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I. CLASSES OF DRUGSChemotherapeutic agents are customarily divided into several classes. For two of the classes, the alkylating agents and the antimetabolites, the names indicate the mechanism of cytotoxic action of the drugs in their class. For the hormonal agents, the name designates the physiologic action of the drug, and for the natural products, the name reflects the source of the agents. The biologic response modifiers include agents that mimic, stimulate, enhance, inhibit, or otherwise alter the host responses to the cancer. Molecular targeted agents affect defined and putative abnormalities in the cancer cell and its environment. Drugs that do not fit easily into other categories are grouped together as miscellaneous agents. Data for individual agents are given in Section III of this chapter.Within each class are several types of agents (Table 33.1). As with the criteria for separating into class, the types are also grouped according to the mechanism of action, biochemical structure or derivation, and physiologic action. In some instances, these groupings into classes and types are arbitrary, and some drugs seem to fit into either more than one category or none. However, the classification of chemotherapeutic agents in this fashion is helpful in several respects. For example, because the antimetabolites interfere with purine and pyrimidine metabolism and the formation of DNA and RNA, they are all at least cell cycle-specific and in some instances primarily cell cycle 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.The classification scheme also may help to predict cross-resistance between drugs. Tumors that are resistant to one of the nitrogen mustard types of alkylating agents thus would be likely to be resistant to another of that same type, but not necessarily to one of the other types of alkylating agents such as the nitrosoureas or the metal salts (e.g., cisplatin). The classification system does not help in predicting multidrug resistance, which may have several phenotypes.
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A. Alkylating agents
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1. General description. The alkylating agents are a diverse group of chemical compounds capable of forming molecular bonds with nucleic acids, proteins, and many molecules of low molecular weight. The compounds either are electrophiles or generate electrophiles in vivo to produce polarized molecules with positively charged regions. These polarized molecules then can interact with electron-rich regions of most cellular molecules. The cytotoxic effect of the alkylating agents appears to relate primarily to the interaction between the electrophiles and DNA. This interaction may result in substitution reactions, crosslinking 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.TABLE 33.1 Classification of Classical and Molecular Targeted Agents
Class and Type
Agents
Alkylating agents
Alkyl sulfonate
Busulfan
Ethylenimine derivative
Thiotepa (triethylenethiophosphoramide)
Metal salt
Carboplatin, cisplatin, oxaliplatin
Nitrogen mustard
Bendamustine, chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan
Nitrosourea
Carmustine, lomustine, streptozocin
Triazene-imidazole carboxamide
Dacarbazine, temozolamide
Antimetabolites
Antifolates
Methotrexate, pemetrexed, pralatrexate
Purine analogs
Cladribine, 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
Cabazitaxel, docetaxel, paclitaxel
Mitotic inhibitor
Eribulin, ixabepilone, 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
GNRH receptor antagonist
Degarelix
LHRH agonist
Goserelin, leuprolide, triptorelin
Polypeptide hormone release suppression
Octreotide
Progestin
Megestrol acetate, medroxyprogesterone acetate
Selective estrogen-receptor-modulator (estrogen antagonist)
Fulvestrant, raloxifene, tamoxifen, toremifene
Somatostatin analog
Octreotide
Thyroid hormones
Levothyroxine, liothyronine
Molecularly targeted agents
Cyclin-dependent kinase inhibitor
Flavopiridol
Gene expression modulators
Retinoids, rexinoids, romidepsin
IL-2 receptor toxin
Denileukin diftitox
Monoclonal antibody
Alemtuzumab, cetuximab, gemtuzumab, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, trastuzumab, rituximab, iodine-131 tositumomab
mTOR kinase inhibitor
Everolimus, temsirolimus
PARP1 inhibitor
Olaparib
Proteosome inhibitor
Bortezomib
Receptor tyrosine kinase inhibitors, multikinase inhibitors
Dasatinib, erlotinib, gefitinib, imatinib mesylate, lapatinib, midostaurin, pazopanib, semaxanib, sorafenib, sunitinib, vandetanib
Retinoic acid receptor expression modification
Tretinoin (all-trans-retinoic acid)
Biologic response modifiers
Interferons
Interferon-α2a, interferon-α2b
Interleukins
Aldesleukin (IL-2), oprelvekin, denileukin diftitox
Myeloid- and erythroid-stimulating factors
Epoetin, filgrastim, sargramostim
Nonspecific immunomodulation
Thalidomide, lenalidomide
Vaccine (autologous)
Sipuleucel-T
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
Substituted melamine
Altretamine (hexamethylmelamine)
Substituted urea
Hydroxycarbamide (hydroxyurea)
GNRH, gonadotropin-releasing hormone; IL, interleukin; LHRH, luteinizing hormone-releasing hormone; mTOR, mammalian target of rapamycin; PARP, poly(ADP-ribose) polymerase.
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2. Types of alkylating agents
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a. Nitrogen mustards. These compounds produce highly reactive carbonium ions that react with the electron-rich areas of susceptible molecules. They vary in reactivity from mechlorethamine, which is highly unstable in aqueous form, to cyclophosphamide, which must be biochemically activated in the liver. Bendamustine, a mechlorethamine derivative, contains a purinelike benzimidazole ring, and the exact mechanism of action of this unique agent is unknown.
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b. Ethylenimine derivatives. Triethylenethiophosphoramide (thiotepa) is the only compound in this group that has much clinical use. Ethylenimine derivatives are capable of the same kinds of reactions as the nitrogen mustards.
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c. Alkyl sulfonates. Busulfan is the only clinically active compound in this group. It appears to interact more with cellular thiol groups than with nucleic acids.
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d. Triazines. Dacarbazine and its relative temozolomide are believed to act primarily as alkylators of DNA.
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e. Nitrosoureas. The nitrosoureas undergo rapid, spontaneous activation in aqueous solution to form products capable of alkylation and carbamoylation. They are unique among the alkylating agents with respect to not being cross-resistant with other alkylating agents, being highly lipid soluble, and having delayed myelosuppressive effects (6 to 8 weeks).
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f. Metal salts. Cisplatin, carboplatin, and oxaliplatin inhibit DNA synthesis probably through the formation of intrastrand crosslinks in DNA and formation of DNA adducts. They also react with DNA through chelation or binding to the cell membrane.
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-
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B. Antimetabolites
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1. General description. The antimetabolites are a group of low-molecular-weight compounds that exert their effect by virtue of their structural or functional similarity to naturally occurring metabolites involved in nucleic acid synthesis. Because they are mistaken by the cell for normal metabolites, they either inhibit critical enzymes involved in nucleic acid synthesis or become incorporated into the nucleic acid and produce incorrect codes. Both mechanisms result in inhibition of DNA synthesis and ultimate cell death. Because of their primary effect on DNA synthesis, the antimetabolites are most active in cells that are actively growing and are largely cell cycle phase-specific.
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2. Types of antimetabolites
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a. Folic acid analogs. Methotrexate, the earliest member of this group and until recently, the only one in wide clinical use, inhibits the enzyme dihydrofolate reductase. This inhibition blocks the production of the reduced N-methylenetetra-hydrofolate, the coenzyme in the synthesis of thymidylic acid. Other metabolic processes in which there is one-carbon unit transfer are also affected but are probably of less importance in the cytotoxic action of methotrexate. Pemetrexed is a multitargeted pyrrolopyrimidine-based antifolate that, when polyglutamated, inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyltransferase. Pralatrexate is a folate analogue that competitively inhibits dihydrofolate reductase. It is also an inhibitor for polyglutamylation by folylpolyglutamyl synthetase.
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b. Pyrimidine analogs. These compounds inhibit critical enzymes necessary for nucleic acid synthesis and may become incorporated into DNA and RNA.
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c. Purine analogs. The specific site of action for the purine analogs is less well defined than for most pyrimidine analogs, although it is well demonstrated that they interfere with normal purine interconversions and thus with DNA and RNA synthesis. Some of the analogs also are incorporated into the nucleic acids. The adenosine deaminase inhibitor pentostatin increases the intracellular concentration of deoxyadenosine triphosphates in lymphoid cells and inhibits DNA synthesis, probably by blocking ribonucleotide reductase. Among the metabolic alterations is nicotinamide adenine dinucleotide depletion, which may result in cell death. Cladribine accumulates in cells as the triphosphate, is incorporated into DNA, and inhibits DNA repair enzymes and RNA synthesis. As with pentostatin, nicotinamide adenine dinucleotide levels are also depleted. Fludarabine is a purine analog that causes inhibition of DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis, though the primary mechanism is not known.
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-
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C. Natural products
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1. General description. The natural products are grouped together not on the basis of activity but because they are derived from natural sources. The clinically useful drugs include plant products, fermentation products of various species of the soil fungus Streptomyces, and bacterial products.
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2. Types of natural products
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a. Mitotic inhibitors. Vincristine, vinblastine, and their semisynthetic derivatives vindesine and vinorelbine are derived from the periwinkle plant (Catharanthus roseus), a species of myrtle. They appear to act primarily through their effect on microtubular protein with a resultant metaphase arrest and inhibition of mitosis. Ixabepilone is an analog of epothilone B (produced by the myxobacterium Sorangium cellulosum) that binds to β-tubulin subunits on microtubules, causes suppression of microtubule dynamics, and blocks the cell in mitosis, which leads to cell death.
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b. Podophyllum derivatives. Etoposide and teniposide, semisynthetic podophyllotoxins derived from the root of the Mayapple plant (Podophyllum peltatum), form a complex with topoisomerase II, an enzyme that is necessary for the completion of DNA replication. This interaction results in DNA strand breakage and arrest of cells in late S and early G2 phases of the cell cycle.
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c. Camptothecins. These agents are analogs of camptothecin, a derivative of the Chinese tree Camptotheca accuminata. The primary target of the two clinically active agents, irinotecan and topotecan, is DNA topoisomerase I.
