Dennis A. Casciato
I. Alkylating agents
B Bendamustine
C Busulfan
D Chlorambucil
E Cyclophosphamide
F Dacarbazine
G Ifosfamide
H Melphalan
I Nitrogen mustard
J Nitrosoureas
K Procarbazine
L Streptozocin
M Temozolomide
N Thiotepa
O Cisplatin
P Carboplatin
Q Oxaliplatin
II. Antimetabolites
B Azacitidine
C Cladribine
D Clofarabine (Clolar)
E Cytarabine
F Decitabine
G Fludarabine
H 5-Fluorouracil
I Leucovorin
J Capecitabine
K Gemcitabine
L Hydroxyurea
M 6-Mercaptopurine
N Methotrexate
O Nelarabine (Arranon)
P Pemetrexed (Alimta)
Q Pentostatin (Nipent)
R Pralatrexate (Folotyn)
S Raltitrexed (Tomudex)
T 6-Thioguanine
U Trimetrexate (Neutrexin)
III. Antitumor antibiotics
B Actinomycin D
C Bleomycin
D Daunorubicin
E Doxorubicin
F Doxorubicin, liposomal
G Epirubicin
H Idarubicin
I Mitomycin
J Mitoxantrone
IV. Mitotic spindle agents
B Paclitaxel (Taxol)
C Paclitaxel (Abraxane)
D Cabazitaxel (Jevtana)
E Docetaxel (Taxotere)
F Eribulin (Halaven)
G Estramustine (Emcyt)
H Ixabepilone (Ixempra)
I Vinblastine
J Vincristine
K Vindesine
L Vinorelbine
V. Topoisomerase inhibitors
B Etoposide
C Irinotecan
D Teniposide
E Topotecan
VI. Tyrosine kinase inhibitors
A Drug interactions with cytochrome P450 (CYP)
B Crizotinib (Xalkori)
C Dasatinib (Sprycel)
D Erlotinib (Tarceva)
E Imatinib (Gleevec)
F Lapatinib (Tykerb)
G Nilotinib (Tasigna)
H Pazopanib (Votrient)
I Sorafenib (Nexavar)
J Sunitinib (Sutent)
VII. Monoclonal antibodies
B Alemtuzumab (Campath)
C Bevacizumab (Avastin)
D Brentuximab vedotin (Adcetris)
E Cetuximab (Erbitux)
F Gemtuzumab (Myelotarg)
G Ipilimumab (Yervoy)
H Ofatumumab (Arzerra)
I Panitumumab (Vectibix)
J Rituximab (Rituxan)
K Trastuzumab (Herceptin)
VIII. Miscellaneous agents
A Anagrelide (Agrylin)
B Arsenic trioxide (Trisenox)
C Asparaginase (Elsoar)
D Asparaginase (Oncaspar)
E Bexarotene (Targretin)
F Bortezomib (Velcade)
G Denileukin diftitox (Ontak)
H Everolimus (Afinitor)
I Hexamethylmelamine (Hexalen)
J Lenalidomide (Revlimid)
K Temsirolimus (Torisel)
L Thalidomide (Thalomid)
M Tretinoin (ATRA)
IX. Hormonal agents
A Adrenocorticosteroids
B Adrenal inhibitors: mitotane
C Androgens
D Antiandrogens
E Estrogens
F Antiestrogens
G Aromatase inhibitors
H LHRH agonists
I Progestins
X. Cytoprotective agents
A Amifostine (Ethyol)
B Dexrazoxane (Zinecard)
I. ALKYLATING AGENTS
A. General pharmacology of alkylating agents. Alkylating agents target DNA and are cytotoxic, mutagenic, and carcinogenic. All agents produce alkylation through the formation of intermediates.
1. Alkylating agents impair cell function by transferring alkyl groups to amino, carboxyl, sulfhydryl, or phosphate groups of biologically important molecules. Most importantly, nucleic acids (DNA and RNA) and proteins are alkylated. The number 7 (N-7) position of guanine in DNA and RNA is the most actively alkylated site; the O-6 group of guanine is alkylated by nitrosoureas. Alkylation of guanine results in abnormal nucleotide sequences, miscoding of messenger RNA, cross-linked DNA strands that cannot replicate, breakage of DNA strands, and other damage to the transcription and translation of genetic material.
2. The primary mode of action for most alkylating agents is by means of cross-linking of DNA strands. Cytotoxicity is probably a result of damage to the DNA templates rather than inactivation of DNA polymerase and other enzymes responsible for DNA synthesis. DNA strand breakage also appears to be a minor determinant of cytotoxicity.
3. Alkylating agents are cell cycle–specific but not phase-specific. The drugs kill a fixed percentage of cells at a given dose.
4. Tumor resistance to these drugs appears to be related to the capacity of cells to repair nucleic acid damage and to inactivate the drugs by conjugation with glutathione.
B. Bendamustine (Treanda)
1. Indications. Chronic lymphocytic leukemia (CLL), low grade B-cell non-Hodgkin lymphoma (NHL) that has progressed within 6 months of treatment with a rituximab-containing regimen
2. Pharmacology. Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring.
a. Mechanisms. Alkylation (see Section A). The exact mechanism of action is unknown.
b. Metabolism. About 90% of the drug is excreted in the feces
3. Toxicity (adverse reactions are more common when dosing for NHL than for CLL). The drug is an irritant.
a. Dose-limiting. Hematosuppression
b. Common. Nausea, vomiting, diarrhea; fever, fatigue, headache, stomatitis, rash
c. Occasional. Anaphylactic reactions, severe skin reactions, acute renal failure; peripheral edema, tachycardia, hypotension, dizziness; myelodysplasia; dysgeusia
4. Administration. Fever, chills, pruritus, and rash commonly occur during the infusion (“infusion reactions”); consider administering an antihistamine, acetaminophen, and corticosteroids prophylactically if these reactions develop and are mild.
a. Supplied as 100 mg vial
b. Dose modification
(1) Dose modification for renal and hepatic function. Use with caution in mild renal or hepatic impairment; do not use if creatinine clearance is <40 mL/min or in moderate or severe hepatic impairment.
(2) Dose modification for grade 3 or higher toxicity: For CLL, reduce dose to 50 mg/m2 on days 1 and 2 of cycle and to 25 mg/m2 on days 1 and 2 if toxicity recurs. For NHL, reduce dose to 90 mg/m2 on days 1 and 2 of cycle and to 60 mg/m2 on days 1 and 2 if toxicity recurs.
c. Dose: For CLL, 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle; for NHL, 120 mg/m2 IV over 60 minutes on days 1 and 2 of a 21-day cycle
d. Drug interactions. Concomitant CYP1A2 inducers or inhibitors may affect the exposure of bendamustine. Drugs that induce CYP1A2 include barbiturates, carbamazepine, phenobarbital, rifampin, and tobacco smoking. Drugs that inhibit CYP1A2 include cimetidine, ciprofloxacin, antiretrovirals, and mexiletine.
