Classification, Use, and Toxicity of Clinically useful Chemotherapy and molecular Targeted Therapy
Anis Toumeh
Roland T. Skeel
I. CLASSES OF DRUGS
Chemotherapeutic agents, whether classical or molecular targeted, 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, and in many cases can also be designated as biologic response modifiers. Drugs that do not fit easily into other categories are grouped together as miscellaneous agents. Summary information on mechanism of action, primary indications, usual dosage and schedule, special precautions, and toxicity for individual agents are given in Section III of this chapter.
Within each class are several types of agents (Table 28.1). As with the criteria for separating into class, the types are also grouped according to the mechanism of action, biochemical structure or derivation, physiologic action, or molecular target. 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. While this knowledge was helpful in planning therapy with classical chemotherapy, this classification is less helpful in planning therapy in the targeted therapy era, as treatment selection is now commonly based on known altered molecular characteristics and pathways of a tumor type or individual tumors.
TABLE 28.1 Classification of Classical and Molecular Targeted Agents | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A. Alkylating agents
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 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 the 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.
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.
B. Antimetabolites
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.
C. Natural products
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.
D. Hormones and hormone antagonists
1. General description. The hormones and hormone antagonists that are clinically active against cancer include steroid estrogens, progestins, androgens, corticoids and their synthetic derivatives, nonsteroidal synthetic compounds with steroid or steroid-antagonist activity, aromatase inhibitors, hypothalamic-pituitary analogs, and thyroid hormones. Each agent has diverse effects. Some effects are mediated directly at the cellular level by the drug binding to specific cytoplasmic receptors or by inhibition or stimulation of the production or action of the hormones. These agents may also act by stimulating or inhibiting natural autocrine and paracrine growth factors (e.g., epidermal growth factor, transforming growth factors [TGFs]-α and -β). The relative roles of the various actions of hormones and hormone antagonists are only partially understood and probably vary among tumor types. For selective estrogen receptor modulators such as tamoxifen, which, when bound to the estrogen receptor, ultimately controls the promoter region of genes that affect cell growth, there are a host of modulating factors including some 20 receptor-interacting proteins and 50 transcription-activating factors as well as many response elements. Other effects are mediated through indirect effects on the hypothalamus and its anterior pituitary-regulating hormones. The final common pathway in most circumstances appears to lead to the malignant cell, which retains some sensitivity to
direct or indirect hormonal control of its growth. An exception to this mechanism is the effect of corticosteroids on leukemias and lymphomas, in which the steroids appear to have direct lytic effects on abnormal lymphoid cells that have high numbers of glucocorticoid receptors.
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.
E. Molecularly targeted agents
1. General. This classification is a relatively recent one in oncology that has become possible because of maturation of knowledge about the molecular events that are responsible for the development of cancer. Understanding of the genetic changes in the cancer cell, the downstream molecular events that follow as a consequence, and the mechanisms by which these events regulate cell growth and death has led to a host of possibilities for the control of cancer growth.
2. Tyrosine kinase and multikinase inhibitors. The first clinical example of this was the signal transduction inhibitor imatinib mesylate, which inactivates the constitutively active fusion product tyrosine kinase arising from the Philadelphia chromosome (Ph) found in chronic myelogenous leukemia (CML), Bcr-Abl, as well as c-KIT kinase, which is overexpressed in (GI) 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 nearly every cancer type.
3. Monoclonal antibodies have emerged over the last 15 to 20 years as useful adjuncts to the medical oncologist’s armamentarium. These agents, which may be directed at growth factors or their receptors, 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 (ado-trastuzumab emtansine, brentuximab vedotin, gemtuzumab). Several molecular targeted agents, such as the immune checkpoint inhibitors, are biologic response modifiers.
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 proteasomes, which mediate protein degradation and play an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis; or perturb other critical pathways.
F. Miscellaneous agents
These are listed in Table 28.1 and include biologic response modifiers, which may have multiple biologic effects (like the interferons or thalidomide-like agents) or may be more specific in activity
(like the monoclonal immune checkpoint inhibitors), and other miscellaneous agents.
(like the monoclonal immune checkpoint inhibitors), and other miscellaneous agents.
Descriptions of specific agents are found in Section III.
II. CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND MOLECULARTARGETED AGENTS
Section III of this chapter contains an alphabetically arranged compendium that contains a description of the chemotherapeutic, biologic, and molecular targeted agents that are recognized to be clinically useful. Each drug is listed by its generic name, with other common names or trade names included. A brief description is given of the probable mechanism of action, clinical uses, recommended doses and schedules, precautions, and side effects.
A. Recommended doses: CAUTION
Although every effort has been made to ensure that the drug dosages and schedules given here are accurate and in accord with published standards, readers are advised to check the product information sheet included in the package of each U.S. Food and Drug Administration (FDA)-approved drug. For drugs or indications not yet approved for general use, active protocol guidelines and any current medical literature should be used to verify recommended dosages, contraindications, and precautions and to review potential toxicity.
B. Dose selection and designation
The doses are listed using body surface area (square meters) as the base for all agents when this is appropriate. Because many of the drugs are given in combination with other agents, doses most commonly used in popular combinations may also be indicated. These data should not be used as the sole source of information for any of the drugs but rather should be used as a guide to confirm and compare dose ranges and schedules and to identify potential problems. For some agents, the area under the curve (AUC) method of dose calculation seems to be most reliable for achieving the most accurate dosing and balance between efficacy and toxicity; when that is the standard, the AUC dose is used.
C. Drug toxicity: frequency designation
The designation of the frequency of toxic side effects is indicated as follows (probability of occurrence equals percentage of patients who may be expected to experience the toxic effect):
Universal (90% to 100%)
Common (15% to 90%)
Occasional (5% to 15%)
Uncommon (1% to 5%)
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. For some toxicities, an actual percentage of observed frequency is also listed.
dose, schedule, and route of drug administration, as well as other concurrent treatment. For some toxicities, an actual percentage of observed frequency is also listed.
D. Dose modification
1. Philosophy. The optimal dose and schedule of a drug are those that give the 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 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
2. Guidelines
a. Nonhematologic toxicity
1) Acute effects. Acute drug toxicity that is limited to 1 to 2 days and is not cumulative is not usually a cause of dose modification unless it is of grade 3 or 4, that is, severe or life-threatening. (For individual toxicities, see the Common Terminology Criteria for Adverse Events v4.0, available on the Internet at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm or downloaded in the latest version from http://evs.nci.nih.gov/ftp1/CTCAE/About.html).1 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 usually is
an indication to discontinue the offending drug, unless there is a reliable and safe way to desensitize the patient. 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.
an indication to discontinue the offending drug, unless there is a reliable and safe way to desensitize the patient. 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.
2) Chronic effects. Chronic or cumulative toxicity such as pulmonary function changes with bleomycin or decreased cardiac function with doxorubicin is nearly always an indication to discontinue the responsible agent. Chronic or cumulative neurotoxicity due to vincristine, cisplatin, paclitaxel, or other agents may require no dose change, reduction, or discontinuation, depending on the severity of the resultant neurologic dysfunction and the patient’s ability to tolerate it.
b. Hematologic toxicity
The degree of myelosuppression and attendant risk of infection and bleeding that are acceptable depend on the cancer, the duration of the 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 scheme shown in Table 28.2 can serve as a guide to reasonable dose changes for drugs whose major toxicity is myelosuppression with a blood count nadir of 7 to 14 days.
c. Dosing for the obese patient
In general, patients who are overweight (body mass index [BMI], 25 to 29.9) and those who are obese (BMI, 30 to 34.9)
should be treated with full doses of chemotherapy, based on the body surface area calculated from their actual weight, particularly when therapy is given with curative intent. Whether this is true for those who are very obese (BMI, 35 to 39.9) or extremely obese (BMI >40) is not clear, owing to a lack of sufficient data. While some clinicians would limit the dose, using a maximum weight based on a BMI of 35 (maximum treatment weight (kg) = 35 × [height (m)]2), it is clear that basing treatment on ideal weight or an average of actual and ideal weight results in undertreatment if used for patients with a BMI of 35 or less.2,3
should be treated with full doses of chemotherapy, based on the body surface area calculated from their actual weight, particularly when therapy is given with curative intent. Whether this is true for those who are very obese (BMI, 35 to 39.9) or extremely obese (BMI >40) is not clear, owing to a lack of sufficient data. While some clinicians would limit the dose, using a maximum weight based on a BMI of 35 (maximum treatment weight (kg) = 35 × [height (m)]2), it is clear that basing treatment on ideal weight or an average of actual and ideal weight results in undertreatment if used for patients with a BMI of 35 or less.2,3
TABLE 28.2 Dose Modifications for Myelosuppressive Drugs With a Nadir* at Less than 3 Weeks | |||||||||||||||||||||||||||||||||||
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III. DATA FOR CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND MOLECULAR TARGETED AGENTS*
Agents or uses 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.
ABIRATERONE ACETATE
Other name. Zytiga.
Mechanism of action. An androgen biosynthesis inhibitor. It inhibits 17 alpha-hyroxylase/C 17, 20-lyase (CYP 17), which results in decreased formation of dehydroepiandrosterone (DHEA) and androstenedione and increased mineralocorticoid production by the adrenal glands.
Primary indication. In combination with prednisone in the treatment of metastatic castration-resistant prostate cancer.
Usual dosage and schedule. 1,000 mg (four 250 mg tablets) orally once daily in combination with prednisone 5 mg orally twice daily. Abiraterone must be taken on an empty stomach, at least 2 hours after or 1 hour before a meal. Recommended starting dose in patients with moderate hepatic impairment (Child-Pugh B) is 250 mg orally once daily. Use with caution with strong CYP3A4 inhibitors or inducers. Dose reduction may be required when used with substrates of CYP2D6 with narrow therapeutic index.
Special precautions
1. Abiraterone can cause fetal harms if administered to pregnant women.
2. Hypertension, hypokalemia, and fluid retention may occur as a result of increased mineralocorticoid production. However, severe reactions are uncommon, and the coadministration of prednisone leads to decreased ACTH secretion and thus reduces the incidence and severity of these reactions.
Toxicity
1. Myelosuppression and other hematologic effects. Lymphopenia is common and occasionally severe.
2. Nausea, vomiting, and other GI effects. Diarrhea and constipation are common, and dyspepsia is occasional.
3. Mucocutaneous effects. Skin rash is occasional, but rarely severe.
4. Immunologic effects and infusion reactions. Urinary and upper respiratory tracts infections can occasionally occur.
5. Miscellaneous effects
a. General. Fatigue is common. Pyrexia is occasional.
b. Respiratory. Cough is occasional. Dyspnea is occasional.
c. Cardiovascular. Edema and hot flashes are common. Hypertension is occasional. Chest pain is uncommon. Cardiac failure (asymptomatic and symptomatic) is uncommon, but can be rarely severe and lead to death. Cardiac arrhythmias including tachy- and brady-arrhythmias are occasional and not usually severe, but can be fatal.
d. Metabolic. Hypertriglyceridemia, hypokalemia, and hypophosphatemia are common.
e. Hepatic. Increased AST and ALT are common. Hyperbilirubinemia is occasional. Liver function tests should be checked at baselines, every 2 weeks for the first 3 months and monthly thereafter. If grade 3 or greater toxicity develops (AST and or ALT greater than five times ULN or total bilirubin greater than three times ULN), dose interruption is
recommended until toxicity improves to grade 1 or less, upon which treatment can be restarted at a reduced dose. In patients with moderate hepatic impairment (Child-Pugh B) who develop grade 3 or higher toxicity, permanent discontinuation of treatment is recommended.
recommended until toxicity improves to grade 1 or less, upon which treatment can be restarted at a reduced dose. In patients with moderate hepatic impairment (Child-Pugh B) who develop grade 3 or higher toxicity, permanent discontinuation of treatment is recommended.
f. Endocrine. Adrenal insufficiency is rare, and the risk is higher during infections, stress, withdrawal from prednisone, and during prednisone dose reductions. Increased dose of steroids may be indicated before, during, and after stressful situations.
g. Genitourinary. Urinary frequency, nocturia and hematuria are occasional.
h. Musculoskeletal and connective tissue. Arthralgia, myalgia, joints swelling, joints stiffness, and muscle spasms are common, but usually not severe.
i. Psychiatric. Insomnia is occasional.