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d. Antibiotics. The antitumor antibiotics are a group of related antimicrobial compounds produced by Streptomyces species in culture. Their cytotoxicity, which limits their antimicrobial usefulness, has proved to be of great value in treating a wide range of cancers. All of the clinically useful antibiotics affect the function and synthesis of nucleic acids.
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(1) Dactinomycin, the anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin), and the anthracenedione mitoxantrone cause topoisomerase II-dependent DNA cleavage and intercalate with the DNA double helix.
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(2) Bleomycins cause DNA strand scission. The resulting fragmentation is believed to underlie the drug’s cytotoxic activity.
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(3) Mitomycin causes cross-links between complementary strands of DNA that impair replication.
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e. Enzymes. Asparaginase, the one example of this type of agent, catalyzes the hydrolysis of asparagine to aspartic acid and ammonia and deprives selected malignant cells of an amino acid essential to their survival.
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-
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D. Hormones and hormone antagonists
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1. General description. The hormones and hormone antagonists that are clinically active against cancer include steroid estrogens, progestins, androgens, corticoids and their synthetic derivatives, nonsteroidal synthetic compounds with steroid or steroid-antagonist activity, aromatase inhibitors, hypothalamic-pituitary analogs, and thyroid hormones. Each agent has diverse effects. Some effects are mediated directly at the cellular level by the drug binding to specific cytoplasmic receptors or by inhibition or stimulation of the production or action of the hormones. These agents may also act by stimulating or inhibiting natural autocrine and paracrine growth factors (e.g., epidermal growth factor, transforming growth factors [TGFs]-α and -β). The relative roles of the various actions of hormones and hormone antagonists are only partially understood and probably vary among tumor types. For selective estrogen receptor modulators such as tamoxifen, which, when bound to the estrogen receptor, ultimately controls the promoter region of genes that affect cell growth, there are a host of modulating factors including some 20 receptor-interacting proteins and 50 transcriptionactivating factors as well as many response elements. Other effects are mediated through indirect effects on the hypothalamus and its anterior pituitary-regulating hormones. The final common pathway in most circumstances appears to lead to the malignant cell, which retains some sensitivity to direct or indirect hormonal control of its growth. An exception to this mechanism is the effect of corticosteroids on leukemias and lymphomas, in which the steroids appear to have direct lytic effects on abnormal lymphoid cells that have high numbers of glucocorticoid receptors.
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2. Types of hormones and hormone antagonists
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a. Androgens may exert their antineoplastic effect by altering pituitary function or directly affecting the neoplastic cell.
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b. Antiandrogens inhibit nuclear androgen binding.
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c. Corticosteroids cause lysis of lymphoid tumors that are rich in specific cytoplasmic receptors and may have other indirect effects as well.
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d. Estrogens suppress testosterone production (through the hypothalamus) in males and alter breast cancer cell response to prolactin.
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e. Progestins appear to act directly at the level of the malignant cell receptor to promote differentiation.
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f. Selective estrogen receptor modulators (acting as estrogen antagonists) compete with estrogen for binding on the cytosol estrogen receptor protein in cancer cells. The receptor/hormone complex ultimately controls the promoter region of genes that affect cell growth.
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g. Aromatase inhibitors are nonsteroidal inhibitors of the aromatization of androgens to estrogens. Aminoglutethimide is relatively nonselective, having many biochemical sites of inhibition of steroidogenesis. Its use requires corticosteroid replacement. In contrast, the selective aromatase inhibitors such as anastrozole or letrozole primarily block the conversion of adrenally generated androstenedione to estrone by aromatase in peripheral tissues without inhibition of progesterone or corticosteroid synthesis.
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h. Hypothalamic hormone analogs, such as the luteinizing hormone-releasing hormone agonists leuprolide or goserelin, can inhibit luteinizing hormone (LH) and follicle-stimulating hormone (FSH; after initial stimulation) and the production of testosterone or estrogen by the gonads.
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i. Thyroid hormones inhibit the release of thyroid-stimulating hormone, thus inhibiting growth of well-differentiated thyroid tumors.
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-
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E. Molecularly targeted agents
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1. General. This classification is a relatively recent one in oncology that has become possible because of maturation of knowledge about the molecular events that are responsible for the development of cancer. Understanding of the genetic changes in the cancer cell, the downstream molecular events that follow as a consequence, and the mechanisms by which these events regulate cell growth and death has led to a host of possibilities for the control of cancer growth.
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2. Tyrosine kinase and multikinase inhibitors. The first clinical example of this was the signal transduction inhibitor imatinib mesylate, which inactivates the constitutively active fusion product tyrosine kinase arising from the Philadelphia chromosome (Ph) found in chronic myelogenous leukemia (CML), Bcr-Abl, as well as c-kit kinase, which is overexpressed in gastrointestinal stromal tumors. There are now a large number of small molecule inhibitors of intracellular kinase activity (receptor and nonreceptor molecules) in clinical use, with demonstrated clinical efficacy in breast cancer, colon cancer, renal cell carcinoma, lung cancer, pancreatic cancer, and hepatoma.
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3. Monoclonal antibodies have emerged over the last 10 to 15 years as useful adjuncts to the medical oncologist’s armamentarium. These agents, which may be directed at growth factors or their receptors, are derived from murine antibodies, may have varying levels of humanization (chimerism), and may be unconjugated (alemtuzumab, bevacizumab, cetuximab, ofatumumab, rituximab, trastuzumab) or conjugated with radionuclides (ibritumomab tiuxetan, tositumomab) or another toxic moiety (gemtuzumab).
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4. Other agents. Other agents affect nuclear activity, such as the binding of all-trans-retinoic acid with cytoplasmic proteins, which in turn interact with nuclear retinoic acid receptors (RARs) that affect expression of genes that control cell growth and differentiation; inhibit proteosomes, which mediate protein degradation and play an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis; or perturb other critical pathways.
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F. Miscellaneous agentsThese are listed in Table 33.1. Descriptions of specific agents are found in Section III.
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II. CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND MOLECULAR TARGETED AGENTSSection III of this chapter contains an alphabetically arranged compendium that contains a description of the chemotherapeutic, biologic, and molecular targeted agents that are recognized to be clinically useful. Each drug is listed by its generic name, with other common names or trade names included. A brief description is given of the probable mechanism of action, clinical uses, recommended doses and schedules, precautions, and side effects.
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A. Recommended doses: CAUTIONAlthough every effort has been made to ensure that the drug dosages and schedules given here are accurate and in accord with published standards, readers are advised to check the product information sheet included in the package of each U.S. Food and Drug Administration (FDA)-approved drug. For drugs not yet approved for general use, active protocol guidelines and any current medical literature should be used to verify recommended dosages, contraindications, and precautions and to review potential toxicity.
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B. Dose selection and designationThe doses are listed using body surface area (square meters) as the base for nearly all the agents included. Adult doses from the literature, which are expressed using a weight base, have been converted by multiplying the milligram-per-kilogram dose by 37 to give the milligram-per-square-meter dose. Doses using a weight base, which have been taken from the pediatric literature, have been converted using a factor of 25. Because many of the drugs are given in combination with other agents, doses most commonly used in popular combinations may also be indicated. These data should not be used as the sole source of information for any of the drugs but rather should be used as a guide to confirm and compare dose ranges and schedules and to identify potential problems. For some agents, the area under the curve (AUC) method of dose calculation seems to be most reliable for achieving the most accurate dosing and balance between efficacy and toxicity; when that is the standard, the AUC dose is used.
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C. Drug toxicity: frequency designationThe designation of the frequency of toxic side effects is indicated as follows (probability of occurrence equals percentage of patients who may be expected to experience the toxic effect):
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Universal (90% to 100%)
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Common (15% to 90%)
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Occasional (5% to 15%)
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Uncommon (1% to 5%)
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Rare (<1%).
These designations are meant only to be guides, and the likelihood of a side effect in each patient depends on that patient’s physical status, including comorbidities, treatment history, dose, schedule, and route of drug administration, as well as other concurrent treatment. -
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D. Dose modification
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1. Philosophy. The optimal dose and schedule of a drug are those that give maximum benefit with tolerable toxicity. Most classical chemotherapeutic agents (and some of the targeted agents) have a steep dose-response curve; therefore, if no toxicity is seen, as a rule, a higher dose (dose escalation) of most of the classical chemotherapeutic agents should be given to get the best possible therapeutic benefit. If toxicity is great, however, the patient’s life may be threatened or the patient may decide that the treatment is worse than the disease and refuse further therapy. How much toxicity the patient and the physician are willing to tolerate depends on the likelihood that more intensive treatment will make a major therapeutic difference (e.g., cure versus no cure) and on the patient’s physical and psychological tolerance for adverse effects.The general grading scheme for all toxicity is as follows:
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0: None
-
1: Mild
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2: Moderate
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3: Severe
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4: Life-threatening.
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2. Guidelines
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a. Nonhematologic toxicity
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(1) Acute effects. Acute drug toxicity that is limited to 1 to 2 days and is not cumulative is not usually a cause of dose modification unless it is of grade 3 or 4, that is, severe or life-threatening. (For individual toxicities, see the Common Terminology Criteria for Adverse Events v4.0, available on the Internet at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.) Occasionally, repeating a dose that caused intractable nausea and vomiting, a temperature higher than 40°C (104°F), or an acute infusion reaction is warranted, but for most other grade 3 or 4 toxicities, the subsequent doses should be reduced by 25% to 50%, assuming that the toxicity is believed to be dose-related. If the acute drug effects (e.g., severe paresthesias or abnormalities of renal or liver function) last longer than 48 hours, the subsequent doses should be reduced by 35% to 50%.A recurrence of the grade 3 or 4 side effects at the reduced doses would be an indication either to reduce by another 25% to 50% or to discontinue the drug altogether. Non-dose-related toxicity such as anaphylaxis is an indication to discontinue the offending drug. Lesser degrees of hypersensitivity can often be dealt with effectively by increasing the dose of protective agents (like dexamethasone or diphenhydramine), desensitization (e.g., carboplatin), or slowing the rate of infusion (e.g., rituximab). For some biologic agents, such as trastuzumab, physiologic effects that look like immunologic hypersensitivity reactions are probably related to cytokine release, occur primarily on first or second infusions, and diminish with continued treatment.
