia is common and occasionally severe.

    • Hypophosphatemia is occasional and may be severe.

    • Hypertriglyceridemia is common and may be severe.

    • Dyspnea is occasional.

    • 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

  • Acute lymphocytic leukemia.

  • Neuroblastoma.

  • Non Hodgkin's lymphomas.

Usual dosage and schedule

  • 165 mg/m2 IV over 30 to 60 min twice weekly for eight to nine doses (with cytarabine).

  • 250 mg/m2 IV over 30 to 60 min weekly for 4 to 8 weeks (with vincristine and prednisone).

Special precautions

  • 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.

  • See package insert for IV preparation and administration equipment requirements.

Toxicity

  • Myelosuppression and other hematologic effects. Common and dose limiting.

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

  • Mucocutaneous effects. Alopecia and mucositis are common.

  • Miscellaneous effects.

    • Hepatic and renal dysfunction are rare.

    • Hypersensitivity reactions with urticaria and flushing are occasional. Anaphylaxis is uncommon.

    • Hypotension is related to drug infusion rate but should be seen only occasionally at the recommended dose schedules.

    • Secondary leukemias are uncommon.

    • Chemical phlebitis is uncommon.

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Thalidomide

Other name

Thalomid.

Mechanism action. Multiple potential mechanisms, including inhibition of VEGF, inhibition of TNF- , direct inhibition of G1 growth and promotion of apoptosis, expansion of NK cells, and costimulation of T cells.

Primary indications

  • Multiple myeloma.

  • Myelodysplastic syndrome.

Usual dosage and schedule

A starting dose of 50 to 100 mg 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 ensure that female patients are not pregnant when the drug is started, and that both female and male patients practice strict birth control measures. Deep venous thrombosis is enhanced by corticosteroids.

Toxicity

  • Myelosuppression and other hematologic effects. None to minimal myelosuppression. Occasional deep venous thrombosis.

  • Nausea, vomiting, and other gastrointestinal effects. Constipation is common.

  • Mucocutaneous effects. Macular rash, usually involving trunk, is common. Alopecia is uncommon. Rare severe or life threatening epidermal damage.

  • Miscellaneous effects.

    • Dose-dependent somnolence and dizziness are 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.

    • Peripheral neuropathy is common (25%) with chronic therapy. Occasional patients develop myalgia, tremor, or muscle spasms.

    • Fatigue is common.

    • Headache is occasional.

    • Edema is occasional to common.

    • Hypothyroidism is occasional.

    • Birth defects. (see Special precautions in the preceding text.)

    • Hypercoagulability with deep venous thrombosis is occasional.

Thiotepa

Other name

Triethylenethiophosphoramide, Thioplex.

Mechanism of action

Alkylating agent similar to mechlorethamine.

Primary indications

  • Superficial papillary carcinoma of urinary bladder.

  • Malignant peritoneal, pleural, or pericardial effusions.

  • Neoplastic meningeal infiltrates.

Usual dosage and schedule

  • 12 mg/m2 IV bolus every 3 weeks in combination with vinblastine and doxorubicin for breast cancer.

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  • 30 to 60 mg in 40 to 50 mL water instilled into the bladder and retained for 1 h. Dose is repeated weekly for 3 to 6 weeks, then every 3 weeks for 5 cycles.

  • 25 to 30 mg/m2 in 50 to 100 mL saline solution as a single intracavitary injection. Dose may be repeated as tolerated, monitoring through blood counts.

  • 10 to 15 mg intrathecally.

  • High-dose therapy using 500 to 1,000 mg/m2 over 3 days has been used followed by stem cell rescue (e. g., bone marrow transplantation).

Special precaution

Dose should be reduced in patients with impaired renal function, as the drug is primarily excreted in the urine.

Toxicity

  • Myelosuppression and other hematologic effects. Dose limiting. Pancytopenia and sepsis may follow intravesical or intracavitary administration. Nadir counts are reached in 1 to 2 weeks; recovery by 4 weeks is usual.

  • Nausea, vomiting, and other gastrointestinal effects. Uncommon.

  • Mucocutaneous effects. Uncommon. Thiotepa is not a vesicant. Hyperpigmentation of skin occurs at high doses.

  • Miscellaneous effects.

    • Local pain, dizziness, headache, and fever are uncommon.

    • Secondary neoplasms are possible.

    • Amenorrhea and azoospermia are common.

    • CNS effects with high-dose therapy.

Topotecan

Other name

Hycamtin.