ADO-TRASTUZUMAB EMTANSINE
Other name. Kadcyla.
Mechanism of action. HER2-targeted antibody-drug conjugate (ADC) combining the humanized anti-HER2 IgG1, trastuzumab with the small molecule microtubule inhibitor, DM1. Upon binding to the subdomain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites.
Primary indication. Metastatic HER2-positive carcinoma of the breast in patients who previously received trastuzumab and a taxane, separately or in combination, and either received prior therapy for advanced disease or developed disease recurrence during or within 6 months of completing adjuvant treatment.
Usual dosage and schedule. 3.6 mg/kg by intravenous (IV) infusion every 3 weeks. The first infusion is given over 90 minutes, and patients are monitored for infusion-related reactions up to 90 minutes after the infusion. Subsequent infusions are given over 30 minutes. It should not be given concurrently with trastuzumab or pertuzumab. The infusion rate should be slowed or interrupted if the patient develops infusion-related reactions. Permanent discontinuation is recommended for severe reactions. Dose adjustment/interruptions or permanent discontinuation may be required for increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy. The dose must not be reescalated after a dose reduction is made.
Special precautions
1. Pulmonary toxicity. Cases of severe, and sometimes fatal, pneumonitis and interstitial lung disease leading to acute respiratory distress syndrome have been reported in up to 1.2% of patients. Permanent discontinuation is recommended if diagnosis is confirmed or strongly suspected after exclusion of other possible causes.
2. Infusion-related and hypersensitivity reactions manifested by fever, chills, flushing, dyspnea, hypotension, bronchospasms, wheezing, and tachycardia can occur in 1.4% of patients. Although these cases are usually mild and resolve with rate slowing or treatment interruption with appropriate medical management, some cases can be severe and fatal. Treatment discontinuation is recommended in patients who develop severe, anaphylactic-like reaction. Extravasation reactions (erythema, tenderness, skin irritation, pain and/or swelling) can occur usually within 24 hours of infusion. These reactions are usually mild, and general supportive care is recommended as there is no specific treatment.
3. Bleeding (including epistaxis, CNS, respiratory, and GI) is common (32.2%). Severe hemorrhagic reactions are uncommon, but can be fatal. Coadministration of medications known to increase the risk of bleeding should be taken with caution.
4. Embryo-fetal toxicity. Verification of pregnancy status prior to initiation of therapy in women of childbearing age and the use of effective birth control measures during and up to 6 months after the last dose of treatment is recommended.
5. Ado-trastuzumab emtansine can cause left ventricular dysfunction, although it is uncommon. Assessment at base line, as well as every 3 months while on treatment, with echocardiogram or multigated acquisition (MUGA) scan is recommended. If the left ventricular ejection fraction (LVEF) is <40% or 40% to 45% with >10% decrease in the absolute value, treatment interruption and reassessment in 3 weeks is recommended, and permanent discontinuation is warranted if the LVEF does not improve or declines further.
6. Severe, and sometimes fatal, hepatotoxicity and hepatic failure can occur. Periodic monitoring of liver function tests is recommended. Dose reduction/interruption may be required for elevated transaminases and/or total bilirubin. However, permanent discontinuation is recommended if the AST or ALT is >three times ULN concomitantly with total bilirubin >two times ULN. Do not treat if active hepatitis B or C. Nodular regenerative hyperplasia and portal hypertension were rarely described and warrant permanent discontinuation of treatment.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia and anemia are common, but rarely severe. Thrombocytopenia is common and occasionally severe. The incidence of thrombocytopenia is higher in the Asian population.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, diarrhea, xerostomia, and constipation are common. Dyspepsia is occasional.
3. Mucocutaneous effects. Stomatitis is occasional. Rash and pruritus are occasional.
4. Immunologic effects and infusion reactions. See Special Precautions.
5. Miscellaneous effects
a. General. Fatigue, asthenia, and pyrexia are common.
b. Respiratory. Dyspnea is occasional. Cough and epistaxis are common.
c. Cardiovascular. Peripheral edema is occasional. Hypertension is occasional.
d. Metabolic. Hypokalemia is occasional.
e. Neurologic. Dysgeusia and dizziness are occasional. Headache is common. Peripheral sensory neuropathy is common and mostly mild. Grade 3 or greater is uncommon, but treatment interruption is recommended until it resolves to grade 2 or less.
f. Hepatic. Increased AST/ALT and/or total bilirubin is common and occasionally severe.
g. Musculoskeletal and connective tissue. Arthralgia and musculoskeletal pain are common. Myalgia is occasional.
h. Psychiatric. Insomnia is occasional.
i. Ophthalmic. Blurred vision, conjunctivitis, dry eyes, and increased lacrimation are uncommon.
AFATINIB
Other name. Gilotrif.
Mechanism of action. Tyrosine kinase inhibitor; afatinib binds covalently to the kinase domains of ErbB1(EGFR), ErbB2(HER2), and ErbB4(HER4) and inhibits tyrosine kinase autophosphorylation, irreversibly resulting in downregulation of ErbB signaling.
Primary indications. Metastatic non-small cell lung cancer (NSCLC) tumors that harbor epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations.
Usual dosage and schedule. 40 mg orally daily until disease progression or unacceptable toxicity. Dose to be taken at least 1 hour before or 2 hours after a meal. Missed doses must not be taken within 12 hours of the next scheduled dose. Reduced doses are indicated following temporary discontinuation for adverse drug reactions and may be needed for patients who are concurrently taking P-glycoprotein inhibitors.
Special precautions. Afatinib can cause fetal harm when administered to a pregnant woman. Fatal cases of severe hepatic toxicity, interstitial lung disease, and diarrhea can occur. Discontinue treatment in patients who develop life-threatening bullous, blistering, or exfoliating lesions, and in any confirmed case of interstitial lung disease or severe keratitis. Must not be used with vinorelbine in HER2-positive metastatic breast cancer.
Toxicity
1. Myelosuppression and other hematologic effects. Not reported. However, paronychia is common, and cystitis is occasional.
2. Nausea, vomiting, and other GI effects. Diarrhea is universal, with severe cases (grade 3 or greater) occurring in 15% of cases in the first 6 weeks of treatment, and can result in severe, and rarely fatal, dehydration with
or without renal impairment. Abnormalities in liver function tests are occasional and rarely fatal.
or without renal impairment. Abnormalities in liver function tests are occasional and rarely fatal.
3. Mucocutaneous effects. Cutaneous reactions consisting of rash, erythema, and acneiform rash are universal. Grade 3 reactions can occur in 16% of cases. The incidence of grade 1 to 3 palmar-plantar erythrodysesthesia syndrome in clinical trials was 7%. Severe bullous and exfoliating dermatitis is rare. Stomatitis is common and occasionally grade 3 or higher.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects.
a. Renal impairment as a result of diarrhea is occasional and uncommonly severe.
b. Conjunctivitis is uncommon, and severe cases that progress to ulcerative keratitis are rare.
c. Interstitial lung disease or reactions that mimic this occur in up to 20% and may be fatal.
d. Ventricular dysfunction is uncommon.
e. Fever, weight loss, pruritis, and hypokalemia are occasional.
ALTRETAMINE
Other names. Hexamethylmelamine, Hexalen, HXM.
Mechanism of action. Unknown. Although it structurally resembles the known alkylating agent triethylenemelamine, it has some antimetabolite characteristics.
Primary indication. Carcinoma of the ovary, persistent or recurrent after first-line therapy.
Usual dosage and schedule
1. 260 mg/m2 PO daily in three or four divided doses after meals and at bedtime for 14 or 21 days every 4 weeks when used as a single agent.
2. 150 to 200 mg/m2 PO daily in three or four divided doses for 2 out of 3 or 4 weeks when used in combination.
Special precautions. Concurrent altretamine and antidepressants of the monoamine oxidase (MAO) inhibitor class may cause severe orthostatic hypotension. Cimetidine may increase toxicity.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and thrombocytopenia are uncommon, though lesser degrees are common. Anemia is common.
2. Nausea, vomiting, and other GI effects. Mild-to-moderate nausea, vomiting, and other GI 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.
ANAGRELIDE
Other names. Imidazo(2,1-b)quinazolin-2-one, Agrelin.
Mechanism of action. Mechanism for thrombocytopenia unknown, but may be due to impaired megakaryocyte function. Inhibitor of platelet aggregation, but not at usual therapeutic doses.
Primary indication. Uncontrolled thrombocytosis in chronic myeloproliferative disorders, such as essential thrombocythemia, chronic granulocytic leukemia, and polycythemia rubra vera.
Usual dosage and schedule. (Supplied as 0.5-mg and 1-mg capsules.)
1. 0.5 mg PO q.i.d. or 1 mg PO b.i.d. Increase by 0.5 mg/day every 5 to 7 days if no response. Maximum daily dose is 10 mg/day. Maximum single dose is 2.5 mg. Higher doses cause postural hypotension.
2. Alternate dosing schedules:
a. Elderly: 0.5 mg PO daily, increase by 0.5 mg each week.
b. Abnormal renal or hepatic function: 0.5 mg PO b.i.d.
Special precautions. Contraindicated in pregnancy and in patients with severe hepatic impairment. Use with caution in patients with heart disease. Tachycardia and forceful heartbeat may be exacerbated by caffeine; consumption of caffeine should be avoided for 1 hour before and after anagrelide is taken. Use other drugs that inhibit platelet aggregation (such as nonsteroidal anti-inflammatory drugs (NSAIDs)) with caution. Monitor platelet count every few days during the first week, then weekly until the maintenance dose is reached.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia is rare. Anemia is common but mild. Thrombocytopenic hemorrhage is uncommon.
2. Nausea, vomiting, and other GI 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.
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.
ANASTROZOLE
Other name. Arimidex.
Mechanism of action. Decreases estrogen biosynthesis by selective inhibition of aromatase (estrogen synthetase).
Primary indications
1. Carcinoma of the breast as adjuvant treatment in postmenopausal women with positive hormone receptors.
2. Carcinoma of the breast that is advanced or metastatic as first therapy in postmenopausal women with positive or unknown hormone receptors, alone or in combination with Fluvestrant.
3. Carcinoma of the breast that is advanced or metastatic as second therapy in postmenopausal women with progression following initial response to tamoxifen.
4. Prevention of breast cancer in women at high risk, including prior ductal carcinoma in situ (DCIS), who have contraindications to tamoxifen.
Usual dosage and schedule. 1 mg PO daily.
Special precautions. Potential hazard to fetus if given during pregnancy. In women with preexisting ischemic heart disease, an increased incidence of ischemic cardiovascular events occurred with anastrozole use compared with tamoxifen use. Consider obtaining bone mineral density testing prior to initiation of anastrozole and treating as clinically indicated.
Toxicity
1. Myelosuppression and other hematologic effects. No dose-related myelosuppression. Thromboembolic events are uncommon (3%).
2. Nausea and vomiting, other GI 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 of fractures (10%).
g. Vaginal bleeding is uncommon, and endometrial cancer is rare (0.2%).
ARSENIC TRIOXIDE
Other name. Trisenox.
Mechanism of action. Although the mechanism is incompletely understood, effects of arsenic trioxide include morphologic changes and DNA fragmentation characteristic of apoptosis and alteration of the fusion protein PML-RAR alpha.
Primary indication
Acute promyelocytic leukemia that is refractory to, or has relapsed from, retinoid and anthracycline therapy and has t(15;17) translocation or PML/RAR alpha gene expression.
Usual dosage and schedule
1. Induction. 0.15 mg/kg IV daily until marrow remission. Maximum of 60 doses.
2. Consolidation. 0.15 mg/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 AV block with fatal ventricular arrhythmia. Electrolyte (including magnesium) abnormalities should be corrected prior to initiation of therapy, and patients with prolonged QT intervals should have measures taken to reduce this prolongation prior to treatment with arsenic trioxide. A QT value >500 msec during therapy is an indication to suspend arsenic trioxide treatment and to initiate measures to correct other risk factors that may be contributing to the prolongation of the QT.