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(2) Chronic effects. Chronic or cumulative toxicity such as pulmonary function changes with bleomycin or decreased cardiac function with doxorubicin is nearly always an indication to discontinue the responsible agent. Chronic or cumulative neurotoxicity due to vincristine, cisplatin, paclitaxel, or other agents may require no dose change, reduction, or discontinuation, depending on the severity of the resultant neurologic dysfunction and the patient’s ability to tolerate it.
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b. Hematologic toxicity. The degree of myelosuppression and attendant risk of infection and bleeding that are acceptable depend on the cancer, the duration of the 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 33.2 and 33.3 can serve as a guide to reasonable dose changes for drugs whose major toxicity is myelosuppression. Separate schemes are given for drugs with relatively short myelosuppression and for drugs such as the nitrosoureas that have more prolonged myelosuppression.
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c. Dosing for the obese patient. In general, patients who are overweight (body mass index [BMI] 25-29.9) and those who are obese (BMI 30-34.9) should be treated with full doses of chemotherapy, based on the body surface area calculated from their actual weight. Whether this is true for those who are very obese (BMI 35-39.9) or extremely obese (BMI >40) is not clear, owing to a lack of sufficient data. Many clinicians would limit the dose, using a maximum weight based on a BMI of 35 (maximum treatment weight (kg) = 35 × [height (m)]2).TABLE 33.2 Dose Modifications for Myelosuppressive Drugs With a Nadir* at Less Than 3 Weeks
Degree of Suppression
ANC (WBC)/µL on Day of Scheduled Treatment†
Platelets/µL on Day of Scheduled Treatment
Dose as Percentage of Immediately Preceding Cycle
Minimal
≥1500 (≥3500)
and
≥100,000
100
Mild
1200-1500(3000-3500)
or
75,000-100,000
75
Moderate
1000-1200(2500-3000)
or
50,000-75,000
50
Severe
<1000 (<2500)
or
<50,000
0 (delay 1 week)
ANC, absolute neutrophil count; WBC, white blood cell count.
* If the nadir of ANC is <1000/µL and is associated with fever of >38.3°C (101°F) or the nadir of platelets is <40,000/µL, 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.† ANC is the preferred parameter, if available. If counts are rising at the end of a treatment cycle, it is often appropriate to delay 1 week and then treat according to the dose modification scheme shown here.
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III. DATA FOR CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND MOLECULAR TARGETED AGENTSNote: Although every effort has been made to ensure that the drug dosage and schedules herein are accurate and in accordance with published standards, users are advised to check the product information sheet included in the package of each FDA-approved drug and FDA-National Cancer Institute guidelines for drugs that are not yet approved for general use to verify recommended dosages, contraindications, and precautions.TABLE 33.3 Dose Modifications for Myelosuppressive Drugs* With a Nadir at 3 Weeks or Later
Point in Time
ANC (WBC)/µL
Platelets/µL
Dose as Percentage of Immediately Preceding Cycle
I.
On day of scheduled treatment†
≥1800 (≥3500)
and
≥100,000
Dose modified for nadir only
<1800 (<3500)
or
<100,000
0‡
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-week delay
≥1800 (≥3500)
and
≥100,000
Dose modified for nadir only
1200-1800(2500-3500)
or
75,000-100,000
75
<1200
or
<75,000
Continue to hold
ANC, absolute neutrophil count; WBC, white blood cell count.
*Nitrosoureas or other agents with prolonged nadir.† ANC is the preferred parameter to use.‡ Withhold treatment and repeat count in 2 weeks. At 2 weeks, treat on basis of lowest dose indicated by nadir (II) or delay (III) section of table.
Agents that have not yet been approved by the FDA may be included because they either have shown preliminary efficacy in clinical trials or are currently being investigated and show promise of benefit. As their efficacy and toxicity are more firmly established, it is expected that some will be approved by the FDA for general use, whereas others will remain investigational or be dropped from further study.
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1. Renal cell carcinoma
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2. Melanoma.
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1. 600,000 IU/kg (22 × 106 IU/m2) as a 15-minute IV infusion every 8 hours for up to 14 doses on days 1 to 5. Repeat on days 15 to 19. Repeat cycle in 6 to 12 weeks if stable or responding disease. This schedule has the most experience and is generally the recommended regimen.
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2. 18 × 106 IU/m2/24 hours as a continuous IV infusion (CIVI) daily for up to 5 days. Repeat in 4 weeks. Repeat cycle in 4 to 6 weeks if stable or responding disease.
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3. 22 × 106 IU/m2 as a 15-minute infusion for 5 consecutive days for 2 successive weeks. Repeat every 3 to 6 weeks as tolerated. In some regimens, it is preceded by 3 days with a single dose of low-dose cyclophosphamide, 350 mg/m2 IV push.
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1. Myelosuppression and other hematologic effects. Uncommon at lower doses; common but rarely serious at higher doses. Anemia requiring transfusion is common at higher doses. Thrombocytopenia is common at higher doses.
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2. Nausea, vomiting, and other gastrointestinal effects:
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a. Anorexia, nausea, vomiting, and diarrhea are common.
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b. Transient liver function abnormalities, including hyperbilirubinemia and hypoalbuminemia and elevation of the prothrombin time (PT) and partial thromboplastin time, are common.
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c. Colonic perforations are rare.
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3. Mucocutaneous effects. Mucositis is occasional to common. Alopecia is uncommon. Pruritic erythematous rash is common.
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4. Cardiovascular effects:
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a. Arrhythmias are common and dose-related.
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b. Hypotension is dose-related but is occasionally seen at the lower dose schedules.
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c. Myocardial injury is seen primarily at the higher dose schedules.
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d. Pulmonary edema from capillary leak syndrome is common with intensive dose regimens.
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e. Weight gain is common from edema, particularly in more intensive dose regimens.
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5. Neuropsychiatric effects:
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6. Renal function impairment. Common but reversible. More frequent laboratory abnormalities include creatinine elevation, hypomagnesemia, acidosis, hypocalcemia, hypophosphatemia, hypokalemia, hypouricemia, and hypoalbuminemia.
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7. Fever. With or without chills, fever is common and may be severe.
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8. Bacterial infection. Occasional. Probably related to chemotactic defect induced in granulocytes.
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9. Myalgias and arthralgias. Occasional to common.
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10. Malaise and fatigue. Common and dose-related.
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1. Acetaminophen 650 mg by mouth before therapy and every 6 hours for one or two doses for outpatient IL-2 dosing; every 6 hours for 3 doses for inpatient IL-2 regimens.
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2. Cimetidine 800 mg by mouth, or other histamine H2-receptor antagonist before therapy and daily for duration of treatment.
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3. Antiemetics: granisetron, ondansetron, or other 5HT3 antagonist; metoclopramide, and prochlorperazine may be used. Do not use dexamethasone.
-
4. Meperidine 25 to 50 mg IV when chills start after first dose. For subsequent doses, meperidine 50 mg by mouth 1.5 hours before chills are predicated to start, based on the first treatment.
-
5. Hydromorphone 0.5 to 1 mg IV may be substituted for meperidine in patients who tolerate meperidine poorly.
-
6. Diphenoxylate with atropine (Lomotil) 1 tablet up to six times daily for diarrhea.
-
7. Hydroxyzine 25 to 50 mg every 6 hours for itching.
-
1. B-cell chronic lymphocytic leukemia
-
2. Nonmalignant conditions and graft-versus-host disease.
-
1. Initiation: 3 mg as a 2-hour IV infusion daily.
-
2. Escalation: When infusion related toxicities are lower than grade 2, the dose is escalated to 10 mg as a 2-hour IV infusion daily. When the 10-mg dose is tolerated, maintenance therapy is initiated.
-
3. Maintenance: 30 mg as a 2-hour IV infusion three times a week—on alternate days—for 12 weeks.
-
1. Myelosuppression and other hematologic effects. Lymphopenia is universal. Neutropenia, anemia, and thrombocytopenia are common and often severe (grade 3) or greater. Opportunistic and other infections, including pneumonia and sepsis, are seen in 10% to 15% of patients. Autoimmune hemolytic anemia and thrombocytopenia are uncommon (1% to 2%). Pancytopenia and marrow hypoplasia are uncommon but may require permanent discontinuation of therapy. Because of the high incidence of opportunistic infections, prophylaxis against Pneumocystis jiroveci pneumonia and herpes virus infections during and at least 2 months after completion of treatment is recommended.*
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common; diarrhea, abdominal pain, and dyspepsia are occasional.
-
3. Mucocutaneous effects. Rash, urticaria, pruritis, and increased sweating are common. Stomatitis is occasional.
-
4. Infusion-related events. Rigors, fever, nausea and vomiting, and rash—including urticaria—are common. Shortness of breath, hypotension, bronchospasm, headache, pruritis, and diarrhea are occasional. Angioedema is uncommon.
-
5. Miscellaneous effects:
-
a. Respiratory: Dyspnea, cough, and bronchitis are common. Pneumonia, pharyngitis, bronchospasm, and rhinitis are occasional.
-
b. Cardiovascular: Hypotension is common; hypertension occasional. Tachycardia and supraventricular tachycardia are occasional, but usually not severe. Syncope is uncommon.