C. Busulfan (Myleran)
1. Indications. Chronic myelogenous leukemia (CML) palliation, bone marrow transplantation (high doses)
2. Pharmacology
a. Mechanism. Alkylation (see Section A)
b. Metabolism. Acts directly; catabolized to inactive products that are excreted in the urine.
3. Toxicity
a. Dose-limiting. Reversible and irreversible myelosuppression with slow recovery; blood cell counts fall for about 2 weeks after discontinuation of drug.
b. Common. Gastrointestinal (GI) upset (mild), sterility
c. Occasional. Skin hyperpigmentation, alopecia, rash; gynecomastia, cataracts, LFT abnormalities; seizures
d. Rare. Pulmonary fibrosis (“busulfan lung”; see Chapter 29, Section IV.A), retroperitoneal fibrosis, endocardial fibrosis; addisonian-like asthenia (without biochemical evidence of adrenal insufficiency); hypotension, impotence, hemorrhagic cystitis, secondary neoplasms
4. Administration
a. Supplied as 2-mg tablets
b. Dose modification. Hematologic
c. Dose. Usually 2 to 8 mg/d PO; or 0.05 mg/kg/d for CML
d. Drug interactions.
(1) Drugs that induce or inhibit CYP3A4 (see Section VI.A.)
(2) Itraconazole and metronidazole reduce busulfan metabolism resulting in increased therapeutic and toxic effects. St. John’s wort increases busulfan elimination.
D. Chlorambucil (Leukeran)
1. Indications. Chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia
2. Pharmacology
a. Mechanism. Alkylation (see Section I.A)
b. Metabolism. Acts directly; spontaneously hydrolyzed to inactive and active products (e.g., phenylacetic acid mustard); also is extensively metabolized by the hepatic P450 microsomal system. The drug and metabolic products are excreted in urine.
3. Toxicity. Least toxic alkylating agent
a. Dose-limiting. Myelosuppression
b. Occasional. GI upset (minimal or absent at usual doses), mild LFT abnormalities, sterility, rash
c. Rare. Rash, alopecia, fever; cachexia, pulmonary fibrosis, neurologic or ocular toxicity, cystitis; acute leukemia
4. Administration
a. Supplied as 2-mg tablets
b. Dose modification. Hematologic
c. Dose. Various dosage schedules are used. For example, 0.1 to 0.2 mg/kg/d PO for 3 to 6 weeks and then decrease dose for maintenance
d. Drug interactions. Phenobarbital, phenytoin, and other drugs that stimulate the liver’s P450 system may lead to increased production of toxic metabolites.
E. Cyclophosphamide (Cytoxan)
1. Indications. Used in a wide variety of conditions
2. Pharmacology
a. Mechanism. Alkylation (see Section I.A); also inhibits DNA synthesis. Cell cycle–nonspecific and active in all phases of the cell cycle.
b. Metabolism. Native drug is inactive and requires activation by liver P450 microsomal oxidase system to form an aldehyde that decomposes in plasma and peripheral tissues to yield acrolein and an alkylating metabolite (e.g., phosphoramide mustard). The P450 system also metabolizes metabolites to inactive compounds. Active and inactive metabolites are excreted in urine.
3. Toxicity
a. Dose-limiting
(1) Myelosuppression. Leukopenia develops 8 to 14 days after administration. Thrombocytopenia occurs but is rarely significant.
(2) Effects on urinary bladder. Degradative products are responsible for hemorrhagic cystitis, which can be prevented by maintaining a high urine output. Hemorrhagic cystitis is more common and can be severe when massive doses are used (e.g., for bone marrow transplantation); under these circumstances, the use of mesna can be preventative. Urinary bladder fibrosis with telangiectasia of the mucosa can occur (usually after long-term oral therapy) without episodes of cystitis. Bladder carcinoma has occurred.
b. Side effects
(1) Common. Alopecia, stomatitis, aspermia, amenorrhea; headache (fast onset, short duration). Nausea and vomiting are common after doses of 700 mg/m2 or more.
(2) Occasional. Skin or fingernail hyperpigmentation; metallic taste during injection; sneezing or a cold sensation in the nose after injection; abnormal LFTs, dizziness; allergy, fever
(3) Rare. Transient syndrome of inappropriate secretion of antidiuretic hormone (SIADH, especially if given with a large volume of fluid), hypothyroidism, cataracts, jaundice, pulmonary fibrosis; cardiac necrosis and acute myopericarditis (with high doses); secondary neoplasms (acute leukemia, bladder carcinoma)
4. Administration. The drug should be administered with a large volume of fluid in the morning or early afternoon to avoid cystitis.
a. Supplied as 25- or 50-mg tablets; vials contain 500 to 2,000 mg
b. Dose modification. Hematologic; may be required for hepatic or renal functional impairment
c. Dose. Cyclophosphamide is frequently employed as part of combination chemotherapy regimens. Some common doses are 0.5 to 1.5 g/m2 IV every 3 weeks or 50 to 200 mg/m2 PO for 14 days every 28 days.
d. Drug interactions. Phenobarbital, phenytoin, and other drugs that stimulate the liver’s P450 system may lead to increased production of toxic metabolites.
(1) Digoxin levels decreased with cyclophosphamide.
(2) Interacts with warfarin to prolong the prothrombin time further
(3) Interacts with succinyl choline to increase neuromuscular blockade
(4) Allopurinol increases myelosuppression with concomitant use.
(5) Cimetidine may decrease rate of active metabolite formation and inhibit antineoplastic activity.
F. Dacarbazine [dimethyl-triazeno-imidazol-carboxamide (DTIC, DIC), imidazole carboxamide]
1. Indications. Hodgkin lymphoma, malignant melanoma, sarcomas, neuroblastoma
2. Pharmacology
a. Mechanisms. Inhibits purine, RNA, and protein synthesis. Has some alkylating activity. Causes DNA methylation and direct DNA damage. Cell cycle–nonspecific.
b. Metabolism. Native drug inactive; requires activation by oxidative N-methylation by the hepatic P450 microsomal system. Excreted in urine predominantly (50% of the drug is unchanged); minor hepatobiliary and pulmonary excretion.
3. Toxicity
a. Dose-limiting. Myelosuppression; nadir blood counts occur 2 to 4 weeks after treatment
b. Common. Nausea and vomiting (often severe), anorexia; pain along the injection site
c. Occasional. Alopecia, facial flushing, photosensitivity, abnormal LFTs. Flu-like syndrome (malaise, myalgia, chills, and fever) developing 1 week after treatment and lasting several days
d. Rare. Diarrhea, stomatitis; cerebral dysfunction; hepatic veno-occlusive disease, hepatic necrosis; azotemia; anaphylaxis
4. Administration. Dacarbazine is often used in combination with chemotherapy regimens. Withdrawing blood into the drug-filled syringe before injecting the mixture reduces the pain of injection. The drug is a vesicant if injected subcutaneously.
a. Supplied as 100- and 200-mg vials
b. Dose modification. Necessary for patients with impaired bone marrow, hepatic, or renal dysfunction
c. Dose
(1) 375 mg/m2 every 15 days in ABVD regimen for Hodgkin lymphoma, or
(2) 220 mg/m2 IV daily for 3 days every 21 to 28 days
d. Drug interactions.