Acute promyelocytic leukemic differentiation syndrome, similar to that seen with retinoic acid, may be seen and is potentially fatal. This syndrome consists of fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions with or without leukocytosis. High-dose corticosteroids (e.g., dexamethasone, 10 mg b.i.d) should be started at the first signs of this syndrome and continued until it has subsided.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, thrombocytopenia, and neutropenia are occasional. Leukocytosis is common. Disseminated intravascular coagulation is occasional and may be severe. Infections and neutropenic fever are occasional.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and abdominal pain are common (>50%). GI 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 mucocutaneous 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 auscultatory findings are occasional to common (8% to 20%).
f. Renal. Renal failure is occasional.
ASPARAGINASE
Other names. L-Asparaginase, Elspar, Kidrolase, pegaspargase, Oncaspar, Erwinaze (asparaginase Erwinia chrysanthemi).
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 monomethoxy polyethylene glycol (PEG). This modification increases its half-life in the plasma by a factor of 4 to about 5.7 days and reduces its recognition by the immune system, which allows the drug to be used in patients previously hypersensitive to native L-asparaginase.
Primary indication. Acute lymphocytic leukemia, primarily for induction therapy.
Usual dosage and schedule. All schedules are used in combination with other drugs. The schedules listed are only a few of many acceptable dosing schedules.
1. L-asparaginase. 6,000 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. 2,500 IU/m2 intramuscular (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.
Special precautions. Asparaginase is contraindicated in patients with pancreatitis or a history of pancreatitis. Asparaginase is contraindicated in patients who have had significant hemorrhagic events associated with prior L-asparaginase therapy. Pegaspargase is also contraindicated in patients who have had previous serious allergic reactions, such as generalized urticaria, bronchospasm, laryngeal edema, hypotension, or other unacceptable adverse reactions to prior pegaspargase.
Be prepared to treat anaphylaxis at each administration of the drug. Epinephrine, antihistamines, corticosteroids, and life-support equipment should be readily available.
Giving concurrently with or immediately before vincristine may increase vincristine toxicity.
The IM route is preferred for pegaspargase, because of a lower incidence of hepatotoxicity, coagulopathy, and GI and renal disorders compared with the IV route of administration.
Toxicity
1. Myelosuppression and other hematologic effects. Occasional myelosuppression. CNS thrombosis and other coagulopathies are uncommon.
2. Nausea, vomiting, and other GI effects. Occasional and usually mild. (see below 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 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 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.
1. 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.
AXITINIB
Other name. Inlyta.
Mechanism of action. Multi-receptor tyrosine kinases inhibitor, including vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3, which results in decreased angiogenesis, tumor growth, and cancer progression.
Primary indications. Advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.
Usual dosage and schedule. 5 mg orally every 12 hours. A dose escalation to 7 mg twice daily may be used if treatment is well tolerated for at least 2 consecutive weeks with no grade 2 or higher adverse events and if patients remain normotensive and not receiving antihypertension medications. A second dose escalation to 10 mg twice daily under the same criteria can be done. The concomitant use of strong CYP3A4/5 inhibitors should be avoided. Starting dose should be decreased to 50% in patients with moderate (Child-Pugh B) hepatic impairment, while treatment should be avoided in patients with severe (Child-Pugh C) hepatic impairment.
Special precautions
1. Axitinib can cause fetal harm if administered to a pregnant woman.
2. As with other agents with antiangiogenic effect, wound healing complications can occur, and thus, treatment should be held at least 24 hours prior to scheduled surgery. The decision to resume therapy after surgery should be based on clinical judgment of adequate wound healing.
3. GI fistula formation and perforations have been reported and can be fatal.
4. Hemorrhagic events including cerebral hemorrhage, hematuria, hemoptysis, lower GI hemorrhage, and melena are common, but severe reactions are rare and can be fatal.
5. Axitinib has not been studied in patients who have evidence of untreated brain metastasis.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are occasional. Anemia and lymphopenia are common. Polycythemia is rare.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe. Nausea, vomiting, and constipation are common. Stomatitis, dysgeusia, dyspepsia, and abdominal pain are occasional.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome is common and occasionally severe. Rash, pruritus, dry skin, and mucosal inflammation are occasional. Alopecia and erythema are uncommon.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Fatigue, asthenia, and decreased appetite are common. Tinnitus is uncommon.
b. Respiratory. Dysphonia is common. Cough and dyspnea are occasional.
c. Cardiovascular. Treatment-related hypertension is common with median onset of 1 to 4 weeks. It can be severe in up to 16% of cases and rarely lead to hypertensive crisis. Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions are uncommon, but can be fatal. Venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis are uncommon and can be fatal.
d. Metabolic. Hypocalcemia, hyperglycemia, hypernatremia, and increase in lipase and amylase are common. Hyperkalemia, hypophosphatemia, hyponatremia, and hypoglycemia are occasional.
e. Hepatic. Elevation in ALT, AST, or both are common, and periodic monitoring of liver function is recommended.
f. Neurologic. Reversible posterior leukoencephalopathy syndrome (RPLS), which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances, and is diagnosed by MRI, is rare. Headache and dizziness are occasional.
g. Endocrine. Hypothyroidism is common, while hyperthyroidism is rare. Monitoring of thyroid function should be done at baseline and periodically during treatment.
h. Genitourinary. Proteinuria is occasional and uncommonly severe. Creatinine increase is common and rarely severe.
i. Musculoskeletal and connective tissue. Arthralgia, myalgia, and pain in extremities are occasional.
AZACITIDINE
Other name. Vidaza.
Mechanism of action. Pyrimidine analog that inhibits methyltransferase, causing hypomethylation of DNA and thus, it is believed, results in cellular differentiation or apoptosis. May restore normal function of genes that are critical for the control of cellular differentiation and proliferation. Nonproliferating cells are relatively insensitive to azacitidine.
Primary indication. Myelodysplastic syndrome (MDS).
Usual dosage and schedule. 75 mg/m2 SC or IV daily for 7 days, repeated every 4 weeks. Dose may be increased to 100 mg/m2 if no toxicity other than nausea and vomiting. Therapy may be continued so long as the patient has improved from the drug.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common. Febrile neutropenia is four times as common as in patients receiving supportive care. Petechiae or ecchymosis are occasional.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and diarrhea or constipation are common. Abdominal pain is occasional.
3. Mucocutaneous effects. Pharyngitis and stomatitis—occasional. Skin rash is occasional, urticaria is 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—uncommon. Edema is occasional. Tachycardia or other more serious cardiac disorders—uncommon.
b. Fever is common.
c. Fatigue and weakness—common.
d. Arthralgias and back pain are occasional.
e. Hypokalemia—occasional.
BELINOSTAT
Other name. Beleodaq.
Mechanism of action. Histone deacetylase (HDAC) inhibitor. It causes accumulation of acetylated histones and other proteins, including cell cycle arrest and/or apoptosis of some transformed cells. It has preferential cytotoxicity toward tumor cells compared with normal cells.
Primary indications. Relapsed or refractory peripheral T-cell lymphoma (PTCL).
Usual dosage and schedule. The recommended dose is 1,000 mg/m2 IV on days 1 to 5 of each 21-day cycle. Cycles are continued until disease progression or intolerable toxicity. Dose modifications may be required for neutropenia and/or thrombocytopenia. All nonhematologic toxicities need to be of grade 2 or less prior to each treatment cycle. The starting dose should be reduced to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele.
Special precautions. Belinostat can cause teratogenicity and/or embryo-fetal lethality. Patients with moderate-to-severe hepatic impairment (total bilirubin >1.5 times the ULN) were excluded from clinical trials and there is insufficient evidence to recommend a dose for those patients. Hepatic failure, tumor lysis syndrome in patients with bulky disease, ventricular fibrillation, and pneumonia can occur.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common. Thrombocytopenia is occasional. Leukopenia (neutropenia and lymphopenia) with serious or fatal infections including pneumonia and sepsis can also occur.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, and diarrhea are common.
3. Mucocutaneous effects. Rash and pruritus are common. Abdominal pain is occasional.
4. Immunologic effects and infusion reactions. Infusion site pain can occur in up to 14% of patients.
5. Miscellaneous effects
a. Hepatic. Fatal hepatotoxicity and liver function abnormalities can occur.
b. Pyrexia and fatigue are common.
c. Neurologic. Headache and dizziness are occasional.
d. Respiratory. Cough and dyspnea are common.
e. Cardiovascular. Peripheral edema is common. Prolonged QT interval and fatal ventricular fibrillation can occur.
BENDAMUSTINE
Other names. Treanda, bendamustine hydrochloride.
Mechanism of action. Bendamustine is an alkylating agent that is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. It forms interstrand DNA crosslinks that lead to cell death in both resting and dividing cells, though the exact mechanism of cell death is not clear.
Primary indications
1. Chronic lymphocytic leukemia (CLL)
2. Indolent B-cell non-Hodgkin lymphoma
Usual dosage and schedule
1. CLL. 90 to 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6 cycles.
2. Non-Hodgkin lymphoma. 120 mg/m2 IV over 30 minutes on days 1 and 2 of a 21-day cycle, up to 8 cycles.
Initiation of successive cycles of therapy is usually delayed until there is an absolute neutrophil count (ANC) ≥1 × 109/L and a platelet count ≥75 × 109/L. Dose reductions of 50% to 75% should be initiated for grade 3 to 4 hematologic or nonhematologic toxicity.
Special precautions. Infusion reactions consisting of fever, chills, pruritis, and rash are common. Severe anaphylactic or anaphylactoid reactions, particularly in the second or subsequent cycles of therapy, may rarely occur. Antihistamines (e.g., diphenhydramine and cimetidine) and corticosteroids are commonly used to minimize the severity of infusion reactions. Tumor lysis syndrome has been observed, particularly in the first cycle
of therapy. Toxic epidermal necrolysis has rarely occurred when bendamustine was given with rituximab. Stevens-Johnson syndrome has rarely occurred when bendamustine was administered concomitantly with allopurinol. The relationship of these severe reactions to bendamustine is not known. If severe skin reactions occur, bendamustine should be withheld or discontinued. Do not give if known hypersensitivity to bendamustine or mannitol. Bendamustine can cause fetal harm and must not be administered to pregnant women.
of therapy. Toxic epidermal necrolysis has rarely occurred when bendamustine was given with rituximab. Stevens-Johnson syndrome has rarely occurred when bendamustine was administered concomitantly with allopurinol. The relationship of these severe reactions to bendamustine is not known. If severe skin reactions occur, bendamustine should be withheld or discontinued. Do not give if known hypersensitivity to bendamustine or mannitol. Bendamustine can cause fetal harm and must not be administered to pregnant women.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is common and in the higher dosage ranges is universal. 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 GI effects. Nausea, vomiting, and diarrhea are occasional to common and dose dependent, but rarely severe. Anorexia, dyspepsia, gastroesophageal reflux, upper abdominal pain, and distension 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.
BEVACIZUMAB
Other name. Avastin.
Mechanism of action. Binds VGEF and prevents interaction of VEGF with its receptors on the surface of endothelial cells. This in turn impairs endothelial cell proliferation and new blood vessel formation, impeding tumor growth and metastasis.
Primary indications
1. Breast, colon, kidney, rectum, and nonsquamous NSCLC, usually with other agents.
2. Glioblastoma, alone or with other agents.
3. Ovarian, fallopian tube, or primary peritoneal cancer in the recurrent, platinum resistant setting.
4. Cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent or metastatic disease.
Usual dosage and schedule
1. 5 to 10 mg/kg IV once every 2 weeks.
2. 15 mg/kg IV once every 3 weeks.