-
c. Hypersensitivity reactions to alemtuzumab may occur (2%) and result in hypersensitivity to other monoclonal antibodies.
-
d. Neuropsychiatric: Insomnia, depression, and somnolence are occasional. Headache, dysthesias, dizziness, and tremor are occasional.
-
e. Infections: Reactivation of hepatitis B and other viruses is uncommon to rare.
-
-
1. Myelosuppression and other hematologic effects. None.
-
2. Nausea, vomiting, and other gastrointestinal effects. None
-
3. Mucocutaneous effects. Skin reactions with erythema, scaling, irritation, redness, rash, or other dermatitis are common. Pruritis, exfoliative dermatitis, or other erosive or draining skin lesions are occasional.
-
4. Miscellaneous effects:
-
a. Neurologic complaints of burning or pain are common.
-
b. Edema is occasional.
-
-
1. 260 mg/m2 by mouth daily in three or four divided doses after meals and at bedtime for 14 or 21 days every 4 weeks when used as a single agent.
-
2. 150 to 200 mg/m2 by mouth daily in three or four divided doses for 2 out of 3 or 4 weeks when used in combination.
-
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and thrombocytopenia are uncommon, though lesser degrees are common. Anemia is common.
-
2. Nausea, vomiting, and other gastrointestinal effects. Mild to moderate nausea, vomiting, and other gastrointestinal effects occur in about 30% of patients and are rarely severe. Diarrhea is occasional. Tolerance may develop.
-
3. Mucocutaneous effects. Alopecia, skin rash, and pruritus are rare.
-
4. Miscellaneous effects:
-
a. Peripheral sensory neuropathies are common and may be ameliorated by pyridoxine, but tumor response may be compromised.
-
b. Central nervous system (CNS) effects, including agitation, confusion, hallucinations, depression, and parkinsonian-like symptoms are uncommon with recommended intermittent schedule.
-
c. Decreased renal function is occasional.
-
d. Increased alkaline phosphatase level is occasional.
-
-
1. For reduction of cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced cancer.
-
2. For reduction of moderate to severe xerostomia from radiation of the head and neck where the radiation port includes a substantial portion of the parotid glands.
-
1. For reduction of cumulative renal toxicity with chemotherapy: 910 mg/m2 IV over 15 minutes once daily, starting 30 minutes before chemotherapy.
-
2. For reduction of xerostomia from radiation of the head and neck: 200 mg/m2 administered once daily as a 3-minute IV infusion, starting 15 to 30 minutes prior to standard fraction radiation therapy (1.8 to 2.0 Gy).
-
1. Myelosuppression and other hematologic effects. Not increased by amifostine.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common and may be severe.
-
3. Mucocutaneous effects. Rarely, serious cutaneous reactions have been associated with amifostine administration. They have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and exfoliative dermatitis.
-
4. Miscellaneous effects:
-
a. Transient hypotension during the infusion is common. Loss of consciousness may occur, but is usually easily reversed.
-
b. Flushing and feeling of warmth are occasional.
-
c. Chilling and feeling of coldness are occasional.
-
d. Dizziness, somnolence, hiccups, and sneezing are occasional.
-
e. Allergic reactions are rare but have included anaphylactic reactions.
-
f. Hypocalcemia is rare.
-
g. Seizures are rare.
-
-
1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are rare; if they occur, they resolve rapidly when the drug is stopped.
-
2. Nausea, vomiting, and other gastrointestinal effects. Occasional and usually mild.
-
3. Mucocutaneous effects. A morbilliform rash is commonly seen during the first week of treatment, but it usually disappears within 1 week.
-
4. Hormonal effects:
-
a. Adrenal insufficiency is common without replacement hydrocortisone in patients with normal adrenal glands.
-
b. Hypothyroidism is uncommon.
-
c. Masculinization is possible.
-
-
5. Neurologic effects:
-
a. Lethargy is common. Although usually mild and transient, it is occasionally severe.
-
b. Vertigo, nystagmus, and ataxia are occasional.
-
c. Headache is uncommon.
-
-
6. Miscellaneous effects:
-
a. Facial flushing is uncommon.
-
b. Periorbital edema is uncommon.
-
c. Cholestatic jaundice is rare.
-
d. Fever is uncommon.
-
-
1. 0.5 mg by mouth four times a day or 1 mg by mouth twice a day. Increase by 0.5 mg/d every 5 to 7 days if no response. Maximum daily dose is 10 mg/day. Maximum single dose is 2.5 mg. Higher doses cause postural hypotension.
-
2. Alternate dosing schedules:
-
a. Elderly: 0.5 mg by mouth daily, increase by 0.5 mg each week.
-
b. Abnormal renal or hepatic function: 0.5 mg by mouth twice a day.
-
-
1. Myelosuppression and other hematologic effects. Leukopenia is rare. Anemia is common but mild. Thrombocytopenic hemorrhage is uncommon.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are occasional. Diarrhea, gas, and abdominal pain are common; pancreatitis is rare. Lactase supplementation eliminates diarrhea (anagrelide formulated with lactose). Hepatic enzyme elevation is rare, but caution is recommended when there is evidence of hepatic dysfunction.
-
3. Mucocutaneous. Rash, including urticaria, is occasional (8%). Hyperpigmentation is rare. Sun sensitivity is possible.
-
4. Miscellaneous effects:
-
a. Cardiovascular: Palpitations, forceful heartbeat, and tachycardia are common. Congestive heart failure is uncommon, but fluid retention or edema is common. Tachyarrhythmias (including atrial fibrillation and premature atrial beats) are occasional. Angina, cardiomyopathy, or other severe cardiovascular effects are rare, although there are somewhat more frequent (8%) episodes of chest pain. Drinking alcoholic beverages may cause flushing. Higher than recommended single doses cause postural hypotension. Cardiovascular effects appear to result from vasodilation, positive inotropy, and decreased renal blood flow.
-
b. Neurologic: Headaches are common and occasionally are severe; they usually diminish in about 2 weeks. Weakness (asthenia) is common. Dizziness is occasional.
-
c. Pulmonary: Infiltrates are rare but are a reason to stop anagrelide and treat with steroids.
-
-
1. Carcinoma of the breast as adjuvant treatment in postmenopausal women with positive hormone receptors.
-
2. Carcinoma of the breast that is advanced or metastatic as first therapy in postmenopausal women with positive or unknown hormone receptors.
-
3. Carcinoma of the breast that is advanced or metastatic as second therapy in postmenopausal women with progression following initial response to tamoxifen.
-
1. Myelosuppression and other hematologic effects. No dose-related myelosuppression. Thromboembolic events are uncommon (3%).
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, diarrhea, and constipation are occasional. Vomiting is uncommon.
-
3. Mucocutaneous effects. Rash is occasional. Hot flushes are common (35%). Vaginal dryness and leukorrhea are uncommon.
-
4. Miscellaneous effects:
-
a. Asthenia is common. Headache and dizziness are occasional.
-
b. Musculoskeletal pain is occasional. Arthralgia is occasional.
-
c. Peripheral edema and weight gain are occasional (lower than with megestrol).
-
d. Dyspnea and cough are occasional.
-
e. Cataracts are occasional (6%).
-
f. Decreased bone mineral density with osteoporosis is occasional (11%), and there is increased risk for fractures (10%).
-
g. Vaginal bleeding is uncommon, and endometrial cancer is rare (0.2%).
-
-
1. Induction: 0.15 mg/kg IV daily until marrow remission. Maximum of 60 doses.
-
2. Consolidation: 0.15 mg/kg IV daily for 25 doses over a period of up to 5 weeks. Consolidation is started 3 to 6 weeks after completion of induction therapy.
-
1. Myelosuppression and other hematologic effects. Anemia, thrombocytopenia, and neutropenia are occasional. Leukocytosis is common. Disseminated intravascular coagulation is occasional and may be severe. Infections and neutropenic fever are occasional.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, diarrhea, and abdominal pain are common (>50%). Gastrointestinal bleeding, with or without diarrhea, is occasional (8%). Constipation, anorexia, and other abdominal distress are occasional.
-
3. Mucocutaneous effects. Sore throat is common (40%). Dermatitis, pruritis, and ecchymosis are also common. More severe mucocutanous reactions including local exfoliation, urticaria, and oral blistering are occasional to uncommon. Epistaxis is common (25%). Eye irritation and injection are occasional.
-
4. Miscellaneous effects:
-
a. Cardiovascular: Tachycardia and prolonged QT interval are common. This may lead to complete AV block with fatal ventricular arrhythmia.
-
b. Acute promyelocytic leukemic differentiation syndrome, similar to that seen with retinoic acid, may be seen. This consists of fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions with or without leukocytosis. This syndrome may be fatal.
-
c. General and administration site: Headache and insomnia are common. Edema and pleural effusion are common (though not commonly serious), and general weight gain is occasional. Drug hypersensitivity is uncommon. Injection site edema, erythema, and pain are occasional.
-
d. Metabolic: Hypokalemia, hypomagnesemia, and hyperglycemia are common (45% to 50%). Hyperkalemia is occasional to common (18%), as are elevated transaminases, hypocalcemia, and hypoglycemia.
-
e. Pulmonary: Cough and dyspnea are common (>50%). Pleural effusion, hypoxia, wheezing, and asymptomatic ascultatory findings are occasional to common (8% to 20%).
-
f. Renal: Renal failure is occasional.
-
-
1. L-asparaginase 6000 IU/m2 SC on days 5, 8, 11, 15, and 22 of the treatment period.
-
2. L-asparaginase 10,000 IU IV daily for 10 successive days beginning on day 17 of the treatment period.
-
3. Pegaspargase 2500 IU/m2 intramuscularly (IM; or IV) once every 14 days, either for first-line acute lymphocytic leukemia or in patients who have developed hypersensitivity to native forms of asparaginase. For IM use, limit volume at single injection site to 2 mL. For IV administration, give over 1 to 2 hours in saline or normal saline with 5% dextrose.