(1) DTIC elimination may be altered by drugs that inhibit or induce the P450 system (e.g., barbiturates, phenytoin, rifampin, ciprofloxacin, isoniazid, disulfiram).
(2) DTIC may reduce levodopa effects with concomitant use; levodopa dosage increase may be required.
G. Ifosfamide (isophosphamide, Ifex)
1. Indications. Lymphomas, sarcomas, relapsed testicular tumors, and various carcinomas
2. Pharmacology
a. Mechanisms. An alkylating agent (see Section I.A); DNA cross-linking and chain breakage. Metabolites are alkylating agents that are similar to cyclophosphamide but are not cross-resistant.
b. Metabolism. Extensively metabolized by the hepatic P450 microsomal system. Activated at a fourfold slower rate than cyclophosphamide because of a lower affinity for the P450 system. Inactive until activated by hepatic microsomal enzymes. Like cyclophosphamide, the drug undergoes hepatic activation to an aldehyde form that decomposes in plasma and peripheral tissues to yield acrolein and its alkylating metabolite. Acrolein is highly toxic to urothelial mucosa. The chloroacetaldehyde metabolite may be responsible for much of the neurotoxic effects, particularly in patients with renal dysfunction. Drug and metabolites are excreted in urine.
3. Toxicity
a. Dose-limiting. Myelosuppression, hemorrhagic cystitis, encephalopathy
b. Common. Alopecia; anorexia, constipation, nausea, and vomiting; amenorrhea, oligospermia, and infertility
c. Neurotoxicity (especially with hepatic or renal dysfunction, hypoalbuminemia, low bicarbonate levels, or with rapid infusion): Somnolence, confusion, depression, hallucinations, dizziness, cranial nerve dysfunction, and ataxia. These effects usually resolve within 3 days of discontinuation of drug.
d. Occasional. Salivation, stomatitis, diarrhea; urticaria, hyperpigmentation, nail ridging; abnormal LFTs, phlebitis, fever; hypotension, hypertension, hypokalemia; renal tubular acidosis (at high doses); SIADH
e. Rare. Coma; renal tubular acidosis, or Fanconi-like syndrome
4. Administration. Aggressive concomitant hydration (2 to 4 L/d) and mesna are given to reduce the incidence of hemorrhagic cystitis. Monitor urine for hematuria before each dose. Use antiemetics prophylactically.
a. Supplied as 1- and 3-g prepackaged vials with mesna
b. Dose modification. Hematologic and renal dysfunction
c. Dose. 1,000 to 1,200 mg/m2 IV over 30 minutes for 3 to 5 days every 3 to 4 weeks. Various dosages and dose schedules are available (e.g., see Appendix D and Chapter 17, Sarcomas).
d. Mesna (sodium 2-mercaptoethanesulfonate, Mesnex) is an uroprotective agent when administering ifosfamide or cyclophosphamide. Alternative dose schedules for mesna, which is given in the same mg dose as the alkylating agent, are
(1) Equal doses of ifosfamide and mesna in the same bag when given as a continuous infusion
(2) Twenty percent of the mesna dose given IV bolus at the time of administration of ifosfamide and then forty percent PO at 2 hours and forty percent at 6 hours after each dose of ifosfamide/cyclophosphamide
(3) When given by IV bolus, the total dose of mesna is 60% of the ifosfamide dose. One-third of the mesna dose (20% of the ifosfamide dose) is given 15 minutes before, 4 hours after, and 8 hours after ifosfamide.
e. Drug interactions. Phenobarbital, phenytoin, and other drugs that stimulate the liver’s P450 system may lead to increased production of toxic metabolites.
(1) Digoxin levels are decreased with cyclophosphamide.
(2) Interacts with warfarin to prolong the prothrombin time further
(3) Interacts with succinyl choline to increase neuromuscular blockade
(4) Cimetidine and allopurinol increase ifosfamide toxicity.
H. Melphalan (Alkeran, phenylalanine mustard, L-PAM)
1. Indications. Multiple myeloma. The injection form is used in bone marrow transplantation. Previously used in ovarian carcinoma.
2. Pharmacology
a. Mechanism. Alkylation (see Section I.A)
b. Metabolism. Acts directly. Ninety percent of the drug is bound to plasma proteins and undergoes rapid hydrolysis in the bloodstream to inert products. Melphalan is excreted in the urine (about 30%) as unchanged drug and metabolites, and the remainder is cleared in feces.
3. Toxicity
a. Dose-limiting. Myelosuppression may be cumulative and recovery may be prolonged.
b. Occasional. Anorexia, nausea, vomiting, mucositis, sterility
c. Rare. Alopecia, pruritus, rash, hypersensitivity; secondary malignancies (acute leukemia); pulmonary fibrosis, vasculitis, cataracts
4. Administration
a. Supplied as 2-mg tablets
b. Dose modification. Hematologic; administer cautiously in patients with azotemia
c. Dose. If no myelosuppression is observed after oral dosing, poor oral absorption should be suspected. For continuous therapy: 0.10 to 0.15 mg/kg PO daily for 2 to 3 weeks, no therapy for 2 to 4 weeks, then 2 to 4 mg PO daily. For pulse therapy: 0.2 mg/kg (10 mg/m2) PO daily for 4 days every 4 to 6 weeks.
d. Drug interactions
(1) Cimetidine may result in reduced serum melphalan levels.
(2) Cyclosporine enhances the risk of renal toxicity from melphalan.
I. Nitrogen mustard (mechlorethamine, Mustargen)
1. Indication. Hodgkin lymphoma; topical use for T-cell lymphoma
2. Pharmacology
a. Mechanism. Rapid alkylation of DNA, RNA, and protein (see Section I.A). Cell cycle–nonspecific with activity in all phases of the cell cycle.
b. Metabolism. Native drug is highly active and is rapidly deactivated within the blood by rapid hydrolysis; the elimination half-life is 15 minutes. Metabolites are mostly excreted in urine.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Severe nausea and vomiting beginning 1 hour after administration; skin necrosis if extravasated (sodium thiosulfate may be tried); burning at IV injection site and facial flushing; metallic taste; discoloration of the infused vein; abnormal LFTs within 1 week of therapy (up to 90% of patients)
c. Occasional. Alopecia, sterility, diarrhea, thrombophlebitis, gynecomastia
d. Rare. Neurotoxicity (including hearing loss), angioedema, secondary neoplasms
4. Administration. Patients should always be premedicated with antiemetics. The drug should be administered through the tubing of a running intravenous line using extravasation precautions.
a. Supplied as 10-mg vials
b. Dose modification. Hematologic; none required for hepatic or renal impairment
c. Dose. 10 mg/m2 as a single or divided dose monthly or 6 mg/m2 on day 1 and day 8 of the MOPP regimen (see Appendix D-1)
d. Drug interactions. Sodium thiosulfate inactivates mechlorethamine.