Special precautions. GI perforation occurs in up to 4% of patients, and may have a fatal outcome. Impaired wound healing may rarely lead to anastomotic dehiscence. Bevacizumab should not be initiated for at least 28 days following major surgery. The interval between termination of bevacizumab and subsequent surgery should take into account the accumulation ratio of 2.8 (with every 2-week dosing) and the half-life of approximately 20 days. Blood pressure monitoring is recommended every 2 to 3 weeks because of the risk of hypertension. RPLS has been reported rarely; if it occurs, therapy must be discontinued immediately and treatment for hypertension initiated if it is present. Urinary protein should be evaluated prior to each treatment with a urine dipstick, and if 2+ or greater, the patient should undergo further assessment to rule out severe proteinuria, such as with a urine protein-creatinine (UPC) ratio. Hold therapy if UPC >3.5.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia is common, but associated primarily with the cytotoxic agents used together with bevacizumab. Thrombocytopenia is uncommon. Minor bleeding, such as epistaxis, is common; severe hemorrhage is not, except for hemoptysis in patients with squamous cell carcinomas of the lung. Serious, and in some cases fatal, hemoptysis has occurred in NSCLC, 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 GI effects. Anorexia, nausea, vomiting, and constipation are common. Diarrhea is common, particularly when used with fluorouracil and irinotecan chemotherapy. Abdominal pain is common. GI hemorrhage is occasional; perforation is uncommon.
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—common
b. Cardiovascular and respiratory—Hypertension is common and occasionally is severe (>200/110 mm Hg). Blood pressure >160/100 or rise of >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 hours) is uncommon and rarely leads to nephrotic syndrome (<1%), but requires holding bevacizumab and rechecking prior to next cycle.
e. Osteonecrosis of the jaw.
BEXAROTENE (Capsules)
Other name. Targretin.
Mechanism of action. A member of the subclass of retinoids (rexinoid) that selectively activates retinoid X receptors (RXRs). These receptors are distinct from RARs, but also act as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. The exact mechanism in cutaneous T-cell lymphoma (CTCL) is unknown.
Primary indication. Cutaneous manifestations of CTCL in patients refractory to at least one prior systemic therapy.
Usual dosage and schedule. 300 mg/m2/day to start as a single oral daily dose taken with a meal. Dosage is adjusted downward by 100 mg/m2/day decrements for toxicity, or upward to 400 mg/m2/day if there has been no response and good tolerability after 8 weeks of treatment. Treatment may be continued for up to 2 years.
Special precautions. Avoid use in pregnant women because of marked teratogenic potential.
Toxicity
1. Myelosuppression and other hematologic effects. Mild-to-moderate leukopenia is occasional to common with a time of onset of 4 to 8 weeks. Severe or worse leukopenia is occasional.
2. Nausea, vomiting, and other GI 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 LDH, SGOT, serum glutamic pyruvic transaminase (SGPT), gamma-glutamyl transpeptidase (GGTP), alkaline phosphatase is occasional.
f. Hypothyroidism—Common, with decreased T4 and thyroid stimulating hormone (TSH).
g. Peripheral edema—Occasional.
h. Hypernatremia is rare.
BICALUTAMIDE
Other name. Casodex.
Mechanism of action. A nonsteroidal antiandrogen that is a competitive inhibitor of androgens at the cellular androgen receptor in target tissues, such as the prostate.
Primary indication. Carcinoma of the prostate.
Usual dosage and schedule. 50 mg daily in combination with LHRH analog.
Special precautions. Rare cases of severe liver injury have been reported. Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment.
Toxicity
1. Myelosuppression and other hematologic effects. No myelosuppression. May interact with warfarin and increase INR.
2. Nausea, vomiting, and other GI effects. Nausea, diarrhea, flatulence, and constipation are occasional; vomiting is uncommon.
3. Mucocutaneous effects. Mild skin rash is occasional.
4. Miscellaneous effects
a. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot flashes, impotence, and loss of libido are common but reversible after cessation of therapy.
b. Elevated liver function tests are uncommon, but severe hepatic failure has been observed only rarely.
c. Dyspnea and cough are seen occasionally.
d. Adverse cardiovascular events are similar to those seen with orchiectomy.
e. Dizziness or vertigo is occasional.
BLEOMYCIN
Other name. Blenoxane.
Mechanism of action. Bleomycin binds to DNA, causes single- and double-strand scission, and inhibits further DNA, RNA, and protein synthesis.
Primary indications
Testis, head and neck, penis, cervix, vulva, anus, and skin carcinomas. Hodgkin and non-Hodgkin lymphomas. Pleural effusions—used as sclerosing agent.
Usual dosage and schedule
1. 10 to 20 U/m2 IV or IM once or twice a week or
2. 30 U IV push weekly for 9 to 12 weeks in combination with other drugs for testis cancer.
3. 60 U in 50 mL of normal saline instilled intrapleurally.
Special precautions
1. In patients with lymphoma, a test dose of 1 or 2 U 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 | % of Full Dose |
2.5-4 | 25 |
4-6 | 20 |
6-10 | 10 |
3. The cumulative lifetime dose should not exceed 400 U because of the dose-related incidence of severe pulmonary fibrosis. Smaller limits may be appropriate for older patients or those with preexisting pulmonary disease. Frequent evaluation of pulmonary status, including symptoms of cough or dyspnea, rales, infiltrates on chest X-ray film, and pulmonary function studies are recommended to avert serious pulmonary sequelae.
4. Glass containers are recommended for continuous infusion to minimize drug instability.
5. High Fio2 (fraction of inspired oxygen) (such as might be used during surgery) should be avoided as it exacerbates lung injury, sometimes acutely.
Toxicity
1. Myelosuppression and other hematologic effects. Significant depression of counts is uncommon. This factor permits bleomycin to be used in full doses with myelosuppressive drugs.
2. Nausea, vomiting, and other GI 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 above).
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, joint swelling is rare.
b. IM or SQ injection may cause pain at injection site.
BLINATUMOMAB
Other name. Blincyto.
Mechanism of action. A bispecific CD19-directed CD3 T-cell engager. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. By mediating the formation of synapse between T cells and tumor cells, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines and proliferation of T-cells, it causes redirected lysis of CD19+ cells.
Primary indications. Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Usual dosage and schedule. Treatment course consists of up to two cycles of induction followed by three additional consolidation cycles (up to a total of five cycles). A single cycle consists of 4 weeks of continuous IV infusion via a pump followed by 2 weeks treatment-free interval. For patients at least 45 kg in weight:
Cycle 1: 9 µg/day on days 1 to 7 followed by 28 µg/day on days 8 to 28.
For subsequent cycles: 28 µg/day on days 1 to 28.
Hospitalization is recommended for the first 9 days of cycle 1 and the first 2 days of the subsequent cycles. Dexamethasone 20 mg IV should be given 1 hour prior to the first dose of each cycle, prior to a step dose (cycle 1 day 8) and when restarting an infusion after an interruption of 4 hours or more. A new cycle should be started if infusion interruption after an adverse event is longer than 7 days, whereas for less than a 7-day-long interruption, the same cycle can be continued for a total of 28 days, including the days before and after the interruption.
Special precautions
1. Blinatumomab can cause fetal harms if administered to a pregnant woman based on its mechanism of action. Since there is no adequate evidence in pregnant women, it should be used in this patient population only if benefits justify potential risks to the fetus.
2. Initiation of treatment causes transient release of cytokines that may suppress CYP450 enzymes, especially during the first 9 days of the first
cycle and during the first 2 days of subsequent cycles. Dose adjustment and close monitoring of CYP450 substrates (like warfarin and cyclosporine) are warranted.
cycle and during the first 2 days of subsequent cycles. Dose adjustment and close monitoring of CYP450 substrates (like warfarin and cyclosporine) are warranted.
3. Life-threatening and fatal cytokine release syndrome, seizures, tumor lysis syndrome, and infections can occur.
4. Special caution must be used during preparation and administration as errors in both have occurred resulting in under- or overdosing.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are occasional. Anemia and neutropenia are common and occasionally severe. Febrile neutropenia is common and can be life-threatening. Leukocytosis and lymphopenia are uncommon.
2. Nausea, vomiting, and other GI effects. Nausea, constipation, and diarrhea are common but rarely severe. Abdominal pain and vomiting are occasional.
3. Mucocutaneous effects. Rash (popular, maculopapular, and vesicular) is common but uncommonly severe.
4. Immunologic effects and infusion reactions. Cytokines release syndrome (CRS), which may be indistinguishable from infusion reactions, can occur and rarely be fatal. Signs and symptoms can include: pyrexia, hypotension, bronchospasm, headaches, nausea, hyperbilirubinemia, and elevation in ALT and/or AST. Cases of disseminated intravascular coagulation (DIC) and hemophagocytic lymphohistiocytosis (HLH) have also been described. Hypogammaglobulinemia is occasional. Increased risk of bacterial, fungal, and viral infections has been reported, with severe infections occurring in up to 25% of cases. These infections can be life-threatening, and administration of prophylactic antibiotics may be indicated on a case-by-case basis.
5. Miscellaneous effects
a. General. Pyrexia is common and occasionally severe. Fatigue is common and chills are occasional.
b. Respiratory. Cough and dyspnea are common, but uncommonly severe.
c. Cardiovascular. Tachycardia is occasional. Peripheral edema is common. Capillary leak syndrome is rare.
d. Metabolic. Hypokalemia is common. Hypomagnesemia, hypophosphatemia, and hyperglycemia are occasional.
e. Hepatic. Elevated liver enzymes is occasional especially during the first 2 weeks of treatment, but rarely results in discontinuation of treatment.
f. Neurologic. Headaches and tremor are common. Dizziness is occasional. Convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders are uncommon, but can be severe in 15% of cases. Due to these potential toxicities, patients should refrain from driving and engaging in hazardous occupations or activities such as heavy or potentially dangerous machines while treatment is being administered. Although
leukoencephalopathic changes on cranial MRI can occur especially in patients with history of prior cranial irradiation and/or antileukemic chemotherapy, the clinical significance of such changes is unknown.
leukoencephalopathic changes on cranial MRI can occur especially in patients with history of prior cranial irradiation and/or antileukemic chemotherapy, the clinical significance of such changes is unknown.
g. Musculoskeletal and connective tissue. Arthralgia, back pain, pain in extremities, and bone pain are occasional.
h. Psychiatric. Insomnia is occasional.
BORTEZOMIB
Other name. Velcade.
Mechanism of action. A reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, which mediates ubiquitinated protein degradation and plays an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis. Disruption of these homeostatic mechanisms can lead to cell death. Bortezomib is metabolized by liver enzymes.
Primary indications
1. Multiple myeloma
2. Mantle cell lymphoma
Usual dosage and schedule
1. Multiple myeloma. 1.3 mg/m2 SC (preferred) or 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. Weekly dose may be increased to 1.5 mg/m2. Similar schedules used in combination with other agents.
2. Mantle cell lymphoma. 1.3 mg/m2 SC or IV bolus twice weekly (days 1, 4, 8, 11 every 3 weeks for up to eight cycles. Frequency may be reduced to weekly, 3 weeks out of 4 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 ULN). Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
Special precautions. Cardiogenic shock, congestive heart failure, and respiratory insufficiency have been rarely observed. Anaphylaxis has also been observed. Patients with hepatic impairment should be monitored closely, as bortezomib is metabolized by liver enzymes. Consider acyclovir 400 mg b.i.d for Herpes zoster prophylaxis.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common; neutropenia is only occasionally severe (grade 3 or 4). Thrombocytopenia is severe in 30% of patients.
Disseminated intravascular coagulation has been observed (rare to uncommon).
Disseminated intravascular coagulation has been observed (rare to uncommon).
2. Nausea, vomiting, and other GI 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. Neurotoxicity is often less with SC rather than IV administration.
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. Increased incidence of H. zoster compared with controls—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 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 are probably uncommon to rare as a consequence of the drug.
e. Infiltrative pulmonary disease—rare, but may be severe or fatal.
f. Hepatitis and pancreatitis have been observed—probably rare.
BOSUTINIB
Other name. Bosulif.
Mechanism of action. A tyrosine kinase inhibitor that inhibits the Bcr-Abl kinase (including imatinib-resistant forms of Bcr-Abl) and the Src-family kinases including Src, Lyn, and Hck.
Primary indications. Chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy.
Usual dosage and schedule. 500 mg orally once daily with food. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dose escalation to 600 mg once daily can be considered in patients who do not reach complete hematologic response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have grade 3 or higher adverse reactions. Concomitant use of strong or moderate CYP3A inhibitors, strong or moderate CYP3A inducers, and/or P-gp substrates should be avoided. In patients with preexisting mild, moderate, and severe hepatic impairment, the recommended dose of Bosulif is 200 mg daily.