-
1. Myelosuppression and other hematologic effects. Occasional myelosuppression. CNS thrombosis and other coagulopathies are uncommon.
-
2. Nausea, vomiting, and other gastrointestinal effects. Occasional and usually mild (see subsequent discussion for liver and pancreas effects).
-
3. Mucocutaneous effects. No toxicity occurs except as a sign of hypersensitivity.
-
4. Anaphylaxis. Mild to severe hypersensitivity reactions, including anaphylaxis, occur in 20% to 30% of patients. Such reaction is less likely to occur during the first few days of treatment. It is particularly common with intermittent schedules or repeat cycles. If the patient develops hypersensitivity to the Escherichia coli-derived enzyme (Elspar), Erwinia-derived asparaginase may be safely substituted because the two enzyme preparations are not cross-reactive. Note that hypersensitivity may also develop to Erwinia-derived asparaginase, and continued preparedness to treat anaphylaxis must be maintained.If given via the IM route, asparaginase should be given in an extremity so that a tourniquet can be applied to slow the systemic release of asparaginase should anaphylaxis occur.Approximately 30% of patients previously sensitive to L-asparaginase will have a hypersensitivity reaction to pegaspargase, while only 10% of those who were not hypersensitive to the native form will have a hypersensitivity reaction to the PEG-modified drug.
-
5. Miscellaneous effects:
-
a. Mild fever and malaise are common and occasionally progress to severe chills and malignant hyperthermia.
-
b. Hepatotoxicity is common and occasionally severe. Abnormalities observed include elevations of serum glutamic-oxaloacetic transaminase (SGOT), alkaline phosphatase, and bilirubin; depressed levels of hepatic-derived clotting factors and albumin; and hepatocellular fatty metamorphosis.
-
c. Renal failure is rare.
-
d. Pancreatic endocrine and exocrine dysfunction, often with manifestations of pancreatitis, occasionally occurs. Nonketotic hyperglycemia is uncommon.
-
e. CNS effects (depression, somnolence, fatigue, confusion, agitation, hallucinations, or coma) are seen occasionally. They are usually reversible following discontinuation of the drug.
-
-
1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common. Febrile neutropenia is four times as common as in patients receiving supportive care. Petechiae or ecchymosis are occasional.
-
2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and diarrhea or constipation are common. Abdominal pain is occasional.
-
3. Mucocutaneous effects. Pharyngitis and stomatitis are occasional. Skin rash and urticaria are occasional. Injection site pain is common.
-
4. Neurotoxicity. Insomnia is common. Lethargy, dizziness, or confusional state are occasional.
-
5. Miscellaneous effects:
-
a. Cardiorespiratory: Cough and dyspnea are common. Pulmonary edema is uncommon. Edema is occasional. Tachycardia or other more serious cardiac disorders are uncommon.
-
b. Fever is common.
-
c. Fatigue and weakness are common.
-
d. Arthralgias and back pain are occasional.
-
e. Hypokalemia is occasional.
-
-
1. Chronic lymphocytic leukemia
-
2. Indolent B-cell non-Hodgkin lymphoma.
-
1. Chronic lymphocytic leukemia: 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6 cycles.
-
2. Non-Hodgkin lymphoma: 120 mg/m2 IV over 30 minutes on days 1 and 2 of a 21-day cycle, up to 8 cycles.
-
1. Myelosuppression and other hematologic effects. Myelosuppression is common and is universal in the higher dosage ranges. Grade 3 to 4 leukopenia (both neutrophils and lymphocytes) is common. Grade 3 to 4 anemia and thrombocytopenia are occasional. Infections overall are occasional. Pneumonia and neutropenic sepsis are uncommon but may be fatal.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are occasional to common and dose-dependent, but rarely severe. Anorexia, dyspepsia, gastroesophageal reflux, upper abdominal pain, and distention are occasional.
-
3. Mucocutaneous effects. Skin rash and pruritis are occasional, including toxic skin reactions and bullous exanthema.
-
4. Immunologic effects and infusion reactions. Infusion reactions consisting of fever, chills, pruritis, and rash are common. Severe anaphylactic or anaphylactoid reactions, particularly in the second or subsequent cycles of therapy, are rare. Preventive measures, including antihistamines and corticosteroids, should be given if grade 1 or 2 infusion reactions were experienced in a prior cycle. Bendamustine should generally not be repeated if patients have had a prior grade 3 or 4 infusion reaction.
-
5. Miscellaneous effects:
-
a. Fever (occasionally with chills) and fatigue are common; weakness and weight loss are occasional.
-
b. Tumor lysis syndrome, including hyperuricemia, may occur, primarily with the first cycle of therapy, and lead to acute renal failure. With concomitant allopurinol, watch closely for severe skin reactions.
-
c. Hypokalemia is only occasional, but may be severe.
-
d. Cough, dyspnea, throat pain, wheezing, and nasal congestion are occasional to common.
-
e. Hypotension is occasional.
-
-
1. Breast, colon, kidney, rectum, and nonsquamous non-small-cell lung cancers, usually with other agents.
-
2. Glioblastoma, alone or with other agents.
-
1. 5 to 10 mg/kg IV once every 2 weeks
-
2. 15 mg/kg IV once every 3 weeks.
-
1. Myelosuppression and other hematologic effects. Leukopenia is common but associated primarily with the cytotoxic agents used together with bevacizumab. Thrombocytopenia is uncommon. Minor bleeding, such as epistaxis, is common; severe hemorrhage is not common, except for hemoptysis in patients with squamous cell carcinomas of the lung. Serious, and in some cases fatal, hemoptysis has occurred in non-small-cell lung cancer, with the highest risk appearing in patients with squamous cell histology; other severe or fatal hemorrhage, including CNS bleeding, has occurred. Thromboembolic events are occasional and may be severe.
-
2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, and constipation are common. Diarrhea is common, particularly when used with fluorouracil and irinotecan chemotherapy. Abdominal pain is common. Gastrointestinal hemorrhage is occasional.
-
3. Mucocutaneous effects. Dry skin, skin discoloration, stomatitis, and exfoliative dermatitis are occasional to common. Alopecia, skin ulcers, and nail changes are uncommon.
-
4. Immunologic effects and infusion reactions. Infusion reactions with hypertension, wheezing, stridor, desaturation, chest pain, headaches, and diaphoresis are uncommon. Severe reactions are rare (0.2%).
-
5. Miscellaneous effects:
-
a. Fatigue, weakness, and headache are common.
-
b. Cardiovascular and respiratory: Hypertension is common and occasionally is severe (>200/110 mm Hg). Blood pressure greater than 160/100 or rise of greater than 30 mm Hg requires holding therapy, at least temporarily. Hypotension is occasional. Dyspnea is occasional. Congestive heart failure is uncommon, but risk with anthracyclines is increased (14%). Venous thromboembolic events are increased by about 15% compared with chemotherapy not containing bevacizumab.
-
c. Neurologic: Dizziness is common. RPLS has been reported rarely (<0.1%); if it occurs, therapy must be discontinued immediately and treatment for hypertension initiated if it is present.
-
d. Metabolic: Proteinuria is common, but severe proteinuria (>3.5 g/24 h) is uncommon and rarely leads to nephrotic syndrome (<1%), but requires holding bevacizumab and rechecking prior to next cycle.
-
-
1. Myelosuppression and other hematologic effects. Mild to moderate leukopenia is occasional to common with a time of onset of 4 to 8 weeks. Severe or worse leukopenia is occasional.
-
2. Nausea, vomiting, and other gastrointestinal effects. Mild nausea, abdominal pain, and diarrhea are occasional. Vomiting and anorexia are uncommon. Inflammatory bowel disease and pancreatitis (associated with hypertriglyceridemia) are rare.
-
3. Mucocutaneous effects. Skin reactions are occasional to common. They include redness, dryness, and pruritus of the skin and mucous membranes; possible vesicle formation; exfoliative dermatitis; cheilitis; and conjunctivitis. There also may be increased skin photosensitivity (e.g., to sun) and the nails may become brittle. Alopecia is uncommon.
-
4. Miscellaneous effects:
-
a. Cataracts and corneal ulcerations or opacities are uncommon.
-
b. Systemic: Arthralgias, bone pain, muscle aches are occasional. Fever, chills, and headache (flu syndrome) are occasional.
-
c. Hypertriglyceridemia (80%) and hypercholesterolemia (35% to 40%) are common. Hypertriglyceridemia is usually more severe. These are reversible with discontinuation of therapy and may be reduced by antilipemic therapy.
-
d. Neurologic: Headache is common. Lethargy, fatigue, confusion, and mental depression are uncommon; pseudotumor cerebri is rare.
-
e. Hepatotoxicity with increased lactate dehydrogenase (LDH), SGOT, serum glutamic-pyruvic transaminase (SGPT), gamma-glutamyl transpeptidase (GGTP), and alkaline phosphatase is occasional.
-
f. Hypothyroidism is common, with decreased T4 and thyroid-stimulating hormone (TSH).
-
g. Peripheral edema is occasional.
-
h. Hypernatremia is rare.
-
-
1. Myelosuppression and other hematologic effects. Uncommon.
-
2. Nausea, vomiting, and other gastrointestinal effects. Not expected.
-
3. Mucocutaneous effects. Skin reactions are occasional to common. They include pain, redness, dryness, and pruritus of the skin; possible vesicle formation; exfoliative dermatitis. There also may be increased skin photosensitivity (e.g., to sun).
-
4. Miscellaneous effects:
-
a. Hypertriglyceridemia is occasional.