J. Nitrosoureas. Carmustine [BCNU, bischlorethyl nitrosourea (BiCNU)]; lomustine [CCNU, cyclohexyl chlorethyl nitrosourea (CeeNU)]; streptozocin, which is a nitrosourea with a different mechanism of action (see Section I.K)
1. Indications. Brain cancer, myeloma, melanoma, and some carcinomas
2. Pharmacology
a. Mechanism. Alkylation of DNA and RNA (see Section I.A); DNA cross-linking; inhibition of DNA polymerase, DNA repair, and RNA synthesis. Cell cycle–nonspecific.
b. Metabolism. Highly lipid-soluble drugs that enter the brain. Rapid spontaneous decomposition to active and inert products; the drugs also are metabolized. Most of the intact drug and metabolic products are excreted in urine; some products have an enterohepatic cycle.
3. Toxicity
a. Dose-limiting. Myelosuppression is prolonged, cumulative, and substantially aggravated by concurrent radiation therapy.
b. Common. Nausea and vomiting may last 8 to 24 hours. BCNU causes local pain during injection or hypotension during a too rapid or concentrated injection.
c. Occasional. Stomatitis, esophagitis, diarrhea, LFT abnormalities; alopecia, facial flushing, brown discoloration of skin; interstitial lung disease with pulmonary fibrosis (with prolonged therapy and higher doses, especially with cumulative doses >1,400 mg/m2); dizziness, optic neuritis, ataxia, organic brain syndrome; renal insufficiency
d. Rare. Secondary malignancies
4. Administration. Avoid alcohol at least 1 hour before and after CCNU.
a. Supplied as 100-mg vials of BCNU; 10-, 40-, and 100-mg capsules of CCNU in a dose pack of 300 mg
b. Dose modification. Hematologic and renal
c. Dose
(1) BCNU: 150 to 200 mg/m2 IV (as a single dose or divided over 2 days) every 6 to 8 weeks. Do not infuse over longer than 2 hours because of incompatibility of the drug with intravenous tubing. If blood and BCNU are mixed in the syringe before administration, the painfulness of injection may be decreased.
(2) CCNU: 100 to 130 mg/m2 PO every 6 to 8 weeks
d. Drug interactions
(1) With cimetidine to decrease nitrosourea metabolism, resulting in increased hematosuppression
(2) BCNU may lower levels of digoxin and phenytoin.
(3) Amphotericin B enhances cellular uptake of BCNU, resulting in increased host toxicity.
K. Procarbazine (N-methylhydrazine, Matulane, Natulan)
1. Indications. Hodgkin lymphoma, cutaneous T-cell lymphoma
2. Pharmacology
a. Mechanism. DNA alkylation and depolymerization. Methylation of nucleic acids. Inhibition of DNA, RNA, and protein synthesis.
b. Metabolism. Rapidly and extensively metabolized by the hepatic P450 microsomal system. Metabolic activation of the drug is required. Readily enters the cerebrospinal fluid. Degraded in the liver to inactive compounds, which are excreted in urine (70%). Less than 10% of the drug is excreted in unchanged form.
3. Toxicity
a. Dose-limiting. Myelosuppression, which is most pronounced 4 weeks after starting treatment
b. Common. Nausea and vomiting, which decrease with continued use; flu-like syndrome (usually with initial therapy); sensitizes tissues to radiation; amenorrhea and azoospermia, sterility
c. Occasional. Dermatitis, hyperpigmentation, photosensitivity; stomatitis, dysphagia, diarrhea; hypotension, tachycardia; urinary frequency, hematuria; gynecomastia
d. Neurologic. Procarbazine results in disorders of consciousness or mild peripheral neuropathies in about 10% of cases. These abnormalities are reversible and rarely serious enough to alter drug dosage. Manifestations of toxicity include sedation, depression, agitation, psychosis, decreased deep-tendon reflexes, paresthesias, myalgias, and ataxia.
e. Rare. Xerostomia, retinal hemorrhage, photophobia, papilledema; hyper-sensitivity pneumonitis, secondary malignancy
4. Administration. Avoid alcohol, tyramine-containing foods, tricyclic anti-depressants, antihistamines, dark beer, wine, cheeses, bananas, yogurt, and pickled or smoked foods.
a. Supplied as 50-mg capsules
b. Dose modification. Reduce dose in patients with hepatic, renal, or bone marrow dysfunction.
c. Dose. 60 to 100 mg/m2 PO daily for 10 to 14 days in combination regimens
d. Drug interactions. Procarbazine is a monoamine oxidase inhibitor and thus interacts with numerous agents. For the most part, these interacting agents should be avoided for about 2 weeks after stopping procarbazine. Potential reactions from procarbazine interactions with other drugs include the following:
(1) Disulfiram (Antabuse)-like reactions: Alcohol
(2) Severe hypertension
(a) Sympathomimetic amines, levodopa, methyldopa; cocaine, narcotics; buspirone, methylphenidate (Ritalin); dextromethorphan (with hyperpyrexia); caffeine
(b) Foods and beverages containing amines (e.g., aged cheese, beer, and wine [with or without alcohol]; smoked or pickled meats, poultry or fish; fermented sausage; any overripe fruit)
(3) Hypotension: Hypotension-producing medications, spinal anesthetics
(4) CNS depression and anticholinergic effects: Antihistamines, phenothiazines, barbiturates, and other CNS depressants
(5) Hyperpyrexia, convulsions, and death: Tricyclic antidepressants, monamine oxidase inhibitors, fluoxetine; sympathomimetic amines; meperidine and other narcotics (also possibly hypotension, respiratory depression, and coma)
(6) Hypoglycemia with insulin or sulfonylureas
(7) Increased anticoagulant effect with coumarin derivatives
(8) Shaking, hyperventilation, confusion, and so forth, with tryptophan
L. Streptozocin (streptozotocin, Zanosar)
1. Indications. Islet cell cancer of the pancreas (in combination with fluorouracil), carcinoid tumors
2. Pharmacology
a. Mechanism. Alkylating agent (see Section I.A). A cell cycle–nonspecific nitrosourea analog. Inhibits DNA synthesis and the DNA repair enzyme, guanine-O6-methyl transferase; affects pyrimidine nucleotide metabolism and inhibits enzymes involved in gluconeogenesis. Selectively targets pancreatic β cells, presumably due to the glucose moiety on the molecule.
b. Metabolism. Drug is a type of nitrosourea that is extensively metabolized by the liver to active metabolites and has a short plasma half-life (<1 hour). Crosses the blood–brain barrier. Excreted in urine as metabolites and unchanged drug.