Special precautions
1. Bosutinib can cause fetal harm if administered to a pregnant woman.
2. Fluid retention that may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema is common, but uncommonly severe and can be fatal, requiring dose interruptions, modifications, or even permanent discontinuation.
3. Hypersensitivity reactions have been reported in less than 10% of patients and anaphylactic shock occurred in less than 0.2% of treated patients.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and thrombocytopenia are common and can be severe. Febrile neutropenia can occur in less than 10% of cases. CBC monitoring should be done at baseline, weekly for the first month and monthly thereafter.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, and diarrhea are common. Diarrhea can be occasionally severe. These reactions can be managed using standards of care. Dose interruptions/adjustments may be indicated for severe reactions. Gastritis is occasional. Pancreatitis and GI hemorrhage are rare.
3. Mucocutaneous effects. Skin rash is common and occasionally severe. Pruritus is occasional. Erythema multiforme is rare.
4. Immunologic effects and infusion reactions. Upper and lower respiratory tract infections are occasional but rarely severe.
5. Miscellaneous effects
a. General. Fatigue and pyrexia are common. Asthenia is occasional. Tinnitus has been reported in less than 10% of patients.
b. Respiratory. Cough is common and dyspnea is occasional.
c. Cardiovascular. QTc prolongation to more than 500 msec is rare, but caution should be used in patients with underlying cardiovascular disease and other risk factors for QTc prolongation.
d. Metabolic. Hypophosphatemia and elevation in lipase level are occasional. Hyperkalemia as well as elevation in creatinine level and acute renal failure have been reported in less than 10% of patients, the latter of which may be related to dehydration rather than direct drug-related toxicity.
e. Hepatic. Drug-induced liver injury is rare. Moderate elevations in ALT or AST (<3 × ULN) are common and may require dose interruption/modification. Monitoring of liver function tests should be done on a monthly basis or as clinically indicated.
f. Neurologic. Headache is common, and dizziness is occasional.
g. Musculoskeletal and connective tissue. Arthralgia, myalgia, and back pain are occasional.
BRENTUXIMAB VEDOTIN
Other name. Adcetris.
Mechanism of action. Brentuximab vedotin is an ADC, which is a chimeric IgG1 directed against CD30 that is covalently attached to the small
molecule, MMAE (monomethyl auristatin E), a microtubule disrupting agent via a linker. The binding of the ADC to CD30-expressing cells results in internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells.
molecule, MMAE (monomethyl auristatin E), a microtubule disrupting agent via a linker. The binding of the ADC to CD30-expressing cells results in internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells.
Primary indications
1. Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates.
2. Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multiagent chemotherapy regimen.
3. Classical HL as consolidation treatment for patients at high risk of relapse or progression post autologous hematopoietic stem cell transplantation.
Usual dosage and schedule. 1.8 mg/kg administered as an IV infusion over 30 minutes every 3 weeks (maximum of 16 cycles). Coadministration with strong CYP3A4 inhibitors and inducers results in increase and decrease in the ADC exposure, respectively, with the former potentially increasing toxicity. Dose interruptions/modifications may be required for peripheral neuropathy and neutropenia.
Special precautions
1. Brentuximab vedotin can cause fetal harm if administered to a pregnant woman.
2. A fatal case of progressive multifocal leukoencephalopathy (PML) has been reported.
3. Tumor lysis syndrome may occur especially in patients with rapidly proliferating tumor and high tumor burden.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are common and occasionally severe. Lymphadenopathy is occasional but rarely severe. Neutropenia is common and occasionally severe. It can also be prolonged (>1 week). Cases of upper respiratory tract infections were reported in 47% of patients, all of which were mild. Cases of urinary tract infection, pyelonephritis, and septic shock were uncommonly reported.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, diarrhea, and constipation are common but uncommonly severe.
3. Mucocutaneous effects. Rash and pruritus are common. Alopecia is occasional. Dry skin is uncommon.
4. Immunologic effects and infusion reactions. Infusion-related reactions (including chills, nausea, dyspnea, pruritus, pyrexia, cough, and anaphylaxis) have occurred. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Premedication for subsequent infusions with acetaminophen, an antihistamine and a corticosteroid is recommended. Transient and persistent
antibodies to the ADC can develop in 30% and 7%, respectively. A higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies. Stevens-Johnson syndrome has been reported.
antibodies to the ADC can develop in 30% and 7%, respectively. A higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies. Stevens-Johnson syndrome has been reported.
5. Miscellaneous effects
a. General. Fatigue and pyrexia are common. Chills and night sweats are occasional.
b. Respiratory. Cough is common. Dyspnea and oropharyngeal pain are occasional. Cases of pneumonitis, pulmonary embolism, and pneumothorax were reported in 2% of patients.
c. Cardiovascular. Peripheral edema is uncommon. Supraventricular tachycardia was reported in 3% of patients.
d. Metabolic. Decreased weight and appetite are occasional.
e. Neurologic. ADC-induced peripheral sensory and motor neuropathy is common and is cumulative. This can persist even after discontinuation of treatment. Headache is common and dizziness is occasional.
f. Musculoskeletal and connective tissue. Arthralgia and myalgia are common. Back pain, pain in extremity, and muscle spasms are occasional.
g. Psychiatric. Insomnia is occasional.
CABAZITAXEL
Other name. Jevtana. Mechanism of action. Microtubule inhibitor binds to tubulin, which leads to the stabilization of microtubules, and the inhibition of mitotic and interphase cellular functions.
Primary indication. Carcinoma of the prostate, metastatic, previously treated with a docetaxel-containing regimen.
Usual dosage and schedule. 25 mg/m2 IV over 1 hour every 3 weeks in combination with prednisone 10 mg daily. Reduce dose to 20 mg/m2 if the patient experiences prolonged grade 3 or higher neutropenia, febrile neutropenia, or severe or persistent diarrhea.
Special precautions. Hypersensitivity reactions can occur, and therefore patients should be premedicated with corticosteroids and histamine H1 and H2 antagonists. Should not be given to patients with hepatic impairment. Patients aged 65 years and older are more likely to experience adverse effects from cabazitaxel treatment. Because cabazitaxel is metabolized primarily through CYP3A, coadministration with strong CYP3A inhibitors should be avoided.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, anemia, and thrombocytopenia are common. Grade 3 to 4 febrile neutropenia is occasional, but may be fatal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, anorexia, diarrhea, and constipation are common, but infrequently (2% to 6%) severe.
3. Mucocutaneous effects. Alopecia is occasional.
4. Immunologic effects and infusion reactions. Hypersensitivity reactions are uncommon, but may occur within a few minutes following initiation of therapy; they may be associated with rash, erythema, hypotension, and bronchospasm.
5. Miscellaneous effects
a. Fatigue and weakness are common. Fever is occasional.
b. Renal failure is uncommon, but may be fatal (rare). Hematuria is occasional.
c. Peripheral edema—occasional.
d. Cardiac arrhythmias and hypotension are uncommon.
e. Back pain and arthralgias are occasional.
f. Peripheral neuropathy and headache are occasional.
g. Dyspnea and cough are occasional.
CABOZANTINIB
Other name. Cometriq.
Mechanism of action. Inhibits the tyrosine kinase activity of RET, MET, VEGFR-1 and 2, KIT, TRKB, FLT-3, AXL, and TIE-2, which are involved in oncogenesis, metastasis, tumor angiogenesis, and maintaining tumor microenvironment.
Primary indications. Progressive, metastatic medullary thyroid cancer.
Usual dosage and schedule. 140 mg orally daily. To be taken at least 2 hours after or 1 hour before a meal. Certain foods (grapefruit, grapefruits) or nutritional supplements known to inhibit cytochrome P450 should not be taken during treatment period. Missed doses can be taken up to 12 hours before the next dose.
Special precautions. Cabozantinib can cause fetal harm if administered to a pregnant woman and can cause male infertility. Coadministration with substrates of P-glycoprotein can increase the plasma concentration of the latter. It is recommended not to coadminister cabozantinib with strong CYP3A4 inhibitors and/or inducers. If the use of a strong CYP3A4 inhibitor is required, the dose of cabozantinib should be decreased by 40 mg prior to initiation until 2 or 3 days after discontinuation of the strong inhibitor. If the use of a strong CYP3A4 inducer is required, the dose of cabozantinib should be increased by 40 mg prior to initiation until 2 or 3 days after discontinuation of the strong inducer. Moderate and severe hepatic impairment should preclude the use of cabozantinib. Dose interruptions are recommended for grade 4 hematologic toxicities, grade 3 or higher nonhematologic toxicities, and for intolerable grade 2 adverse reactions. Permanent discontinuation is required for: visceral perforations, fistulas formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, malignant hypertension and hypertensive crisis, osteonecrosis of the jaw, and RPLS.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are common, mostly grade 1 and 2. Lymphopenia is common with grade 3 toxicity occurring in up to 16% of patients. The incidence of serious (grade 3 or higher) hemorrhagic events was observed in 3% of patients treated with cabozantinib. These reactions can be fatal and permanent discontinuation of treatment is indicated. Cabozantinib can impair wound healing and cause healing complications. Withholding treatment at least 28 days prior to scheduled surgeries is recommended, and treatment resumption postsurgery is indicated after adequate wound healing.
2. Nausea, vomiting, and other GI effects. Serious GI perforations and fistulas (including esophageal) and non-GI (tracheal) fistulas formation can occur in 3%, 1%, and 4%, respectively, and can be fatal. Abdominal pain, stomatitis, nausea, vomiting, diarrhea, and constipation are common. Diarrhea can be grade 3 or greater in 16% of cases. Dysphagia and dyspepsia are occasional.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome (PPES) can occur in up to 50% of patients, with grade 3 or higher reported in 13% of cases. Rash, dry skin, and alopecia are common. Hyperkeratosis is occasional. Hair color changes (depigmentation/graying) can occur in up to 34% of patients.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Decreased appetite, fatigue, asthenia, and weight loss are common.
b. Respiratory. Dysphonia was reported in 20% of patients, all grade 1 or 2.
c. Cardiovascular. Elevation in blood pressure is universal with most cases being pre- or stage I hypertension. Stage I or II hypertension can occur in up to 61% of patients. Mild cases can be managed with antihypertensive medications. More severe cases or those that are not adequately controlled with medications may require dose reduction/interruption and/or permanent discontinuation. Increased risk of both venous and arterial thromboembolic events have been reported; 6% and 2%, respectively. Permanent discontinuation is recommended in patients who develop treatment-related acute myocardial infarction or other serious thromboembolic complications. Although 10 to 15 msec increase in QTc interval was observed at 4 weeks after initiation of treatment, changes in wave form morphology or new rhythms were not observed and no patients had a QTc interval >500 msec.
d. Metabolic. Electrolytes disturbances, including hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia are common. Grade 3 or higher hypocalcemia was observed in 12% of patients.
e. Hepatic. Increase in AST, ALT, ALP, and total bilirubin is common but grade 3 or higher are uncommon.
f. Neurologic. Dysgeusia and headache are common. Peripheral neuropathy is occasional. Although RPLS is rare (occurred in one patient
across clinical trials), clinical suspicion is warranted in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental status, and evaluation with MRI is indicated to make the diagnosis. Permanent discontinuation of cabozantinib is recommended if the diagnosis is confirmed.
across clinical trials), clinical suspicion is warranted in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental status, and evaluation with MRI is indicated to make the diagnosis. Permanent discontinuation of cabozantinib is recommended if the diagnosis is confirmed.
g. Genitourinary. Nephrotic range proteinuria and nephrotic syndrome can occur. Regular monitoring of urine protein is recommended and permanent discontinuation is warranted in patients who develop nephrotic syndrome.
h. Musculoskeletal and connective tissue. Musculoskeletal chest pain, arthralgia, and muscle spasms are occasional. Osteonecrosis of the jaw (ONJ) can occur and manifests as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, gingival ulceration or erosion, or slow healing after dental surgery. Periodic oral examination is recommended. Treatment should be held for at least 28 days prior to scheduled surgery, if possible.
i. Psychiatric. Grade 1 or 2 anxiety was reported in 9% of patients taking cabozantinib versus 2% of patients taking placebo.