-
b. Neurologic: Headache and paresthesias are occasional.
-
c. Peripheral edema is occasional.
-
-
1. Myelosuppression and other hematologic effects. No myelosuppression. May interact with warfarin and increase International Normalized Ratio (INR).
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, diarrhea, flatulence, and constipation are occasional; vomiting is uncommon.
-
3. Mucocutaneous effects. Mild skin rash is occasional.
-
4. Miscellaneous effects:
-
a. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot flashes, impotence, and loss of libido, are common but reversible after cessation of therapy.
-
b. Elevated liver function tests are uncommon, but severe hepatic failure has been observed only rarely.
-
c. Dyspnea and cough are seen occasionally.
-
d. Adverse cardiovascular events are similar to those seen with orchiectomy.
-
e. Dizziness or vertigo is occasional.
-
-
Testis, head and neck, penis, cervix, vulva, anus, and skin carcinomas
-
Hodgkin and non-Hodgkin lymphomas
-
Pleural effusions—used as sclerosing agent.
-
1. 10 to 20 units/m2 IV or IM once or twice a week, or
-
2. 30 units IV push weekly for 9 to 12 weeks in combination with other drugs for cancer of the testis.
-
3. 60 units in 50 mL of normal saline instilled intrapleurally.
-
1. In patients with lymphoma, a test dose of one or two units should be given IM prior to the first dose of bleomycin because of the possibility of anaphylactoid, acute pulmonary, or severe hyperpyretic responses. If no acute reaction occurs within 4 hours, regular dosing may begin.
-
2. Reduce dose for renal failure.
Serum Creatinine
Percent of Full Dose
2.5-4.0
25
4.0-6.0
20
6.0-10.0
10
-
3. The cumulative lifetime dose should not exceed 400 units because of the dose-related incidence of severe pulmonary fibrosis. Smaller limits may be appropriate for older patients or those with pre-existing pulmonary disease. Frequent evaluation of pulmonary status, including symptoms of cough or dyspnea, rales, infiltrates on chest x-ray film, and pulmonary function studies are recommended to avert serious pulmonary sequelae.
-
4. Glass containers are recommended for continuous infusion to minimize drug instability.
-
5. High fraction of inspired oxygen (such as might be used during surgery) should be avoided as it exacerbates lung injury, sometimes acutely.
-
1. Myelosuppression and other hematologic effects. Significant depression of counts is uncommon. This factor permits bleomycin to be used in full doses with myelosuppressive drugs.
-
2. Nausea, vomiting, and other gastrointestinal effects. Occasional and self-limiting.
-
3. Mucocutaneous effects. Alopecia, stomatitis, erythema, edema, thickening of nail bed, and hyperpigmentation and desquamation of skin are common.
-
4. Pulmonary effects:
-
a. Acute anaphylactoid or pulmonary edema-like response is occasional in patients with lymphoma (see special precautions discussed previously).
-
b. Dose-related pneumonitis with cough, dyspnea, rales, and infiltrates, progressing to pulmonary fibrosis.
-
-
5. Fever. Common. Occasionally, severe hyperpyrexia, diaphoresis, dehydration, and hypotension have occurred and resulted in renal failure and death. Antipyretics help control fever.
-
6. Miscellaneous effects:
-
a. Lethargy, headache, and joint swelling are rare.
-
b. IM or SQ injection may cause pain at injection site.
-
-
1. Multiple myeloma
-
2. Mantle cell lymphoma.
-
1. Multiple myeloma: 1.3 mg/m2 IV bolus twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32), often together with oral melphalan and oral prednisone (days 1 to 4 every 6 weeks) for four 6-week treatment cycles. Then once weekly (days 1, 8, 22, and 29) together with oral melphalan and oral prednisone (days 1 to 4 every 6 weeks) for five more 6-week treatment cycles. The intensity may be modified by giving the twice weekly component for one cycle only followed by eight cycles of the weekly schedule, or by using the weekly schedule for all nine cycles. Similar schedule used in combination with other agents.
-
2. Mantle cell lymphoma: 1.3 mg/m2 IV bolus twice weekly (days 1, 4, 8, and 11 every 3 weeks) for up to eight cycles. Frequency may be reduced to weekly for 3 out of 4 weeks for maintenance.
-
3. Reduce each dose to 0.7 mg/m2 in the first cycle for patients with moderate or severe liver function impairment (bilirubin >1.5 upper limit of normal [ULN]). Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
-
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common; neutropenia is only occasionally severe (grade 3 or 4). Thrombocytopenia is severe in 30% of patients. Disseminated intravascular coagulation has been observed (rare to uncommon).
-
2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, diarrhea, and constipation are common. Dehydration is a concern because of vomiting and diarrhea and may be seen occasionally.
-
3. Mucocutaneous effects. Rash is common (20%).
-
4. Neurotoxicity. Peripheral neuropathy is common and occasionally (7%) severe. This is frequently manifest by paresthesias and dysesthesias. Headache is common.
-
5. Immunologic effects and infusion reactions. Hypersensitivity reactions have been seen, including anaphylactic reactions and immune complex mediated hypersensitivity (rare). Tumor lysis syndrome may be seen in patients with a high tumor burden. The incidence of herpes zoster is increased compared with controls and is occasional.
-
6. Miscellaneous effects:
-
a. Fatigue and weakness are common.
-
b. Arthralgias, muscle cramps, and back pain are occasional.
-
c. Fever is common.
-
d. Cardiovascular: Hypotension is occasional, is seen throughout therapy, and may or may not be orthostatic. Peripheral edema is common. Other cardiovascular events during treatment have included severe congestive heart failure, AV block, angina, atrial fibrillation, and flutter—these are probably uncommon to rare as a consequence of the drug.
-
e. Infiltrative pulmonary disease is rare, but may be severe or fatal.
-
f. Hepatitis and pancreatitis have been observed and are probably rare.
-
-
1. Standard doses: CML
-
2. High doses with stem cell rescue: Acute leukemia, lymphoma, chronic granulocytic leukemia.
-
1. 3 to 4 mg/m2 by mouth daily for remission induction in adults until the leukocyte count is 50% of the original level, then 1 to 2 mg/m2 by mouth daily. Busulfan may be given continuously or intermittently for maintenance.
-
2. High doses with stem cell rescue—consult specific protocols. Not recommended outside of research setting. High-dose therapy requires pretreatment with phenytoin.
-
1. Myelosuppression and other hematologic effects. Dose-limiting. A fall in the leukocyte count may not begin for 2 weeks after starting therapy, and it is likely to continue for 2 weeks after therapy has been stopped. Recovery of marrow function may be delayed for 3 to 6 weeks after the drug has been discontinued. High-dose therapy requires stem cell rescue (e.g., bone marrow transplantation).
-
2. Nausea, vomiting, and other gastrointestinal effects. Rare at standard doses.
-
3. Mucocutaneous effects. Hyperpigmentation occurs occasionally, particularly in skin creases.
-
4. Miscellaneous effects
-
a. Pulmonary effects: Interstitial pulmonary fibrosis is rare and is an indication to discontinue drug. Corticosteroids may improve symptoms and minimize permanent lung damage.
-
b. Metabolic effects: Adrenal insufficiency syndrome is rare. Hyperuricemia may occur when the leukemia cell count is rapidly reduced. Ovarian suppression and amenorrhea are common.
-
c. Secondary neoplasia is possible.
-
d. Fatal hepatic veno-occlusive disease with high-dose therapy is occasional.
-
e. Seizures after high-dose therapy are occasional.
-
-
1. Myelosuppression and other hematologic effects. Neutropenia, anemia, and thrombocytopenia are common. Grade 3 to 4 febrile neutropenia is occasional but may be fatal.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, anorexia, diarrhea, and constipation are common, but infrequently (2% to 6%) severe.
-
3. Mucocutaneous effects. Alopecia is occasional.
-
5. Miscellaneous effects:
-
a. Fatigue and weakness are common. Fever is occasional.
-
b. Renal failure is uncommon, but may be fatal (rare). Hematuria is occasional.
-
c. Peripheral edema is occasional.
-
d. Cardiac arrythmias and hypotension are uncommon.
-
e. Back pain and arthralgias are occasional.
-
f. Peripheral neuropathy and headache are occasional.
-
g. Dyspnea and cough are occasional.
-
-
1. Metastatic breast cancer that is resistant to anthracycline- and paclitaxel-containing chemotherapy regimens. May also be used in patients in whom anthracyclines are contraindicated.
-
2. Colorectal (adjuvant or metastatic), small bowel, stomach, pancreas, and biliary carcinomas.
-
1. 1000 to 1250 mg/m2 orally twice daily for 2 weeks as a single agent, followed by a 1-week rest, given as 3-week cycles.
-
2. 850 to 1250 mg/m2 orally twice daily for 2 weeks when used in combination with other drugs, followed by a 1-week rest, given as 3-week cycles.
-
3. 800 mg/m2 orally twice daily 5 days per week during radiotherapy as a radiosensitizer.
-
1. Myelosuppression and other hematologic effects. Common, but when used as a single agent, these usually are mild to moderate with anemia predominating. Neutropenia is common when used in combination and may be associated with neutropenic fever.
-
2. Nausea, vomiting, and other gastrointestinal effects. Both nausea (45%) and vomiting (35%) are common, but usually not severe. Diarrhea is common (55%); in up to 15% of patients, it is severe to life-threatening. Gastrointestinal motility disorders, including ileus, may be seen, and necrotizing enterocolitis has been reported. Abdominal pain is occasional to common. Anorexia is occasional to common (26%). Hyperbilirubinemia is common (48%) but only occasionally severe or life-threatening.
-
3. Mucocutaneous effects. Hand-foot syndrome is common (54%) and may be severe. Dermatitis is also common (27%), as is stomatitis, but it is uncommon that these are severe. Eye irritation and increased lacrimation are occasional.