3. Toxicity
a. Dose-limiting. Nephrotoxicity initially appears as proteinuria and progresses to glycosuria, aminoaciduria, proximal renal tubular acidosis, nephrogenic diabetes insipidus, and renal failure if the drug is continued.
b. Common. Nausea and vomiting (often severe), myelosuppression (mild, but may be cumulative), hypoglycemia after infusion, vein irritation during infusion, altered glucose metabolism with either hypoglycemia or hyperglycemia
c. Occasional. Diarrhea, abdominal cramps, LFT abnormalities
d. Rare. Central nervous system toxicity, fever, secondary malignancies
4. Administration. Urinalysis and serum creatinine levels are monitored before each dose. Patients are routinely premedicated with antiemetics. The dose is administered over 30 to 60 minutes to prevent local pain.
a. Supplied as 1-g vials
b. Dose modification. Proteinuria or elevated serum creatinine levels contraindicate use of the drug until the abnormalities resolve.
c. Dose. 1.0 g/m2 IV weekly for 6 weeks, then off treatment for 4 weeks, or 0.5 g/m2 IV daily for 5 days every 6 weeks
M. Temozolomide (methozolastone, Temodar, Temodal)
1. Indications. Brain tumors; metastatic melanoma
2. Pharmacology. Structurally and functionally similar to dacarbazine
a. Mechanisms. Structurally and functionally similar to dacarbazine. Metabolic activation to the reactive compound (MTIC) is required for antitumor activity. The drug methylates guanine residues in DNA and inhibits DNA, RNA, and protein synthesis, but does not cross-link DNA strands. Nonclassic alkylating agent, cell cycle–nonspecific.
b. Metabolism. Excreted predominantly by the renal tubules. Because the drug is lipophilic, it crosses the blood–brain barrier.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Mild to moderately severe nausea and vomiting, diarrhea, headache, fatigue, mild transaminase elevation
c. Occasional. Photosensitivity, myalgias, fever
d. Rare. Prolonged cytopenia, myelodysplastic syndrome
4. Administration. Patients should avoid sun exposure during and for several days after treatment.
a. Supplied as 5-, 20-, 100-, 140-, 180-, and 250-mg capsules and 100 mg vials for IV injection
b. Dose modification. Consider dosage reduction for moderately severe hepatic or renal dysfunction and for elderly patients.
c. Dose. 75 mg/m2 PO daily during radiation therapy; 150 mg/m2 PO for 5 days each month as maintenance therapy, increasing to 200 mg/m2 if tolerated
N. Thiotepa (triethylenethiophosphoramide, Thioplex)
1. Indications. Intracavitary for malignant effusions, intravesicular for urinary bladder, and intrathecal use for meningeal metastasis; severe thrombocytosis. Also can be used for breast and ovarian cancers and for autologous hematopoietic stem cell transplantation.
2. Pharmacology. Ethylenimine analog, chemically related to nitrogen mustard
a. Mechanism. Alkylation (see Section I.A). Alkylates the N-7 position of guanine. Cell cycle–nonspecific.
b. Metabolism. Rapidly decomposed in plasma and excreted in urine. Extensively metabolized by the hepatic P450 microsomal system to active and inactive metabolites.
3. Toxicity
a. Dose-limiting. Myelosuppression, which may be cumulative
b. Common (for intravesicular administration). Chemical cystitis, abdominal pain, hematuria, dysuria, frequency, urgency, ureteral obstruction; nausea and vomiting 6 hours after treatment
c. Occasional. GI upset, abnormal LFTs, rash, hives; hypersensitivity
d. Rare. Alopecia, fever, angioedema, secondary malignancies
4. Administration. Thiotepa has been administered intravenously, intramuscularly, intravesicularly, intrathecally, intra-arterially, intrapleurally, intrapericardially, intraperitoneally, intratumorally, and as an ophthalmic instillation.
a. Supplied as 15-mg vials
b. Dose modification. Necessary for patients with cytopenias
c. Dose. 10 to 20 mg/m2 IV every 3 to 4 weeks; 30 to 60 mg intravesicularly every week for 4 weeks; 1 to 10 mg/m2 intrathecally twice weekly
d. Drug interactions. Increases neuromuscular blockade with succinyl choline
O. Cisplatin [cis-diamminedichloroplatinum (CDDP), Platinol]
1. Indications. A wide variety of malignancies
2. Pharmacology
a. Mechanism. A heavy metal alkylator of DNA. Covalently bonds to proteins, RNA, and especially DNA, forming DNA cross-linking and intrastrand N-7 adducts. The transisomer has virtually no antitumor activity. Acquired resistance to cisplatin involves alterations in transmembrane transport of drugs, intracellular levels of glutathione (GSH) or sulfhydryl-containing proteins, and the capacity to repair cisplatin DNA lesions.
b. Metabolism. Widely distributed in the body, except for the CNS. Long half-life in plasma (up to 3 days); may remain bound in tissues for months. Biliary excretion accounts for <10% of the total drug excretion. Approximately 15% of drug is excreted in the urine unchanged, and 10% to 40% of the remainder is excreted in the urine within 24 hours.
3. Toxicity
a. Dose-limiting
(1) Cumulative renal insufficiency. The incidence of renal insufficiency is about 5% with adequate hydration measures and 25% to 45% without hydration measures.
(2) Peripheral sensory neuropathy develops after the administration of 200 mg/m2 and can become dose-limiting when the cumulative cisplatin dose exceeds 400 mg/m2. Symptoms may progress after treatment is discontinued and include loss of proprioception and vibratory senses, hyporeflexia, and the Lhermitte sign. Symptoms may resolve slowly after many months.
(3) Ototoxicity with tinnitus and high-frequency hearing loss occurs in 5% of patients. Ototoxicity occurs more commonly in patients receiving doses of >100 mg/m2 by rapid infusion or high cumulative doses.
b. Common. Severe nausea and vomiting (both acute and delayed) occur in all treated patients; preventative antiemetic regimens are required. Hypokalemia, hypomagnesemia (occasionally difficult to correct), and mild myelosuppression occur very frequently; anorexia and metallic taste of foods; alopecia; azoospermia, sterility, impotence.
c. Occasional. Alopecia, loss of taste, vein irritation, transiently abnormal LFTs, SIADH, hypophosphatemia, myalgia, fever; optic neuritis
d. Rare. Altered color perception and reversible focal encephalopathy that often causes cortical blindness. Raynaud phenomenon, bradycardia, bundle-branch block, congestive heart failure; anaphylaxis, tetany.
4. Administration
a. Supplied as multidose vials
b. Dose modification. Renal function must return to normal before cisplatin can be given. Many physicians avoid using cisplatin when the creatinine clearance is <40 mL/min. Use with caution in patients with documented hearing impairment.
c. Dose depends on the chemotherapy regimen, of which there are many.
Examples are
(1) 40 to 120 mg/m2 or more IV every 3 to 4 weeks, or
(2) 20 to 40 mg/m2 IV daily for 3 to 5 days every 3 to 4 weeks
d. Method. The principles of cisplatin administration are as follows:
(1) Monitoring. Serum creatinine, electrolytes, magnesium, and calcium levels should be measured daily during therapy. Audiometry is usually not necessary.
(2) Antiemetics. Patients should be given prophylactic antiemetics, such as ondansetron and dexamethasone.
(3) Hydration and diuresis are required when 40 mg/m2 or more of cisplatin is given to increase urine output before administration of the drug. Continue hydration (IV or PO) for 24 hours after the drug is given. Furosemide is given to prevent fluid overload. Intravenous fluids are supplemented with KCl and MgSO4.
(4) Amifostine cytoprotection (see Section X.A). Amifostine and mesna may inactivate the nephrotoxic effect of cisplatin.
e. Drug interactions
(1) Taxanes should be given before cisplatin when used in combination because cisplatin decreases taxane clearance when given immediately prior to taxanes.