CAPECITABINE
Other name. Xeloda.
Mechanism of action. An orally administered prodrug that is converted to fluorouracil intracellularly. When this is converted to the active nucleotide, 5-fluoro-2-deoxyuridine monophosphate, it inhibits the enzyme thymidylate synthetase and blocks DNA synthesis. The triphosphate may also be mistakenly incorporated into RNA, which interferes with RNA processing and protein synthesis.
Primary indications
1. Metastatic breast cancer that is resistant to anthracycline- and paclitaxel-containing chemotherapy regimens. May also be used in patients in whom anthracyclines are contraindicated.
2. Colorectal (adjuvant or metastatic), small bowel, stomach, pancreas, and biliary carcinomas.
Usual dosage and schedule. Generally taken with water, twice daily (about 12 hours between doses) within 30 minutes after a meal. Dose reductions are commonly required, by reducing the daily dose, the number of consecutive daily treatments, or both.
1. 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.
2. 850 to 1,250 mg/m2 orally twice daily for 2 weeks when used in combination with other drugs, followed by a 1-week rest, given as 3-week cycles.
3. 800 mg/m2 orally twice daily 5 days per week during radiotherapy as a radiosensitizer.
Special precautions. Increase in prothrombin time (PT) and International Normalized Ratio (INR) may be seen in patients previously stable on
oral anticoagulants. Monitor PT/INR more frequently when patient is on capecitabine. Patients with moderate renal impairment (CCr 30 to 50 mL/minutes) require a 25% dosage reduction: Diarrhea may be severe and require fluid and electrolyte replacement. Incidence and severity may be worse in patients 80 years of age or older. Therapy may need to be interrupted and subsequent doses decreased for severe or repeated toxicity. Phenytoin levels should be monitored, as elevated levels may occur.
oral anticoagulants. Monitor PT/INR more frequently when patient is on capecitabine. Patients with moderate renal impairment (CCr 30 to 50 mL/minutes) require a 25% dosage reduction: Diarrhea may be severe and require fluid and electrolyte replacement. Incidence and severity may be worse in patients 80 years of age or older. Therapy may need to be interrupted and subsequent doses decreased for severe or repeated toxicity. Phenytoin levels should be monitored, as elevated levels may occur.
Toxicity
1. Myelosuppression and other hematologic effects. Common, but when used as a single agent, these usually are mild to moderate with anemia predominating. Neutropenia is common when used in combination and may be associated with neutropenic fever.
2. Nausea, vomiting, and other GI 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. GI 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%).
3. Mucocutaneous effects. Hand-and-foot syndrome is common (54%) and may be severe. Dermatitis is also common (27%), as is stomatitis, but it is uncommon that these are severe. Eye irritation and increased lacrimation are occasional.
4. Miscellaneous effects
a. Fatigue is common.
b. Paresthesias are occasional.
c. Hyperbilirubinemia is common (48%), but only occasionally severe or life-threatening.
d. Fever is occasional.
e. Headache or dizziness is occasional.
f. Cardiotoxicity is possible as with any fluorinated pyrimidine.
CARBOPLATIN
Other names. Paraplatin, CBDCA.
Mechanism of action. Covalent binding to DNA.
Primary indications. Ovarian, endometrial, breast, bladder, and lung cancers, and other cancers in which cisplatin is active.
Usual dosage and schedule. AUC (area under the curve) dosing (Calvert formula) is generally preferred.
1. Target AUC is commonly 4 to 6, depending on previous treatment and other drugs to be used. Administration dose (mg) = (target AUC) × ([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 1,600 mg/m2 divided over several days have been used followed by stem cell rescue.
Special precautions
Much less renal toxicity than cisplatin, so there is no need for a vigorous hydration schedule or forced diuresis. If AUC dosing is not used, reduce dose to 250 mg/m2 for creatinine clearance of 41 to 59 mL/minute, reduce to 200 mg/m2 for clearance of 16 to 40 mL/minute.
Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin administration. Infusion reactions generally develop after several months of drug tolerance. Epinephrine, corticosteroids, antihistamines, and fluid administration for hypotension have been employed to alleviate symptoms.
Toxicity
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 GI 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. GI 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 above.
5. Miscellaneous effects
a. Peripheral neuropathies or central neurotoxicity are uncommon.
b. Cardiovascular (cardiac failure, embolism, cerebrovascular accidents) 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.
CARFILZOMIB
Other name. Kyprolis.
Mechanism of action. Irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome that mediates ubiquitinated protein degradation and plays an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis.
Primary indications
1. Multiple myeloma in combination with lenalidomide and dexamethasone in patients who have received one to three prior lines of prior therapy.
2. Multiple myeloma after receiving at least two prior therapies including an immunomodulatory agent and bortezomib, and have demonstrated disease progression on or within 60 days of the completion of the last therapy.
Usual dosage and schedule
1. Cycle 1: 20 mg/m2 (maximum BSA of 2.2 m2) IV over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.
2. If tolerated, the dose should be escalated to a target dose of 27 mg/m2 (maximum BSA of 2.2 m2) starting day 8 of cycle 1 and during the subsequent cycles.
Hydrate prior to and subsequent to each dose to reduce risk of renal failure and tumor lysis syndrome. Premedicate with dexamethasone prior to all cycle 1 doses, during first cycle of dose escalation, and if infusion reactions develop or reappear.
Dose adjustments do not need to be made for weight changes of equal or less than 20%.
Special precautions
1. No safe dose has been determined in patients with baseline hepatic impairment.
2. Can cause fetal harm if administered to a pregnant woman.
3. Cases of cardiac arrest, cardiogenic shock, congestive heart failure, pulmonary edema, pulmonary hypertension, and fatal hepatic failure have been observed. Anaphylaxis has also been observed. Consider acyclovir 400 mg b.i.d for H. zoster prophylaxis. Tumor lysis syndrome can rarely occur, especially in patients with high tumor burden.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and lymphopenia are common and occasionally severe. Thrombocytopenia is common and can be grade 4 in 10% of patients. Upper respiratory tract bacterial infections are common but mostly mild. Pneumonia is occasional and rarely fatal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and constipation are common and can be rarely severe.
3. Mucocutaneous effects. Not reported.
4. Immunologic effects and infusion reactions. Infusion reactions, characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions may happen immediately following or up to 24 hours after administration. Administer dexamethasone prior to each treatment to reduce the incidence and severity of reactions. H. zoster reactivation is uncommon but antiviral prophylaxis should be considered.
5. Miscellaneous effects.
a. General. Fatigue, peripheral edema, and pyrexia are common. Chills and anorexia are occasional.
b. Respiratory. Pulmonary arterial hypertension was reported in 2% of patients (grade 3 or greater in less than 1%). Dyspnea is common and rarely severe/fatal. Cough is common.
c. Cardiovascular. Cardiac failure events (congestive heart failure, pulmonary edema, and decrease in ejection fraction) were reported in 7% of patients. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were excluded from the clinical trials. These patients may be at greater risk for cardiac complications. Hypertension is occasional and uncommonly severe.
d. Metabolic. Hyponatremia, hypophosphatemia, hypercalcemia, hyperglycemia, hypokalemia, and hypomagnesemia are occasional.
e. Hepatic. Elevation in AST/ALT and/or bilirubin levels is occasional. Dose adjustments/interruption may be recommended.
f. Neurologic. Peripheral sensory and motor neuropathy occurred in 14% of patients. Grade 3 or 4 toxicity is rare. Dizziness is occasional. Headache is common.
g. Genitourinary. Increase in blood creatinine is common. Renal failure is occasional. These events are occasionally severe and rarely life-threatening.
h. Musculoskeletal and connective tissue. Back pain and arthralgia are common. Muscle spasms, chest wall pain, and pain in extremity are occasional.
i. Psychiatric. Insomnia is occasional.
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 carbamylation 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
A. Systemic therapy:
1. Brain tumors
2. Hodgkin and non-Hodgkin lymphomas
3. Melanoma
B. Implantable carmustine-impregnated wafer. Glioblastoma multiforme
Usual dosage and schedule
A. Systemic therapy:
1. 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 1,000 mg/m2 to limit pulmonary and renal toxicity.
2. 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).
B. 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 (3 to 6 weeks), do not administer drug more often than every 6 weeks. Await a return of normal platelet and granulocyte counts before repeating therapy. Amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension.
Toxicity
A. Systemic therapy:
1. 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.
2. Nausea, vomiting, and other GI effects. Begins 2 hours after therapy and lasts 4 to 6 hours—common.
3. Mucocutaneous effects
a. 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.
b. Hyperpigmentation of skin after accidental contact is common.
4. Miscellaneous effects
a. Hepatotoxicity is uncommon but can be severe.
b. Pulmonary fibrosis is uncommon at low doses, but its frequency increases at doses higher than 1,000 mg/m2.
c. Secondary neoplasia is possible.
d. Renal toxicity is uncommon at doses of less than 1,000 mg/m2.
e. With high-dose therapy, encephalopathy, hepatotoxicity, and pulmonary toxicity are common and dose limiting. Hepatic veno-occlusive disease also occurs (occasional).
B. 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.
CERITINIB
Other name. Zykadia.
Mechanism of action. Inhibitor of receptor tyrosine kinases including ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells.
Primary indications. Locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC in patients who have progressed on or are intolerant of crizotinib.
Usual dosage and schedule. 750 mg orally once daily on an empty stomach (i.e., do not administer within 2 hours of a meal). A recommended dose has not been determined for patients with moderate-to-severe hepatic impairment. Missed doses can be taken up to 12 hours before the next scheduled dose. Dose modifications/interruptions and/or permanent discontinuation may be warranted in hepatic dysfunction, pneumonitis and interstitial lung disease (ILD), QTc prolongation, and bradycardia.
Special precautions
1. Concurrent use of strong CYP3A inhibitors should be avoided. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose by approximately one-third, rounded to the nearest 150-mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume treatment at the dose that was taken prior to initiating the strong CYP3A4 inhibitor.
2. Ceritinib can cause fetal harm if administered to a pregnant woman.
3. Cases of severe/fatal ILD/pneumonitis have been observed.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common and occasionally severe.
2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, vomiting, constipation, abdominal pain, and esophageal disorder are common and occasionally severe, requiring dose interruptions/modifications and symptomatic management.
3. Mucocutaneous effects. Rash is common but rarely severe.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Fatigue is common and occasionally severe. Decreased appetite is common.
b. Respiratory. ILD or pneumonitis has been reported in 4% of patients and was severe in 3%. Permanent discontinuation is recommended upon diagnosis of any grade treatment-related pneumonitis.
c. Cardiovascular. QTc interval prolongation can uncommonly occur and is concentration dependent. Periodic monitoring with electrocardiograms (ECGs) is recommended in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Treatment interruption is indicated in patients who develop a QTc interval greater than 500 msec on at least two separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec. Dose resumption should be at a reduced dose. Permanent discontinuation is recommended in patients who develop QTc interval prolongation in combination with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmias. Bradycardia is uncommon. In cases of symptomatic bradycardia that is not life-threatening, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm
or above, evaluate the use of concomitant medications, and adjust the dose. Permanent discontinuation is indicated for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring.
or above, evaluate the use of concomitant medications, and adjust the dose. Permanent discontinuation is indicated for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring.
d. Elevations in ALT/AST and or bilirubin levels are common and can be severe in up to 27% of patients requiring dose interruptions/modifications. Regular monitoring of hepatic function is recommended once a month and as clinically indicated.
e. Neurologic. Neuropathy syndromes (comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy) can occur in up to 17% of patients.
f. Endocrine. Hyperglycemia is common and occasionally severe. Hypophosphatemia and elevation in lipase level are common and occasionally severe.
g. Genitourinary. Increase in creatinine level is common but uncommonly severe.
h. Ophthalmic vision disorders (comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity) can occur in 9% of patients.
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 potentially most useful in those tumors that overexpress EGFR, but correlation with percent of positive cells or intensity of EGFR expression is weak.