Mechanism of action

Topotecan, a semisynthetic derivative of CPT, 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 topoisomerase I.

Primary indications

  • Ovarian carcinoma.

  • Carcinoma of the cervix.

  • Small cell and non small cell carcinoma of the lung.

Usual dosage and schedule

  • As a single agent, 1. 5 mg/m2 IV as a 30-min infusion daily, five times every 3 weeks.

  • In combination with cisplatin, 0. 75 mg/m2 IV as a 30-min infusion daily, three times every 3 weeks.

Special precautions

None.

Toxicity

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting and diarrhea are common, but usually mild. Other gastrointestinal symptoms, including constipation and abdominal pain, occur occasionally.

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  • Mucocutaneous effects. Alopecia is common; stomatitis is occasional but usually mild; skin rash is rare.

  • Miscellaneous effects.

    • Fever, headache, fatigue, and weakness are common (15% to 25%) but rarely severe.

    • Microscopic hematuria is occasional.

    • Dyspnea occurs occasionally, but it is uncommon for it to be severe.

    • Infection as a consequence of severe leukopenia is common.

Toremifene

Other name

Fareston.

Mechanism 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 PO daily.

Special precautions

Uncertain whether it has any carcinogenic effect on endometrium as has been observed with tamoxifen. May result in increased prothrombin time in patients taking warfarin (Coumadin). Cytochrome P-450 3A4 enzyme inhibitors, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the concentration in the serum.

Toxicity

  • Myelosuppression and other hematologic effects. Uncommon and mild.

  • Nausea, vomiting, and other gastrointestinal effects. Minimal nausea is common early in treatment; vomiting is occasional.

  • 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.

  • Miscellaneous effects.

    • Hot flashes are common.

    • Sweating is occasional.

    • Vaginal bleeding and menstrual irregularity are occasional.

    • Hypercalcemia is uncommon.

    • Thromboembolic phenomena are rare.

131I-Tositumomab

Other name

Bexxar.

Mechanism of action

131I-Tositumomab is a murine Ig-2a monoclonal anti-CD20 antibody radiolabeled with iodine 131 (131I), an emitter of both and radiation. The mechanism of action includes antibody-mediated cytotoxicity and cellularly targeted radiotherapy (radioimmunotherapy [RIT].)

Primary indications

  • Non Hodgkin's lymphoma, chemotherapy refractory, CD-20 positive, low grade or transformed low grade.

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  • Non Hodgkin's lymphoma, follicular, as initial treatment (investigational).

Usual dosage and schedule

  • 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 h before the dosimetric dose and continuing for 14 days after the therapeutic dose to prevent uptake of 131I by the thyroid.

  • Dosimetric dose. 450 mg of unlabeled tositumomab is given as a 1-h infusion followed by a 20-min infusion of 5 mCi (35 mg) of 131I tositumomab to determine the patient-specific activity (mCi) of radiolabeled tositumomab to deliver a therapeutic dose of 65 to 75 cGy 7 to 15 days later.

  • Therapeutic dose. 450 mg of unlabeled tositumomab is given as a 1-h infusion followed by a 20-min infusion of patient specific (in mCi) activity labeled to 35 mg of tositumomab.(Median 90mCi, range ~50-200 mCi.)

Special precautions

Use with caution in patients with more than 25% marrow involvement with lymphoma, prior external beam radiotherapy to more than 25% of the bone marrow, or a history of HAMA or HACA. A saturated solution of potassium iodide, two to three drops orally three times daily, is given beginning 24 h before the dosimetric dose and continuing for 14 days after the therapeutic dose to prevent uptake of 131I by the thyroid.

Toxicity

  • Myelosuppression and other hematologic effects. Myelosuppression is universal, with approximately 35% to 65% of patients having grade 3 or 4 thrombocytopenia or neutropenia. These nadir counts occur at a median of 4 to 7 weeks, last for 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.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea is common; vomiting, abdominal pain, and anorexia are occasional.

  • Mucocutaneous effects. Pruritus, rash, and sweating are occasional.

  • Miscellaneous effects.

    • Immunologic. HAMA or HACA is 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.

    • Infusion-related fever, chills, dizziness, asthenia, wheezing or coughing, nasal congestion, headache, back pain, arthralgia, and hypotension are common, more with dosimetric dose than with therapeutic dose. Most commonly, these are self-limited and mild to moderate in severity.

    • Fatigue or asthenia is common.

    • Cardiorespiratory. Cough, dyspnea, and edema are occasional; hypotension and vasodilatation are uncommon.