(2) Nephrotoxicity risk may be increased with rituximab, aminoglycosides, and other nephrotoxic agents.
(3) Loop diuretics (e.g., bumetanide, furosemide) may potentiate ototoxicity.
(4) Neurotoxicity may be increased with altretamine or vinca alkaloids.
(5) Anticonvulsant (e.g., carbamazepine, phenytoin) serum levels may be decreased.
P. Carboplatin (Paraplatin)
1. Indications. A wide variety of malignancies
2. Pharmacology
a. Mechanisms. Heavy metal alkylating-like agent with mechanisms very similar to cisplatin, but with different toxicity profile. Like cisplatin, it produces predominantly interstrand DNA cross-links rather than DNA–protein cross-links; this effect is apparently cell cycle–nonspecific. Cisplatin and carboplatin exhibit substantial clinical cross-resistance.
b. Metabolism. Plasma half-life of only 2 to 3 hours. Excreted in urine as unchanged drug (70%) and metabolites.
3. Toxicity
a. Dose-limiting. Myelosuppression is significant and cumulative, especially thrombocytopenia. Median nadir hematosuppression at 21 days; increased myelosuppression in patients who have reduced creatinine clearance levels or who have received prior chemotherapy.
b. Common. Nausea, vomiting, myalgias, weakness, and nephrotoxicity (but less severe less common than with cisplatin); pain at injection site; cation electrolyte imbalance
c. Occasional. Reversible abnormal LFTs, azotemia; peripheral neuropathy (5%), visual disturbance; hypersensitivity reactions; amenorrhea, azoospermia, impotence, and sterility
d. Rare. Alopecia, rash, flu-like syndrome, hematuria, hyperamylasemia; hearing loss, optic neuritis; alopecia
4. Administration
a. Supplied as 50-, 150-, 450-mg vials
b. Dose modification. Reduce dosage for creatinine clearance of ≤60 mL/min. Caution is advised when concomitantly administering other myelosuppressive or nephrotoxic drugs.
c. Dose by creatinine clearance (ClearanceCr), as follows:
ClearanceCr ≥ 60 mL/min; dose = 360 mg/m2
ClearanceCr ≥ 41 to 59 mL/min; dose = 250 mg/m2
ClearanceCr ≥ 16 to 40 mL/min; dose = 200 mg/m2
d. Dose by Calvert formula (AUC, area under the curve; GFR, glomerular filtration rate):
Total dose [mg (not per m2)] = (target AUC) × (GFR +25)
Target AUC = 4 to 6 for previously treated patients
Target AUC = 5 to 7 for previously untreated patients
e. Drug interactions.
(1) Taxanes should be generally administered before carboplatin when given concomitantly. However, unlike cisplatin, there is no significant interaction between paclitaxel and carboplatin.
(2) Anticonvulsant (e.g., carbamazepine, phenytoin) serum levels may be decreased.
(3) Aminoglycosides may increase nephrotoxicity.
Q. Oxaliplatin (diaminocyclohexane platinum, Eloxatin)
1. Indications. Colorectal, pancreatic, and gastric cancers
2. Pharmacology
a. Mechanisms. Binds covalently to DNA with preferential binding to the N-7 position of guanine and adenine; intrastrand and interstrand cross-links.
b. Metabolism. Undergoes extensive nonenzymatic conversion to its active cytotoxic species; >50% of the drug is cleared through the kidneys. Only 2% of the drug is excreted in feces.
3. Toxicity
a. Dose-limiting
(1) Acute dysesthesias in the hands, feet, perioral area, or throat develop within hours or up to 2 days after dosing, may be precipitated or exacerbated by exposure to cold (cold air or beverages); usually resolves within 2 weeks; frequently recurs with further dosing and may be ameliorated by prolonging the infusion to 6 hours. Dysphagia, dyspnea without stridor or wheezing, jaw spasms, dysarthria, voice changes, or chest pressure may occur. In contrast to cisplatin, ototoxicity occurs rarely.
(2) Persistent peripheral sensory neuropathy usually characterized by paresthesias, dysesthesias, and hypesthesia, including deficits in proprioception, which is usually reversible within 4 months of discontinuing oxaliplatin.
b. Common. Anorexia, nausea, vomiting, constipation, diarrhea, abdominal pain; fever, fatigue; mild to moderate myelosuppression; mild to moderate LFT abnormalities
c. Occasional. Allergic reactions, mild nephrotoxicity, headache, stomatitis, taste alteration; back pain, arthralgias
d. Rare. Pulmonary fibrosis
4. Administration. The drug cannot be mixed with alkaline medications or media [such as basic solutions of fluorouracil (5-FU)]. The patient should avoid exposure to cold.
a. Supplied as 50- and 100-mg vials
b. Dose modification. Reduce dose for renal dysfunction
c. Dose
(1) FOLFOX-4 regimen: 85 mg/m2 with leucovorin, 200 mg/m2, both given over 2 hours at the same time through Y-tubing on day 1. Then, 5-FU is given first as a bolus at a dose of 400 mg/m2 and then as an infusion of 600 mg/m2over 22 hours. On day 2, leucovorin, 5-FU bolus, and 5-FU infusion over 22 hours are repeated. The cycle is repeated every 2 weeks. Several variations of this regimen are available.
(2) 100 to 130 mg/m2 IV every 3 weeks, either alone or in combination with other drugs.
II. ANTIMETABOLITES
A. General pharmacology of antimetabolites
1. Some antimetabolites are structural analogs of normal molecules that are essential for cell growth and replication. Other antimetabolites inhibit enzymes that are necessary for the synthesis of essential compounds. Their major effect is interfering with the building blocks of DNA synthesis (Fig. 4.1). Their activity, therefore, is greatest in the S phase of the cell cycle. In general, these agents have been most effective when cell proliferation is rapid.
2. The pharmacokinetics of these drugs are characterized by nonlinear dose–response curves; after a certain dose, no more are killed with increasing doses (fluorouracil is an exception). Because of the entry of new cells into the cycle, the length of time that the cells are exposed to the drug is directly proportional to the killing potential.
B. Azacitidine (5-azacitidine, Vidaza)
1. Indication. Acute myelogenous leukemia (experimental); severe myelodys-plastic syndromes (MDS) with an anticipated response in 16% of patients
2. Pharmacology
a. Mechanism. Antimetabolite (cytidine analog). Rapidly phosphorylated and incorporated into DNA and RNA, thereby inhibiting protein synthesis; also inhibits pyrimidine synthesis and DNA methylation.
b. Metabolism. Activated by phosphorylation and deactivated by deamination; similar to cytarabine. Excreted in urine (20% as unchanged drug).