Primary indications
1. Carcinoma of head and neck, in combination with radiation therapy or as first-line therapy with platin-based therapy plus fluorouracil for recurrent locoregional advanced or metastatic disease, or after failure of platinum-based therapy.
2. Colon cancer when KRAS is wild-type either as
a. First-line therapy in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), or
b. After failure of irinotecan and oxaliplatin-based regimens. Often-in combination with irinotecan or other cytotoxic regimens.
3. Lung cancer if EGFR amplification.
Usual dosage and schedule. 400 mg/m2 IV loading dose administered over 2 hours on day 1. Then 250 mg/m2 IV maintenance doses administered
over 1 hour weekly thereafter. May be administered in combination with other agents.
over 1 hour weekly thereafter. May be administered in combination with other agents.
Special precautions. Serious infusion reactions, some fatal, may occur (3% of patients). One-hour observation period is recommended following a cetuximab infusion. Cardiopulmonary arrest or sudden death has occurred in 2% of patients receiving cetuximab in combination with radiation therapy. Severe hypomagnesemia is seen in 10% to 15% of patients, and all patients should have magnesium levels monitored throughout the persistence of cetuximab (8 weeks).
All patients with metastatic colorectal cancer who might be candidates for cetuximab should have their tumor tested for KRAS mutations. If KRAS mutation in codon 12 or 13 is detected, cetuximab should not be given, as the patient is unlikely to benefit.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, diarrhea, and constipation are occasional. Abdominal pain is common.
3. Mucocutaneous effects. Acne-like 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 (approximately 20%), but may be severe.
d. Human antichimeric antibodies (HACAs) are uncommon.
e. Electrolyte depletion, particularly hypomagnesemia, occurs commonly. Hypomagnesemia is occasionally severe.
CHLORAMBUCIL
Other name. Leukeran.
Mechanism of action. Classic alkylating agent, with primary effect on preformed DNA.
Primary indications
1. CLL
2. Low-grade non-Hodgkin lymphoma
Usual dosage and schedule
1. Initially, 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.
2. 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
1. Myelosuppression and other hematologic effects. Dose-limiting and may be prolonged.
2. Nausea, vomiting, and other GI effects. May be seen with higher doses, but are uncommon.
3. Mucocutaneous effects. Rash is uncommon.
4. Miscellaneous effects
a. Liver function abnormalities is rare.
b. Secondary neoplasia is possible.
c. Amenorrhea and azoospermia is 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).
CISPLATIN
Other names. cis-Diamminedichloroplatinum (II), DDP, CDDP, Platinol.
Mechanism of action. Similar to alkylating agents with respect to binding and cross-linking strands of DNA.
Primary indications. Usually used in combination with other cytotoxic drugs.
1. Testis, ovary, endometrial, cervical, bladder, head and neck, GI, and lung carcinomas.
2. Soft tissue and bone sarcomas.
3. Non-Hodgkin lymphoma.
Usual dosage and schedule
1. 40 to 120 mg/m2 IV on day 1 as infusion every 3 weeks.
2. 15 to 20 mg/m2 IV on days 1 to 5 as infusion every 3 to 4 weeks.
3. 30 to 50 mg/m2 IV days 1, 8 every 4 weeks (in combination with other therapy).
Special precautions. Do not administer if serum creatinine level is more than 1.5 mg/dL. Irreversible renal tubular damage may occur if vigorous diuresis is not maintained, particularly with higher doses (>40 mg/m2) and with additional concurrent nephrotoxic drugs, such as the aminoglycosides. At higher doses, diuresis with mannitol with or without furosemide plus vigorous hydration is mandatory.
1. An acceptable method for hydration in patients without cardiovascular impairment for cisplatin doses up to 80 mg/m2 is as follows.
a. Have patient void, and begin infusion of 5% dextrose in half-normal saline with potassium chloride (KCl) 20 mEq/L and magnesium sulfate (MgSO4) 1 g/L (8 mEq/L); run at 500 mL/hour for 1.5 to 2.0 L.
b. After 1 hour of infusion, give 12.5 g 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 g) by IV push if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given.
2. For doses of 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/L and MgSO4 1 g/L (8 mEq/L); 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.
e. Give additional mannitol (12.5 to 50 g by IV push) if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given.
3. For patients with known or suspected cardiovascular impairment (ejection fraction <45%), a less vigorous rate of hydration may be used, provided the dose of cisplatin is limited (e.g., <60 mg/m2). An alternative is to give carboplatin.
Toxicity
1. Myelosuppression and other hematologic effects. Mild to moderate, depending on the dose. Relative lack of myelosuppression and other hematologic 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 GI 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 GI occur occasionally. Nausea, vomiting, and other GI may be minimized by the use of a combination antiemetic regimen.
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. These abnormalities, for example, 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, parallels renal failure.
c. Autonomic dysfunction with symptomatic postural hypotension is occasional.
CLADRIBINE
Other names. 2-Chlorodeoxyadenosine, Leustatin.
Mechanism of action. Deoxyadenosine analog with high cellular specificity for lymphoid cells. Resistant to effect of adenosine deaminase. Accumulates in cells as triphosphate, is incorporated into DNA, and inhibits DNA repair enzymes and RNA synthesis. Also results in NAD depletion. Effect is independent of cell division.
Primary indications. Hairy-cell leukemia, CLL, Waldenström macroglobulinemia, and possibly other lymphoid neoplasms.
Usual dosage and schedule
1. 0.09 mg/kg (3.33 mg/m2) IV daily as a continuous 7-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 CLL without TP53 (17p13) gene deletion).
Special precautions. Give allopurinol, 300 mg daily, as prophylaxis against hyperuricemia. Opportunistic infections occur occasionally and should be watched for closely.
Toxicity
1. Myelosuppression and other hematologic effects. Moderate granulocyte suppression is common. Marrow suppression with leukopenia and thrombocytopenia may be prolonged for over a year. Serious infection is common. Profound suppression of CD4 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 watched for. Some routinely use 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. Autoimmune hemolytic anemia and immune thrombocytopenic purpura occur occasionally; pure red cell aplasia rarely.
2. Nausea, vomiting, and other GI effects. Mild nausea with decrease in appetite is common, but no vomiting is expected. Mild reversible increase in liver function tests may be seen.
3. Mucocutaneous effects. Rash is common. Injection site reactions are occasional.
4. Miscellaneous effects
a. Fever, possibly due to release of pyrogens from tumor cells, is common.
b. Fatigue is common. Headache, dizziness, insomnia, myalgia, and arthralgia are occasional.
c. Edema and tachycardia are occasional.
d. Cough, shortness of breath, and abnormal breath sounds are occasional.
CLOFARABINE
Other name. Clolar.
Mechanism of action. Clofarabine is a nucleoside analog (an adenine derivative), which is a potent inhibitor of ribonucleotide reductase. Also inhibits DNA polymerases and DNA synthesis. Increases intracellular ara-CTP when used with cytarabine.
Primary indications
1. Acute lymphoblastic leukemia in children (age 1 to 21) who have relapsed or are refractory to other therapy.
2. ALL or acute myelogenous leukemia (AML) in adults.
Usual dosage and schedule
1. 52 mg/m2 IV over 2 hours daily for 5 consecutive days. May be repeated in 2 to 6 weeks.
2. 40 mg/m2 IV over 1 hour (days 2 to 6), followed in 4 hours by cytarabine 1 g/m2 IV as a 2-hour infusion (days 1 to 5) in AML in adults. (day 1—only cytarabine; day 6—only clofarabine.)
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 (six cycles maximum).
Special precautions. Capillary leak syndrome and systemic inflammatory response syndrome (SIRS) have been observed with clofarabine administration.
Toxicity
1. Myelosuppression and other hematologic effects. Pancytopenia is common. Febrile neutropenia and documented infections are common.
2. Nausea, vomiting, and other GI 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.
COBIMETINIB
Other name. Cotellic.
Mechanism of action. Reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. Combined use with the BRAF inhibitor, Vemurafenib, results in greater and prolonged growth inhibition of the BRAF V600 mutation positive melanoma cells compared with either drug alone. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cells.
Primary indications
In combination with vemurafenib in BRAFV600E or BRAFV600K mutation-positive unresectable or metastatic melanoma.
Usual dosage and schedule
60 mg orally once daily on days 1 to 21 of every 28-day cycle, until disease progression or intolerable toxicity. Concomitant use with strong CYP3A inducers and/or inhibitors should be avoided. If concurrent short-term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable, reduce cobimetinib dose to 20 mg. While the appropriate dose has not been established for patients with moderate-to-severe hepatic impairment and for those with severe renal impairment (GFR less than 30 mL/minutes/1.73 m2), no dose adjustments are recommended for patients with mild hepatic impairment (normal total bilirubin and AST higher than ULN or any AST and total bilirubin up to 1.0 to 1.5 times the ULN) or for those with mild-to-moderate renal impairment.
Special precautions
1. Cobimetinib is teratogenic and can cause fetal harm if administered to a pregnant woman. It can also impair fertility in men.
2. Cases of hemorrhage were occasionally reported but uncommonly severe. Cerebral hemorrhage is rare.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, lymphopenia, and thrombocytopenia are common but uncommonly severe except for lymphopenia, which can be occasionally severe.
2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, and vomiting are common. Stomatitis is occasional.
3. Mucocutaneous effects. Moderate-to-severe rash can occasionally occur and may result in hospitalization. Photosensitivity is common but uncommonly severe. Patients should avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Acneiform dermatitis is common but uncommonly severe.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Pyrexia is common, and chills are occasional.
b. Cardiovascular. Cardiomyopathy, defined as cardiac failure, left ventricular dysfunction, or decreased LVEF, can occur. Assessment of LVEF
by echocardiogram or MUGA scan before initiating the treatment is recommended. Monitoring with either modality is recommended 1 month after starting treatment and every 2 to 3 months thereafter while on treatment. Of note, the safety of cobimetinib has not been established in patients with baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%. Hypertension occurred in 15% of patients and 4% of cases were grade 3 or greater.
by echocardiogram or MUGA scan before initiating the treatment is recommended. Monitoring with either modality is recommended 1 month after starting treatment and every 2 to 3 months thereafter while on treatment. Of note, the safety of cobimetinib has not been established in patients with baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%. Hypertension occurred in 15% of patients and 4% of cases were grade 3 or greater.
c. Ophthalmic. Serious retinopathy occurred in 26% of patients, and retinal vein occlusion is rare. Periodic eye examination is warranted. Blurry vision is occasional.
d. Musculoskeletal and connective tissue. Cases of rhabdomyolysis have been described in less than 5% of patients.
e. Metabolic. Increased creatinine is universal but uncommonly severe. Increased AST, ALT, alkaline phosphatase, and creatine kinase are common and occasionally severe. Hypophosphatemia and hyponatremia are common and occasionally severe. Hypoalbuminemia, hyperkalemia, and hypokalemia are common but uncommonly severe. Hypocalcemia is common and rarely severe.
f. Secondary malignancies. Secondary cutaneous malignant or premalignant conditions can occasionally occur. Regular skin examination is warranted until 6 months after the last dose, and local treatment for those lesions is indicated with no dose modifications of cobimetinib.
CRIZOTINIB
Other name. Xalkori.
Mechanism of action. Inhibitor of receptor tyrosine kinases including ALK, hepatocyte growth factor receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON). Translocations affecting the ALK gene result in the expression of oncogenic fusion proteins that leads to increased cell proliferation and survival in tumors expressing these proteins.
Primary indications. Locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC.
Usual dosage and schedule. 250 mg orally twice daily with or without food. Missed dose can be taken up to 6 hours before the next scheduled dose to maintain a twice-daily regimen. Avoid use with strong CYP3A inhibitors or inducers. Grapefruit or grapefruit juices may also increase plasma concentration of crizotinib and should be avoided.