-
4. Miscellaneous effects:
-
a. Fatigue is common.
-
b. Paresthesias are occasional.
-
c. Fever is occasional.
-
d. Headache or dizziness is occasional.
-
e. Cardiotoxicity is possible as with any fluorinated pyrimidine.
-
-
1. Target AUC is commonly 4 to 6, depending on previous treatment and other drugs to be used. Administration dose (mg) = (target AUC) × ([creatinine clearance] + 25). Administration dose is given by IV infusion over 15 to 60 minutes and repeated every 4 weeks.
-
2. Higher doses up to 1600 mg/m2 divided over several days have been used followed by stem cell rescue (e.g., bone marrow transplantation).
-
1. 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 to 28).
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea and vomiting are common, but vomiting (65%) is not as frequent or as severe as with cisplatin and can be controlled with combination antiemetic regimens. Liver function abnormalities are common. Gastrointestinal pain is occasional.
-
3. Mucocutaneous effects. Alopecia is uncommon. Mucositis is rare.
-
4. Immunologic effects and infusion reactions. Infusion reactions are occasional but may be severe. These may include rash, urticaria, pruritus, and rarely bronchospasm and hypotension. Desensitization protocols may allow continued therapy with carboplatin, but should be carried out under close observation (see Special precautions).
-
5. Miscellaneous effects:
-
a. Peripheral neuropathies or central neurotoxicity are uncommon.
-
b. Cardiovascular (cardiac failure, embolism, cerebrovascular accidents) complications are uncommon.
-
c. Hemolytic uremic syndrome is rare.
-
d. Renal tubular abnormalities: Elevation in serum creatinine or blood urea nitrogen occurs occasionally. More common is electrolyte loss with decreases in serum sodium, potassium, calcium, and magnesium.
-
-
1. Systemic therapy:
-
a. Brain tumors
-
b. Hodgkin and non-Hodgkin lymphomas
-
c. Melanoma.
-
-
2. Implantable carmustine-impregnated wafer: glioblastoma multiforme.
-
1. Systemic therapy:
-
a. 200 to 240 mg/m2 IV as a 30- to 45-minute infusion every 6 to 8 weeks. Dose often is divided and given over 2 to 3 days. Some recommend limiting the cumulative dose to 1000 mg/m2 to limit pulmonary and renal toxicity.
-
b. Higher doses of up to 600 mg/m2 have been used with stem cell rescue (e.g., bone marrow or peripheral blood stem cell transplantation).
-
-
2. Implantable carmustine-impregnated wafer: Up to eight wafers, each containing 7.7 mg of carmustine, are applied to the resection cavity surface after removal of the tumor.
-
1. Systemic therapy:
-
a. Myelosuppression and other hematologic effects. Delayed and often biphasic, with the nadir at 3 to 6 weeks; it may be cumulative with successive doses. Recovery may be protracted for several months. High-dose therapy requires stem cell rescue.
-
b. Nausea, vomiting, and other gastrointestinal effects. Begins 2 hours after therapy and lasts 4 to 6 hours; it is common.
-
c. Mucocutaneous effects:
-
(1) Facial flushing and a burning sensation at the IV site may be due to alcohol used to reconstitute the drug; this is common with rapid injection.
-
(2) Hyperpigmentation of skin after accidental contact is common.
-
-
d. Miscellaneous effects:
-
(1) Hepatotoxicity is uncommon but can be severe.
-
(2) Pulmonary fibrosis is uncommon at low doses, but its frequency increases at doses higher than 1000 mg/m2.
-
(3) Secondary neoplasia is possible.
-
(4) Renal toxicity is uncommon at doses of less than 1000 mg/m2.
-
(5) With high-dose therapy, encephalopathy, hepatotoxicity, and pulmonary toxicity are common and dose-limiting. Hepatic veno-occlusive disease also occurs (occasional).
-
-
-
2. Implantable carmustine-impregnated wafer. Limited toxicity beyond that expected from craniotomy is seen. Serious intracranial infection was seen in 4% of patients, compared with 1% of placebotreated patients. Brain edema not responsive to steroids may also be seen in a similar percentage of patients. Abnormal wound healing may occur. Remnants of the wafer may be seen for many months after implantation.
-
1. Carcinoma of head and neck, in combination with radiation therapy or after failure of platinum-based therapy.
-
2. Colon cancer when KRAS is wild type, after failure of irinotecan- and oxaliplatin-based regimens. Often in combination with irinotecan or other cytotoxic regimens.
-
3. Lung cancer if EGFR amplification.
-
1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional.
-
2. Nausea, vomiting, and other gastrointestinal effects. Anorexia, nausea, vomiting, diarrhea, and constipation are occasional. Abdominal pain is common.
-
3. Mucocutaneous effects. Acnelike rash is common (76%). Stomatitis is occasional when used alone, but universal when used in combination with radiation therapy. Severe radiation dermatitis may be seen when used concurrently with radiation therapy.
-
4. Miscellaneous effects:
-
a. Asthenia is common; headache and back pain are occasional.
-
b. Weight loss, peripheral edema, and dehydration are occasional.
-
c. Infusion reactions with allergic or hypersensitivity reactions, fever, chills, or dyspnea are occasional to common (˜20%) but may be severe.
-
d. Human antichimeric antibodies (HACAs) are uncommon.
-
e. Electrolyte depletion, particularly hypomagnesemia, occurs commonly. Hypomagnesemia is occasionally severe.
-
-
1. Chronic lymphocytic leukemia
-
2. Low-grade non-Hodgkin lymphoma.
-
1. 3 to 4 mg/m2 by mouth daily until a response is seen or cytopenias occur; then, if necessary, maintain with 1 to 2 mg/m2 by mouth daily.
-
2. 30 mg/m2 by mouth once every 2 weeks (with or without prednisone 80 mg/m2 by mouth on days 1 to 5).
-
1. Myelosuppression and other hematologic effects. Dose-limiting and may be prolonged.
-
2. Nausea, vomiting, and other gastrointestinal effects. May be seen with higher doses but are uncommon.
-
3. Mucocutaneous effects. Rash is uncommon.
-
4. Miscellaneous effects:
-
a. Liver function abnormalities are rare.
-
b. Secondary neoplasia is possible.
-
c. Amenorrhea and azoospermia are common.
-
d. Drug fever is uncommon.
-
e. Pulmonary fibrosis is rare.
-
f. CNS effects including seizure and coma may be seen at very high doses (>100 mg/m2).
-
-
1. Testis, ovary, endometrial, cervical, bladder, head and neck, gastrointestinal, and lung carcinomas
-
2. Soft-tissue and bone sarcomas
-
3. Non-Hodgkin lymphoma.
-
1. 40 to 120 mg/m2 IV on day 1 as infusion every 3 weeks
-
2. 15 to 20 mg/m2 IV on days 1 to 5 as infusion every 3 to 4 weeks.
-
1. An acceptable method for hydration in patients without cardiovascular impairment for cisplatin doses up to 80 mg/m2 is as follows:
-
a. Have patient void and begin infusion of 5% dextrose in halfnormal saline with potassium chloride (KCl) 20 mEq/liter and magnesium sulfate (MgSO4) 1 g/liter (8 mEq/liter); run at 500 mL/hour for 1.5 to 2.0 L.
-
b. After 1 hour of infusion, give 12.5 gm of mannitol by IV push.
-
c. Immediately thereafter, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 hour through the sidearm of the IV, while continuing the hydration.
-
d. Give additional mannitol (12.5 to 50.0 gm) by IV push if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given.
-
-
2. For doses more than 80 mg/m2 a more vigorous hydration is recommended:
-
a. Have patient void and begin infusion of 5% dextrose in half-normal saline with KCl 20 mEq/liter and MgSO4 1 gm/liter (8 mEq/liter); run at 500 mL/hour for 2.5 to 3.0 L.
-
b. After 1 hour of infusion, give 25 g of mannitol by IV push.
-
c. Continue hydration.
-
d. After 2 hours of hydration, if urinary output is at least 250 mL/hour, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 to 2 hours (1 mg/m2/minute) through the sidearm of the IV, while continuing the hydration.
-
-
3. For patients with known or suspected cardiovascular impairment (ejection fraction <45%), a less vigorous rate of hydration may be used, provided the dose of cisplatin is limited (e.g., <60 mg/m2). An alternative is to give carboplatin.
-
1. Myelosuppression and other hematologic effects. Mild to moderate, depending on the dose. Relative lack of myelosuppression and other hematologic effects allows cisplatin to be used in full doses with more myelosuppressive drugs. Anemia is common and may have a hemolytic component. Anemia often is amenable to epoetin therapy.
-
2. Nausea, vomiting, and other gastrointestinal effects. Severe and often intractable vomiting regularly begins within 1 hour of starting cisplatin and lasts 8 to 12 hours. Prolonged nausea, vomiting, and other gastrointestinal effects occur occasionally. Nausea, vomiting, and other gastrointestinal effects may be minimized by the use of a combination antiemetic regimen (see Chapter 26).
-
3. Mucocutaneous effects. None.
-
4. Renal tubular damage. Acute reversible and occasionally irreversible nephrotoxicity may occur, particularly if adequate attention is not given to achieving sufficient hydration and diuresis. Nephrotoxic antibiotics increase risk of acute renal failure.
-
5. Ototoxicity. High-tone hearing loss is common, but significant hearing loss at vocal frequencies occurs only occasionally. Tinnitus is uncommon.
-
6. Severe electrolyte abnormalities. Marked hyponatremia, hypomagnesemia, hypocalcemia, and hypokalemia may be seen up to several days after treatment.