3. Toxicity
a. Dose-limiting. Myelosuppression; nausea and vomiting.
b. Common. Hepatic dysfunction, fatigue, headache, diarrhea, alopecia, fever, injection site erythema
c. Occasional. Neurotoxicity (dizziness, restlessness, confusion), azotemia (transient), arthralgias, hypophosphatemia with myalgia, stomatitis, phlebitis, rash
d. Rare. Progressive lethargy and coma, renal tubular acidosis, rhabdomyolysis, hypotension
Figure 4.1. Sites of action of antimetabolites. 2-Cda, 2-chlorodeoxyadenosine; 5-Aza, 5-azacytidine; 5-FU, 5-fluorouracil; 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; Ara C, cytosine arabinoside; Dcf, deoxycoformycin; Flud, fludarabine; HU, hydroxyurea; MTX, methotrexate; reductase, dihydrofolate reductase.
4. Administration
a. Supplied as 100-mg vials
b. Dose modification. Necessary for patients with impaired liver function. Also reduce dose for patients with renal dysfunction and for serum bicarbonate concentration of <20 mEq/L.
c. Dose. 75 to 100 mg/m2 per day SQ for 7 days every 4 weeks for MDS (several cycles may be required for effectiveness)
d. Drug interactions. None known
C. Cladribine [2-chlordeoxyadenosine (2-CdA), Leustatin]
1. Indications. Hairy cell leukemia, indolent lymphoproliferative disorders
2. Pharmacology. An analog of the purine deoxyadenosine
a. Mechanism. Antimetabolite. The analog accumulates in cells (particularly lymphocytes), blocks adenosine deaminase, and inhibits RNA and DNA synthesis. Inhibits ribonucleotide reductase. Depletes ATP. Induces apoptosis. Active against both dividing and resting cells.
b. Metabolism. Rapidly metabolized and eliminated through the kidneys
3. Toxicity. Patients are at increased risk for opportunistic infections.
a. Dose-limiting. Myelosuppression
b. Common. Immunosuppression with decreases in CD4+ and CD8+ cells; nausea, skin reactions at injection site; fever in 50% (most likely due to tumor’s releasing pyrogens and cytokines), chills, flu-like syndrome
c. Occasional. Neurotoxicity (headache, dizziness), hypersensitivity reactions, fatigue
d. Rare. Severe neurotoxicity, pancreatitis
4. Administration
a. Supplied as 10-mg vials
b. Dose modification. Hematologic; use with caution with renal dysfunction.
c. Dose. Either 0.10 mg/kg/d (4 mg/m2/d) by continuous IV infusion for 7 days, or 0.14 mg/kg daily IV over 2 hours for 5 days
d. Drug interactions. None known
D. Clofarabine (2-chloro-2′-fluorodeoxy-9-beta-D-arabinofurosyladenine, Clolar)
1. Indications. Relapsed or refractory acute lymphoblastic leukemia for patients between 1 and 21 years of age
2. Pharmacology. Purine antimetabolite
3. Toxicity
a. Dose-limiting.
(1) Capillary leak syndrome (CLS)/systemic inflammatory response syndrome (SIRS) is a development following cytokine release and manifested by hypotension, tachycardia, tachypnea, and pulmonary edema.
(2) Hematosuppression (90%)
(3) Hepatotoxicity and nephrotoxicity
b. Common. Tachycardia, hypotension, flushing; headache, fever, chills, fatigue; pruritus, rash; nausea, vomiting, diarrhea; abnormal LFTs (80%; generally occur within 10 days of administration with a duration of ≤2 weeks); increased creatinine (50%), limb pain
c. Occasional. Hypertension, edema, dyspnea, pleural, or pericardial effusion; mucositis; myalgia, arthralgia; irritability, somnolence, agitation; cecitis; CLS (4%), SIRS (2%)
d. Rare. Hepatic veno-occlusive disease, Stevens–Johnson syndrome, hallucination
4. Administration. Consider prophylactic corticosteroids, antiemetics, hydration, and allopurinol. Discontinue if hypotension develops during administration to ensure that it is not due to CLS/SIRS.
a. Supplied as 1 mg/mL in 20 mL vials
b. Dose modification: Use with caution in patients with renal or hepatic impairment. Withhold clofarabine and reinitiate with 25% dose reduction when returned to baseline for neutrophil counts <500/μL lasting ≥4 weeks, increase in creatinine or bilirubin (grade 3), or grade 3 GI toxicity. Discontinue clofarabine for CLS, SIRS, or grade 4 nonhematologic toxicity.
c. Dose for adults: 52 mg/m2 IV over 2 hours for 5 days every 2 to 6 weeks based on recovery from adverse effects or 40 mg/m2 IV over 2 hours for 5 days every 4 weeks
d. Drug interactions. No specific drug interactions have been reported. Avoid using potentially hepatotoxic or nephrotoxic drugs during the days of clofarabine administration.
E. Cytarabine (cytosine arabinoside, Cytosar, ara-C)
1. Indications. Acute leukemia, chronic myelogenous leukemia, lymphoma, meningeal involvement with tumor
2. Pharmacology. An analog of deoxycytidine
a. Mechanism. Antimetabolite. Requires intracellular activation to its phosphorylated derivative (ara-CTP), which inhibits DNA polymerases that are involved in the conversion of cytidine to deoxycytidine; some are incorporated into DNA. Ara-CTP inhibits ribonucleotide reductase, which results in decreased levels of deoxyribonucleotides for DNA synthesis and function. Blocks DNA synthesis and repair and terminates DNA chain elongation. Cell cycle–specific (S phase).
b. Metabolism. Requires activation to ara-CTP by kinase; deactivated by deaminase; ara-C is rapidly and completely deaminated in liver, plasma, and peripheral tissues; ara-C antitumor activity depends on relative amounts of kinase and deaminase in cells. In patients with renal insufficiency, one metabolite (uracil arabinoside) has the ability to produce high concentrations of ara-CTP, which may result in CNS toxicity. Excreted in urine as inactive metabolites.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Nausea, vomiting, mucositis, diarrhea (potentiated by the addition of an anthracycline); conjunctivitis (usually within the first 3 days of high-dose regimens, but reduced with prophylactic glucocorticoids eye drops); hydradenitis, arachnoiditis with intrathecal administration.
c. Neurotoxicity (cerebellar ataxia, lethargy, confusion) begins on the fourth or fifth day of infusion and usually resolves within 7 days. The incidence and severity of toxicity are related to the dose given (especially with total dose of >48 g/m2), the rate of infusion (least incidence for continuous infusions), age (particularly older than 60 years), sex (especially male), and the degree of hepatic or renal dysfunction (particularly with creatinine clearance of <60 mL/min). In some cases, it is irreversible or fatal.
d. Occasional. Alopecia, stomatitis, metallic taste, esophagitis, hepatic dysfunction (mild and reversible), pancreatitis, severe GI ulceration; thrombophlebitis; headache; rash, transient skin erythema without exfoliation. Ara-C syndrome, described in pediatric patients, is an allergic reaction manifested by fever, flu-like syndrome, myalgias, bone pain, maculopapular rash, conjunctivitis, and occasional chest pain (corticosteroids are effective).
e. Rare. Sudden respiratory distress rapidly progressing to noncardiogenic pulmonary edema; pericarditis, cardiomegaly, tamponade; urinary retention.