    • Thyroid suppression is occasional despite prophylaxis with potassium iodide.

    • Myelodysplasia and secondary leukemia are uncommon.

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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 (p185Her2).

Primary indications

  • Carcinoma of the breast that has overexpression of Her2/neu (c-erbB-2), either in advanced disease or as adjuvant therapy.

  • Other carcinomas that exhibit overexpression of Her2.

  • Usual dosage and schedule. 4 mg/kg IV loading dose over 90 min, then 2 mg/kg IV over 30 min weekly.

Special precautions

  • 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.

  • Cardiac dysfunction (cardiac symptoms or an asymptomatic decrease in ejection fraction of 10% or greater) occurs in approximately 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 approximately 1% of patients. Extreme caution should be exercised in treating patients with preexisting cardiac dysfunction.

Toxicity

  • Myelosuppression. Uncommon.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common with the first infusion. Diarrhea is also common.

  • Mucocutaneous effects. A rash is occasional to common, and may be associated with urticaria or pruritus.

  • Miscellaneous effects.

    • Mild-to-moderate chills, fever, asthenia, pain, and headache are common, primarily during the first infusion.

    • Cardiac dysfunction occurs in approximately 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.

    • Chest pain, back pain, dyspnea, and cough are occasional to common.

    • Peripheral edema is occasional.

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Tretinoin

Other names

All-trans-retinoic acid, t-RNA, ATRA, Vesanoid, Retin-A.

Mechanism of action

Binds to cytoplasmic retinoic acid binding proteins and is then 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 messenger ribonucleic acid (mRNA) transcripts are seen for RAR- , the gene for which is on chromosome 17.

Primary indication

Acute promyelocytic leukemia for induction of remission.

Usual dosage and schedule

45 mg/m2 PO daily (divided into 2 doses at least 6 h apart in the morning and 6 h later) until 30 days after complete remission is documented, up to a maximum of 90 days. Therapy is usually initiated concurrently with anthracycline.

Special precautions

Avoid use in pregnant women because of marked teratogenic potential. Advise patient to avoid pregnancy by using two reliable contraceptive methods simultaneously. Retinoic acid acute promyelocytic (RA-APL) syndrome (see following text) may require mechanical ventilation and dexamethasone 10 mg every 12 h 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

  • Myelosuppression and other hematologic effects. Myelosuppression is rare. Forty percent of patients develop leukocytosis, which increases the risk of RA-APL syndrome.

  • Disseminated intravascular coagulation is common (26%).

  • 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.

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

  • Retinoic acid syndrome. High fever, respiratory distress, 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 19).

  • Miscellaneous effects.

    • Cardiovascular. Arrhythmias, flushing, hypotension, hypertension, and phlebitis are occasional. Cardiac failure,

      P.163


      cardiac arrest, pulmonary hypertension, and other more severe cardiovascular problems are uncommon.

    • Cataracts and corneal ulcerations or opacities are uncommon.

    • Musculoskeletal. Arthralgias, bone pain, muscle aches are occasional to common; skeletal hyperostosis is common at higher doses (80 mg/m2/day).

    • Hypertriglyceridemia. Mild-to-moderate elevations are common; marked elevations (>5 times normal) are uncommon; hypercholesterolemia occurs to a lesser degree.

    • Neurologic. Headache is common; paresthesias, dizziness, and visual disturbances are occasional; lethargy, fatigue, and mental depression are uncommon; pseudotumor cerebri is rare.

    • Hepatotoxicity with increased LDH, SGOT, SGPT, GGTP, alkaline phosphatase is common.

    • Hyperhistaminemia with shock is rare.

    • Renal insufficiency is occasional.

    • 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, causes chromosomal damage, and arrests cell cycle in G2. A principal mechanism of valrubicin metabolites is DNA strand breakage mediated by anthracycline effects on topoisomerase II.

Primary indication

Intravesical therapy of BCG-refractory carcinoma in situ (CIS) 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 h before voiding.

Special precautions

Should not be administered if there is any question about perforation of the bladder or integrity of bladder mucosa.

Toxicity

  • Myelosuppression and other hematologic effects. Uncommon, unless bladder rupture or perforation occurs, in which case severe neutropenia can be expected 2 weeks after administration.

  • Nausea, vomiting, and other gastrointestinal effects. Uncommon.

  • Mucocutaneous effects. Rash is uncommon.

  • Miscellaneous effects.