-
7. Anaphylaxis. May occur after several doses. Responds to epinephrine, antihistamines, and corticosteroids.
-
8. Miscellaneous effects:
-
a. Peripheral neuropathies are clinically significant; signs and symptoms are common at cumulative doses more than 300 mg/m2.
-
b. Hyperuricemia is uncommon and parallels renal failure.
-
c. Autonomic dysfunction with symptomatic postural hypotension is occasional.
-
-
1. 0.09 mg/kg (3.33 mg/m2) IV daily as a continuous 7-day infusion
-
2. 0.14 mg/kg (5.2 mg/m2) IV as a 2-hour infusion daily for 5 days
-
3. 0.14 mg/kg (5.2 mg/m2) SC daily for 5 days
-
4. 0.12 mg/kg IV daily × 3 together with cyclophosphamide 250 mg/m2 IV daily × 3 every 28 days up to 6 cycles (for chronic lymphocytic leukemia [CLL] with TP53 [17p13] gene deletion).
-
1. Myelosuppression and other hematologic effects. Moderate granulocyte suppression is common. Marrow suppression with leukopenia and thrombocytopenia may be prolonged for over a year. Serious infection is common. Profound suppression of cluster of differentiation (CD) 4 and CD8 counts is common and often prolonged for over 1 year. Opportunistic infections, including herpes, fungus, and pneumocystis infection, may occur and should be monitored. Some routinely use prophylaxis against one or more of these infections, including acyclovir 400 mg twice a day and trimethoprimsulfamethoxazole one double-strength tablet twice daily on 2 or 3 days a week. Autoimmune hemolytic anemia and immune thrombocytopenic purpura occur occasionally; pure red cell aplasia rarely.
-
2. Nausea, vomiting, and other gastrointestinal effects. Mild nausea with decrease in appetite is common, but no vomiting is expected. Mild reversible increase in liver function tests may be seen.
-
3. Mucocutaneous effects. Rash is common. Injection site reactions are occasional.
-
4. Miscellaneous effects:
-
a. Fever, possibly due to release of pyrogens from tumor cells, is common.
-
b. Fatigue is common. Headache, dizziness, insomnia, myalgia, and arthralgia are occasional.
-
c. Edema and tachycardia are occasional.
-
d. Cough, shortness of breath, and abnormal breath sounds are occasional.
-
-
1. Acute lymphoblastic leukemia (ALL) in children (age 1 to 21 years) who have relapsed or are refractory to other therapy
-
2. Acute lymphoblastic or acute myeloid leukemia (AML) in adults.
-
1. 52 mg/m2 IV over 2 hours daily for 5 consecutive days. May be repeated in 2 to 6 weeks.
-
2. 40 mg/m2 IV over 1 hour (days 2 to 6), followed in 4 hours by cytarabine 1 g/m2 IV as a 2-hour infusion (days 1 to 5) in adults with AML.
-
3. 30 mg/m2 IV over 1 hour daily for 5 days in older adults with AML and unfavorable prognostic factors. For reinduction (day 29) or consolidation (on recovery of counts), dose reduced to 20 mg/m2 IV daily for 5 days (6 cycles maximum).
-
1. Myelosuppression and other hematologic effects. Pancytopenia is common. Febrile neutropenia and documented infections are common.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, diarrhea, and abdominal pain are common. Elevation of transaminases is common and may be severe (grade 3 to 4); jaundice is occasional. Anorexia is common.
-
3. Mucocutaneous effects. Nonspecific dermatitis and pruritis are common. Palmar-plantar erythrodysesthesia is occasional.
-
4. Miscellaneous effects:
-
a. Arthralgia and back pain are occasional.
-
b. Creatinine elevations are uncommon to occasional.
-
c. Fatigue is common. Lethargy is occasional.
-
d. Flushing and hypotension are occasional to common.
-
-
1. Acute and chronic lymphocytic leukemia
-
2. Hodgkin and non-Hodgkin lymphomas
-
3. Multiple myeloma
-
4. Carcinoma of the breast
-
5. Cerebral edema or spinal cord injury (compression)
-
6. Nausea and vomiting from chemotherapy.
-
1. Prednisone: dose varies with neoplasm and combination. Typical regimen, except for acute lymphocytic leukemia, is as follows:
-
a. 40 mg/m2 by mouth days 1 to 14 every 4 weeks, or
-
b. 100 mg/m2 by mouth days 1 to 5 every 4 weeks.
-
-
2. Prednisone: for acute lymphocytic leukemia, 40 to 50 mg/m2 by mouth daily for 28 days.
-
3. Dexamethasone: for cerebral edema or spinal cord injury, 10 mg IV push, then 16 to 32 mg by mouth daily in four divided doses. As signs and symptoms are controlled, gradually reduce to lowest effective dose.
-
1. Myelosuppression and other hematologic effects. No myelosuppression but may exacerbate hypercoagulability when given together with thalidomide or lenolidamide.
-
2. Nausea, vomiting, and other gastrointestinal effects. No acute nausea and vomiting. Epigastric pain, extreme hunger, and occasional peptic ulceration with bleeding may occur even with short courses. Antacids or inhibitors of acid secretion are recommended as prophylaxis.
-
3. Mucocutaneous effects. Acne; increased risk for oral, rectal, and vaginal yeast infections. Thinning of skin and striae develop with continuous use.
-
4. Suppression of adrenal-pituitary axis. May lead to adrenal insufficiency when corticosteroids are withdrawn. This problem is not common with intermittent schedules.
-
5. Metabolic effects. Potassium depletion, sodium and fluid retention, diabetes, increased appetite, loss of muscle mass, myopathy, weight gain, osteoporosis, and development of Cushingoid features. Their frequency depends on dose and duration of therapy.
-
6. Miscellaneous effects:
-
a. CNS effects, including euphoria, depression, and sleeplessness, are common and may progress to dementia or frank psychosis.
-
b. Increased susceptibility to infection is common.
-
c. Subcapsular cataracts in patients are uncommon but have been seen even when used for prophylaxis and treatment of druginduced emesis.
-
-
1. Breast, lung, ovary, testis, and bladder carcinomas
-
2. Bone and soft-tissue sarcomas
-
3. Hodgkin and non-Hodgkin lymphomas
-
4. Acute and chronic lymphocytic leukemias
-
5. Waldenström macroglobulinemia
-
6. Neuroblastoma and Wilms tumor of childhood
-
7. Gestational trophoblastic neoplasms
-
8. Multiple myeloma.
-
1. 1000 to 1500 mg/m2 IV every 3 to 4 weeks, or
-
2. 400 mg/m2 by mouth days 1 to 5 every 3 to 4 weeks, or
-
3. 60 to 120 mg/m2 by mouth daily.
-
4. High-dose regimens (4 to 7 g/m2 divided over 4 days) are investigational and should only be used with some kind of stem cell rescue (e.g., bone marrow transplantation) and mesna bladder protection.
-
1. Myelosuppression and other hematologic effects. Dose-limiting. Platelets are relatively spared. Nadir is reached approximately 10 to 14 days after IV dose with recovery by day 21.
-
2. Nausea, vomiting, and other gastrointestinal effects. Frequent with large IV doses; less common after oral doses. Symptoms begin several hours after treatment and are usually over by the next day.
-
3. Mucocutaneous effects. Reversible alopecia is common, usually starting after 2 to 3 weeks. Skin and nails may become darker. Mucositis is uncommon.
-
4. Bladder damage. Hemorrhagic or nonhemorrhagic cystitis may occur in 5% to 10% of patients treated. It is usually reversible with discontinuation of the drug, but it may persist and lead to fibrosis or death. Frequency is diminished by ample fluid intake and morning administration of the drug. Mesna will protect from this effect.
-
5. Miscellaneous effects:
-
a. Immunosuppression is common.
-
b. Amenorrhea and azoospermia are common.
-
c. Inhibition of antidiuretic hormone is only of significance with very large doses.
-
d. Interstitial pulmonary fibrosis is rare.
-
e. Secondary neoplasia is possible.
-
f. Acute and potentially fatal cardiotoxicity occurs with high-dose therapy. Abnormalities include pericardial effusion, congestive heart failure, decreased voltage on electrocardiogram (ECG), and fibrin microthrombi in cardiac capillaries with endothelial injury and hemorrhagic necrosis.
-
-
1. Acute nonlymphocytic leukemia
-
2. Meningeal lymphoma or leukemia.
-
1. Induction: 100 to 200 mg/m2 IV daily as a continuous infusion for 5 to 7 days (in combination with other drugs).
-
2. Maintenance: 100 mg/m2 SC every 12 hours for 4 or 5 days every 4 weeks (with other drugs).
-
3. Intrathecally:
-
a. 40 to 50 mg/m2 of cytarabine, unencapsulated, every 4 days in preservative-free buffered isotonic diluent
-
b. 50 mg of cytarabine, liposomal, repeated in 14 to 28 days.
-
-
4. High dose:
-
a. Induction: 2 to 3 g/m2 IV over 1 to 2 hours every 12 hours for up to 12 doses.
-
b. Consolidation: 3 g/m2 IV over 3 hours every 12 hours on days 1, 3, and 5.
-
-
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and thrombocytopenia occur, with nadir at 7 to 10 days after treatment has ended and with recovery during the following 2 weeks, depending on the degree of suppression. Megaloblastosis is common.
-
2. Nausea, vomiting, and other gastrointestinal effects. Common, particularly if the drug is given as a push or rapid infusion.
-
3. Mucocutaneous effects. Stomatitis is seen occasionally.
-
4. Miscellaneous effects:
-
a. Flulike syndrome with fever, arthralgia, and sometimes a rash is occasional.
-
b. Transient mild hepatic dysfunction is occasional.
-
-
1. Myelosuppression and other hematologic effects. Universal.
-
2. Nausea, vomiting, and other gastrointestinal effects. Nausea, vomiting, and diarrhea are common.