Special precautions. Crizotinib can cause fetal harm if administered to a pregnant woman. Caution should be undertaken in patients with hepatic impairment as clinical studies excluded patients with baseline AST or ALT greater than 2.5 times the ULN, as well as those with baseline total bilirubin of greater than 1.5 times the ULN. Although no dose adjustment is needed for patients with mild-to-moderate renal impairment, the data about a starting dose for those with severe renal impairment (creatinine clearance [Ccr] < 30 mL/minute) is lacking. Severe, and sometimes fatal, cases of pneumonitis, QTc prolongation, and hepatic toxicity can occur and may warrant permanent discontinuation.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and thrombocytopenia can occur, and dose modification/interruption is recommended for severe (grade 3 or greater) reactions. Treatment-related upper respiratory tract infections are uncommon. Severe and sometimes life-threatening pneumonitis can occur in 1% to 2% of patients. Permanent discontinuation is recommended if treatment-related diagnosis is confirmed or suspected after exclusion of other potential causes.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and constipation are common. Abdominal pain, esophagitis, esophageal ulceration, odynophagia, and dysphagia are occasional.
3. Mucocutaneous effects. Stomatitis is occasional. Rash is occasional.
4. Immunologic effects and infusion reactions. Interstitial lung disease (ILD) and/or pneumonitis occurred in 2.9% of patients. Permanent discontinuation upon diagnosis is warranted.
5. Miscellaneous effects
a. General. Fatigue, decreased appetite, and peripheral edema are common. Fever is rare.
b. Respiratory. Dyspnea and cough are uncommon.
c. Cardiovascular. Bradycardia was reported in 5% of patients, and all cases were grade 1 or 2. QTc prolongation is uncommon. Periodic ECG and electrolytes monitoring is recommended in patients with risk factors for or taking medications known to prolong QTc. Permanent discontinuation is warranted for grade 4 toxicity while dose interruption is recommended for grade 3 until recovery to less than or equal to grade 1 with resumption at a one level dose reduction. Use should be avoided in patients with congenital long QT syndrome.
d. Hepatic. Elevation in ALT and/or AST is occasional and uncommonly severe. Liver function tests should be monitored once a month while on treatment or more frequently if toxicity develops.
e. Neurologic. Dizziness is common. Headache is uncommon and dysgeusia is occasional. Peripheral motor and sensory neuropathy is occasional and mostly grade 1 or 2.
f. Genitourinary. Complex renal cysts occurred in 1% of patients but without renal impairment.
g. Ophthalmic. Vision disorders including visual impairment, blurry vision, photopsia, vitreous floaters, photophobia, and diplopia were reported in 62% of patients. However, none were grade 3 or greater.
h. Musculoskeletal and connective tissue. Arthralgia is uncommon.
i. Psychiatric. Insomnia is uncommon.
CYCLOPHOSPHAMIDE
Other names. CTX, Cytoxan, Neosar.
Mechanism of action. Metabolism of cyclophosphamide by hepatic microsomal enzymes produces active alkylating metabolites. Cyclophosphamide’s primary effect is probably on DNA.
Primary indications
1. Breast, lung, ovary, testis, and bladder carcinomas.
2. Bone and soft tissue sarcomas.
3. Hodgkin and non-Hodgkin lymphomas.
4. ALL and CLL.
5. Waldenström macroglobulinemia.
6. Neuroblastoma and Wilms tumor of childhood.
7. Gestational trophoblastic neoplasms.
8. Multiple myeloma.
Usual dosage and schedule
1. 1,000 to 1,500 mg/m2 IV every 3 to 4 weeks or
2. 400 mg/m2 PO days 1 to 5 every 3 to 4 weeks or
3. 60 to 120 mg/m2 PO daily
4. High-dose regimens (4 to 7 g/m2 divided over 4 days) are investigational and should be used only with stem cell rescue and mesna bladder protection.
Special precautions. Give dose in the morning, maintain ample fluid intake, and have patient empty bladder several times daily to diminish the likelihood of cystitis.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting. Platelets are relatively spared. Nadir is reached about 10 to 14 days after IV dose with recovery by day 21.
2. Nausea, vomiting, and other GI 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 is 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 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).
Mechanism of action. A pyrimidine analog antimetabolite that, when phosphorylated to arabinosyl-cytosinetriphosphate (ara-CTP), is a competitive inhibitor of DNA polymerase.
Primary indications
1. AML
2. Non-Hodgkin lymphoma
3. Meningeal lymphoma or leukemia.
Usual dosage and schedule
1. Induction. 100 mg/m2 IV daily as a continuous infusion for 5 to 7 days (in combination with other drugs).
2. Maintenance. 100 mg/m2 SQ 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.
Special precautions. None for standard doses. High dose, to be given in 1 to 3 hour infusions. Longer infusion enhances toxicity. CNS toxicity is increased in patients with a decreased creatinine clearance. Cytarabine, liposomal (DepoCyt) should be used only intrathecally.
Toxicity (standard dose only)
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and thrombocytopenia occur, with nadir at 7 to 10 days after treatment has ended and with recovery during the following 2 weeks, depending on the degree of suppression. Megaloblastosis is common.
2. Nausea, vomiting, and other GI effects. Common, particularly if the drug is given as a push or rapid infusion.
3. Mucocutaneous effects. Stomatitis is seen occasionally.
4. Miscellaneous effects
a. Flulike syndrome with fever, arthralgia, and sometimes a rash is occasional.
b. Transient mild hepatic dysfunction is occasional.
Toxicity (high dose)
1. Myelosuppression and other hematologic effects. Universal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
3. Mucocutaneous effects. Occasional to common mucositis. Keratoconjunctivitis is common; glucocorticoid eyedrops may ameliorate or prevent in some patients.
4. Neurotoxicity. Cerebellar toxicity is common, particularly in the elderly, but is usually mild and reversible. However, on occasion it has been severe and permanent or fatal.
5. Hepatic toxicity with cholestatic jaundice. Uncommon.
DABRAFENIB
Other name. Tafinlar.
Mechanism of action. Inhibitor of the V600 mutations of the BRAF kinase seen in some melanoma cells as well as other kinases. By this mechanism, it inhibits tumor cells proliferation that is dependent on the constitutive activation of the BRAF proteins, which results from mutations in the BRAF gene. Combined use with the MEK inhibitor, trametinib, results in greater and prolonged growth inhibition of the BRAF V600 mutation-positive melanoma cells compared with either drug alone.
Primary indications
1. As a single agent in BRAFV600E mutation-positive unresectable or metastatic melanoma.
2. In combination with trametinib in BRAFV600E or BRAFV600K mutation-positive unresectable or metastatic melanoma.
Usual dosage and schedule
150 mg oral twice daily, 12 hours apart, as a single agent
150 mg oral twice daily, 12 hours apart, in combination with trametinib taken 2 mg oral once daily.
To be taken 1 hour before or 2 hours after a meal. Missed doses can be taken up to 6 hours prior to the next dose, maintaining twice-daily regimen. Concomitant use with strong CYP3A4 inducers or inhibitors and with strong CYP2C8 inducers or inhibitors should be avoided.
Special precautions
1. New primary malignancies
a. Cutaneous malignancies. Increased incidence of cutaneous squamous cell carcinomas (cuSCC) and keratocanthoma has been reported (19% in patients receiving dabrafenib alone and 7% in patients receiving the combination with trametinib) with median time to develop first cuSCC of 9 weeks. New primary melanoma was reported in 2% of patients receiving dabrafenib alone and in none of the patients receiving the combination with trametinib. New basal cell carcinoma can occur in up to 9% of patients receiving dabrafenib alone and 2% of those receiving the combination with trametinib. Dermatologic examination should be performed prior to initiation of therapy and every 2 months while on treatment, and for up to 6 months after discontinuation.
No dose modifications or interruptions are required in patients who develop new primary cutaneous malignancies.
No dose modifications or interruptions are required in patients who develop new primary cutaneous malignancies.
b. Noncutaneous malignancies. Dabrafenib can cause paradoxical activation of the MAP-kinase signaling pathway, through RAS activation, in exposed BRAF-wild-type cells and promote the growth and development of malignancies. Cases of pancreatic adenocarcinoma, colorectal carcinoma, head and neck carcinoma, and glioblastoma have been reported. Permanent discontinuation of dabrafenib is indicated in such cases, while no dose modifications of trametinib are warranted when the combination is used.
2. Dabrafenib is teratogenic and can cause fetal harm if administered to a pregnant woman. It can also impair fertility in men.
Toxicity
1. Myelosuppression and other hematologic effects. Cases of nasopharyngitis can occur in up to 10% of patients, most of which are grade 1 or 2. Potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Deep venous thrombosis and pulmonary embolus are occasional when used in combination with trametinib. Bleeding is occasional when used with trametinib; uncommon when used as a single agent.
2. Nausea, vomiting, and other GI effects. Constipation is occasional. Pancreatitis is occasional.
3. Mucocutaneous effects. Rash, alopecia, hyperkeratosis, and palmar-plantar erythrodysesthesia are common. Skin papillomas are occasional. Hypersensitivity manifesting as bullous rash has been described in less than 10% of patients.
4. Miscellaneous effects
a. General. Pyrexia is common. Serious febrile reactions (defined as grade 3 or higher or any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure) in the absence of other identifiable causes (like infection) can occur in up to 3.7% of patients. Dose interruptions/reductions or permanent discontinuation may be indicated depending on the severity of the reaction. Mild cases can be managed with antipyretic agents. Sometimes, prophylactic antipyretic or corticosteroid may be required.
b. Respiratory. Cough is occasional.
c. Cardiac. Occasional cardiomyopathy when used in combination with trametinib. Assess LVEF prior to therapy, after 1 month, and every 2 to 3 months thereafter.
d. Metabolic. Hyperglycemia is common, but grade 3 or higher is uncommon. Close monitoring of blood glucose in patients with diabetes mellitus and dose modifications of antidiabetic medications may be required. Hyponatremia is occasional. Hypophosphatemia is common.
e. Neurologic. Headache is common.
f. Genitourinary. Cases of interstitial nephritis have been described in less than 10% of patients.
g. Eye. Retinal pigment epithelial detachment when used with trametinib is uncommon. Uveitis and iritis are rare. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis.
h. Musculoskeletal and connective tissue. Arthralgia is common. Myalgia is occasional.
DACARBAZINE
Other names. Imidazole carboxamide, DIC, DTIC-Dome.
Mechanism of action. Uncertain but probably interacts with preformed macromolecules by alkylation. Inhibits DNA, RNA, and protein synthesis.
Primary indications
1. Melanoma.
2. Soft tissue sarcomas.
3. Hodgkin lymphoma.
Usual dosage and schedule
1. 150 to 250 mg/m2 IV push or rapid infusion on days 1 to 5 every 3 to 4 weeks or
2. 400 to 500 mg/m2 IV push or rapid infusion on days 1 and 2 every 3 to 4 weeks or
3. 200 mg/m2 IV daily as a continuous 96-hour infusion.
Special precautions
1. Administer cautiously to avoid extravasation, as tissue damage may occur.
2. Venous pain along the injection site may be reduced by diluting dacarbazine in 100 to 200 mL of 5% dextrose in water and infusing over 30 minutes rather than injecting rapidly. Ice application may also reduce pain.
Toxicity
1. Myelosuppression and other hematologic effects. Mild to moderate. This factor allows dacarbazine to be used in full doses with other myelosuppressive drugs.
2. Nausea, vomiting, and other GI effects. Common and severe but decrease in intensity with each subsequent daily dose. Onset is within 1 to 3 hours, with duration up to 12 hours.
3. Mucocutaneous effects. Moderately severe tissue damage if extravasation occurs. Alopecia is uncommon. Erythematous or urticarial rash is uncommon.
4. Miscellaneous effects
a. Flulike syndrome with fever, myalgia, and malaise lasting several days is uncommon.
b. 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
1. Gestational trophoblastic neoplasms.
2. Wilms tumor, childhood rhabdomyosarcoma, and Ewing sarcoma.
Usual dosage and schedule
1. Children. 0.40 to 0.45 mg/m2 (up to a maximum of 0.5 mg) IV daily for 5 days every 3 to 5 weeks.
2. Adults
a. 0.40 to 0.45 mg/m2 IV on days 1 to 5 every 2 to 3 weeks.
b. 0.5 mg IV daily for 5 days every 3 to 5 weeks.
Special precautions
1. Administer by slow IV push through the sidearm of a running IV infusion, being careful to avoid extravasation, which causes severe soft tissue damage.
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