    • Local reactions. Frequency, dysuria, urgency, bladder spasm, hematuria, and bladder pain are common. Urinary incontinence and cystitis are occasional. Local burning symptoms associated with the procedure, urethral pain, pelvic pain, and gross hematuria are uncommon to rare.

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    • Body as a whole. Abdominal pain, asthenia, back pain, chest pain, fever, headache, and malaise are uncommon.

Vinblastine

Other name

VLB, Velban.

Mechanism of action

Mitotic inhibition with reversible metaphase arrest due to action on microtubular and spindle contractile proteins.

Primary indications

  • Hodgkin's and non Hodgkin's lymphomas.

  • Testicular, gestational trophoblastic, kidney, and breast carcinomas.

Usual dosage and schedule

  • 4 to 18 mg/m2 IV weekly.

  • 6 mg/m2 IV on days 1 and 15 in combination with doxorubicin, bleomycin, and dacarbazine for lymphomas.

  • 5 mg/m2 IV on day 1 every 3 weeks, in combination with doxorubicin and thiotepa for breast cancer.

Special precautions

Administer as a slow push, taking care to avoid extravasation.

Toxicity

  • 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.

  • Nausea, vomiting, and other gastrointestinal effects. Common but not usually severe.

  • Mucocutaneous effects.

    • Extravasation may lead to severe inflammation, pain, and tissue damage. Local infiltration with 1 to 6 mL of hyaluronidase (150 units/mL) may help.

    • Mild alopecia is common.

    • Stomatitis is occasionally severe.

  • Miscellaneous effects.

    • 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.

    • Transient hepatitis is uncommon.

    • 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

  • Hodgkin's and non Hodgkin's lymphomas.

  • Acute lymphocytic leukemia.

  • Multiple myeloma.

  • Wilms' tumor, neuroblastoma, rhabdomyosarcoma, and Ewing's sarcoma of childhood.

  • Breast carcinoma.

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Usual dosage and schedule

  • 1 to 2 mg/m2 (maximum 2. 0 2.4 mg) IV weekly.

  • 0.4 mg/day as a continuous IV infusion on days 1 to 4.

Special precautions

  • Administer as a slow IV push, taking care to avoid extravasation.

  • 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 vincristine's effect.

  • Reduce dose if liver disease is significant.

  • Stool softeners or high-fiber or bulk diets may avert severe constipation.

Toxicity

  • Myelosuppression and other hematologic effects. Mild and rarely of clinical significance.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are not seen unless paralytic ileus occurs. Constipation is common.

  • Mucocutaneous effects. Severe local inflammation if extravasation occurs. Alopecia is common.

  • Neurotoxicity. Is 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.

  • Miscellaneous effects.

    • Uric acid nephropathy due to rapid tumor cell lysis and release of uric acid is always a potential problem when therapy is first given.

    • Syndrome of inappropriate antidiuretic hormone is rare.

    • Jaw pain is uncommon.

Other names

VDS, Eldisine.

Mechanism of action

Mitotic inhibition with reversible metaphase arrest due to action on microtubule and spindle contractile protein.

Primary indications

  • Lung, breast, and esophageal carcinomas.

  • Hodgkin's and non Hodgkin's lymphomas.

  • Melanoma.

Usual dosage and schedule

  • 2 to 4 mg/m2 IV bolus (over 2 3 min) weekly for induction, then every 2 weeks.

  • 5 mg/m2/day for 5 to 7 days as a continuous infusion.

Special precautions

Take care to avoid extravasation, as the agent is a vesicant.

Toxicity

  • Myelosuppression and other hematologic effects. Leukopenia is common but not usually severe.

  • Nausea, vomiting, and other gastrointestinal effects. Occasional and mild.

  • Mucocutaneous effects. Alopecia is common. Rash is rare.

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  • Neurotoxicity. Dose dependent and cumulative, and includes constipation, paralytic ileus, paresthesia, myalgias, and weakness. Severity is intermediate between vincristine and vinblastine. Cranial neuropathy may manifest as jaw pain.

  • Miscellaneous effects.

    • Chills and fever are occasional.

    • Phlebitis is occasional.

    • Confusion and lethargy are rare.

Vinorelbine

Other name

Navelbine.

Mechanism of action

Binds to tubulin, and depolymerizes microtubules causing mitotic inhibition, similar to other vinca alkaloids. Lower affinity for axonal microtubules is associated with lower neuro toxicity.

Primary indications

  • Metastatic carcinoma of the breast.

  • Non small cell carcinoma of the lung.

Usual dosage and schedule

30 mg/m2 IV as 6- to 10-min rapid infusion weekly when used with a single agent or with cisplatin.

20 to 25 mg/m2 IV as a 6- to 10-min 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 and by 75% for bilirubin levels of more than 3 mg/dL.

Toxicity

  • Myelosuppression and other hematologic effects. Granulocytopenia is common and dose limiting, with nadir at 7 to 10 days. Thrombocytopenia is uncommon. Anemia is occasional to common.

  • Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but usually mild to moderate. Diarrhea occurs occasionally.

  • Mucocutaneous effects. Alopecia, mild diarrhea, and stomatitis are occasional. Severe local inflammation can occur with extravasation.

  • Miscellaneous effects.

    • Neurotoxicity: cumulative but reversible constipation and decreased deep tendon reflexes are occasional; paresthesias are uncommon.

    • Erythema, pain, and skin discoloration at injection site are common; phlebitis at injection site is occasional.

Vorinostat

Other name

Zolinza.

Mechanism of action. Inhibits histone deacetylases (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.

P.167


Primary indication

  • Cutaneous T-cell lymphoma with progressive, persistent, or recurrent skin disease after two other systemic therapies.

Usual dosage and schedule

400 mg PO 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 of fluid 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

  • Myelosuppression and other hematologic effects. Thrombocytopenia is common; anemia and neutropenia are occasional. Increased prothrombin time and INR may be seen with concomitant use of warfarin with vorinostat.

  • Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, and diarrhea are common. Vomiting, constipation, and weight loss are occasional.

  • Mucocutaneous effects. Alopecia is occasional to common.

  • Miscellaneous effects.

    • Blood chemistry abnormalities. Hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and increased creatinine are common and may be severe (grade 3 or higher).

    • Cardiovascular. QTc prolongation on the electrocardiogram is uncommon. Edema is occasional.

    • Neuromuscular. Fatigue is common. Headache, muscle spasms, and dizziness are occasional.

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

  • Hypercalcemia associated with malignancy.

  • Bone metastases from breast cancer, prostate cancer (after progression on hormonal therapy) and from other solid tumors in conjunction with standard antineoplastic therapy.

  • Osteolytic and osteoporotic bone lesions of multiple myeloma.

Usual dosage and schedule

  • Hypercalcemia of malignancy: 4 mg IV as a 15-min infusion. May be repeated every 1 to 8 weeks, as needed.

  • Multiple myeloma or metastatic bone lesions: 4 mg IV as a 15-min infusion every 3 to 4 weeks.

Special precautions

  • Do not infuse over less than 15 min. Potential for renal tubular damage, particularly if infused more rapidly. The risk of adverse reactions, particularly renal adverse reactions may

    P.168


    be greater in patients with impaired renal function. Dose adjustments are not necessary so long as serum creatinine is less than 4.5 mg/dL. Use caution when administered concurrently with aminoglycosides. 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

  • Myelosuppression and other hematologic effects. Rare.

  • Nausea, vomiting, and other gastrointestinal effects. Abdominal pain, anorexia, constipation, nausea, and vomiting are uncommon to occasional.

  • Mucocutaneous effects. Infusion site reaction is occasional.

  • Miscellaneous effects.

    • Flu-like syndrome with fever, chills, skeletal aches and pains are occasional.

    • Hypocalcemia and hypomagnesemia are occasional, but grade 3 or 4 abnormalities are uncommon to rare.

    • Increase of the serum creatinine of 0. 5 mg/dL above baseline is occasional, but elevation to more than 3 times ULN is uncommon.

    • Hypophosphatemia less than 2 mg/dL is occasional, but does not appear to have serious consequences or require treatment.

    • Osteonecrosis of the jaw uncommon to rare.

    • Conjunctivitis or other ocular abnormalities are rare.

    • Potential bronchoconstriction in aspirin-sensitive patients.

Suggested Readings

Chabner B, Longo DL. Cancer chemotherapy and biotherapy: principles and practice, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:1000

Dorr RT, Van Hoff DD, eds. Cancer chemotherapy handbook. Norwalk: Appleton & Lange, 1994:1020.

National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). at http://ctep.cancer.gov/reporting/ctc.html, 2003.

Perry MC. The chemotherapy source book. Philadelphia: Lippincott Williams & Wilkins, 2001:1024.

Tannock IF, Hill RP, eds. The basic science of oncology. New York: McGraw-Hill, 1998:539.



Handbook of Cancer Chemotherapy
Handbook of Cancer Chemotherapy
ISBN: 0781765315
EAN: 2147483647
Year: 2007
Pages: 37

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