4. Administration. Use prophylactic glucocorticoid eye drops for patients receiving high-dose regimens.
a. Supplied as 100-, 500-, 1,000-, and 2,000-mg vials
b. Dose modification. Use cautiously in patients with liver or renal disease or with risk factors for neurotoxicity.
c. Dose
(1) See Chapter 21 for use in patients with lymphoma and Chapter 25 for use in patients with acute leukemia.
(2) For intrathecal administration: 50 to 100 mg in 10-mL saline for 1 to 3 days weekly
(3) Low-dose regimen: 10 mg/m2 SC every 12 to 24 hours for 15 to 21 days
(4) High-dose therapy should be given over 1 to 2 hours
d. Drug interactions
(1) Ara-C antagonizes the efficacy of gentamycin and digoxin
(2) Increased risk of pancreatitis in patients previously treated with L-asparaginase
F. Decitabine (5-aza-2′-deoxycytadine, Dacogen)
1. Indications. Myelodysplastic syndromes, chronic myelomonocytic leukemia
2. Pharmacology. Decitabine is an analogue of the natural nucleoside 2′-decoxycytidine.
a. Mechanisms. Decitabine is believed to exert its antineoplastic effects by inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis.
b. Metabolism. The metabolic fate and route of elimination are not known.
3. Toxicity
a. Dose-limiting. Hematosuppression (nadir at 35 days, recovery at 35 to 50 days)
b. Common. Hematosuppression, fatigue, fever; nausea, constipation (35%), diarrhea; headache, arthralgias, rigors, edema, cough; hyperglycemia, hypokalemia, hypomagnesemia.
4. Administration. Premedicate with antinausea drugs.
a. Supplied as 50-mg vials as a lyophilized powder
b. Dose modification: Reduce dose to 11 mg/m2 if hematologic recovery requires more than 6 weeks. Decitabine should be discontinued if the serum creatinine is ≥2 mg/dL or SGPT or bilirubin is greater than or equal to twice the upper limit of normal. The dose should also be reduced for grade 3 or 4 nonmyelosuppressive toxicities.
c. Dose. 15 mg/m2 IV over 1 hour for 5 days. Cycles are repeated every 4 weeks. Weekly and various other dosing schedules are available. Responses may require three cycles of treatment.
d. Drug interactions. None known
G. Fludarabine (2-fluoroadenine arabinoside-5-phosphate, Fludara, Oforta)
1. Indications. Chronic lymphocytic leukemia, low-grade lymphomas, and cutaneous T-cell lymphomas
2. Pharmacology. The 5′-monophosphate analog of ara-A (arabinofuranosyladenosine). The 2-fluoro group on the adenosine ring renders this drug resistant to breakdown by adenosine deaminase (compare with cytarabine).
a. Mechanism. Antimetabolite with high specificity for lymphoid cells. Its active metabolite, 2-fluoro-ara-A, appears to act by inhibiting DNA chain extension, DNA polymerase-α, and ribonucleotide reductase. It has activity against both dividing and resting cells and induces apoptosis.
b. Metabolism. Metabolites and unchanged drug (25%) are excreted primarily in urine.
3. Toxicity
a. Dose-limiting. Myelosuppression, which may be cumulative; severe autoimmune hemolytic anemia that may or may not be responsive to corticosteroids
b. Common. Immunosuppression with decreases in CD4+ and CD8+ T cells in most patients and associated with increased risk for opportunistic infections (recovery may take more than a year); mild nausea and vomiting; fever with associated flu-like syndrome (25%); cough, weakness, arthralgia/myalgias
c. Occasional. Alopecia (mild), abnormal LFTs, tumor lysis syndrome
d. Rare.
(1) Stomatitis, diarrhea; dermatitis; chest pain, hypotension, interstitial pneumonitis; delayed neurotoxicity (usually high doses: somnolence, transient paresthesias, demyelination)
(2) Immune-mediated hematologic effects (autoimmune hemolytic anemia, immunologic thrombocytopenic purpura, acquired hemophilia, transfusion-associated graft-vs.-host disease)
4. Administration
a. Supplied as 50-mg vials (Fludara) and 10-mg tablets (Oforta)
b. Dose modification. Decrease dosage by 25% for patients with creatinine clearance of <10 to 49 mL/min and by 50% or more for clearance of <10 mL/min
c. Dose. 25 mg/m2 IV over 30 minutes or 40 mg/m2 PO daily for 5 consecutive days every 4 weeks; 25 to 30 mg/m2 IV for 3 days every 4 weeks when combined with other agents.
d. Drug interactions.
(1) Fludarabine may enhance cytotoxicity of cyclophosphamide, cisplatin, and mitoxantrone by inhibiting nucleotide repair mechanisms and of cytarabine by inducing expression of deoxycytidine kinase.
(2) The combination of fludarabine plus pentostatin has resulted in a high incidence of fatal pulmonary toxicity.
H. 5-Fluorouracil (5-FU, Adrucil)
1. Indications. Gastrointestinal, breast, pancreatic, and head and neck carcinomas
2. Pharmacology. A fluoropyrimidine analog
a. Mechanism. Antimetabolite. Requires activation to cytotoxic metabolite forms. Interferes with DNA synthesis by blocking thymidylate synthetase, an enzyme involved in the conversion of deoxyuridylic acid to thymidylic acid. Metabolites (e.g., FUTP) are incorporated into several RNA species, which thereby interfere with RNA function and protein synthesis. Incorporation of another metabolite (FdUTP) into DNA results in inhibition of DNA synthesis and function. It is cell-cycle S-phase–specific but acts in other cell cycle phases as well and is unique in having a log linear cell-killing action.
b. Metabolism. 5-FU rapidly enters all tissues, including spinal fluid and malignant effusions. The drug undergoes extensive intracellular activation by a series of phosphorylating enzymes and phosphoribosyl transferase, particularly dihydropyrimidine dehydrogenase. Most of the drug degradation occurs in the liver. Responsive tumors appear to lack degradation enzymes. Metabolism eliminates 90% of 5-FU. Inactive metabolites are excreted in urine, bile, and breath (as carbon dioxide). The elimination half-life is short, ranging from 10 to 20 minutes.
3. Toxicity is more common and more severe in patients with dihydropyrimidine dehydrogenase deficiency.
a. Dose-limiting. Myelosuppression (less common with continuous infusion); mucositis (more common with 5-day infusion); diarrhea.
b. Common. Nasal discharge; eye irritation, and excessive lacrimation due to dacryocystitis and lacrimal duct stenosis; dry skin, photosensitivity, and pigmentation of the infused vein.
c. Neurologic. Reversible cerebellar dysfunction, somnolence, confusion or seizures occurs in about 1% of patients. Symptoms usually disappear 1 to 6 weeks after the drug is discontinued, but they abate after the dose is reduced or even if the same dose is maintained.
d. Occasional. Esophagitis; hand–foot syndrome with protracted infusion (paresthesia, erythema, and swelling of the palms and soles); coronary vasospasm (particularly in patients with a prior history of myocardial ischemia); thrombophlebitis; nausea, vomiting.
e. Rare. Alopecia, dermatitis, loss of nails, dark bands on nails; blurred vision, “black hairy tongue” (hypertrophy of filiform papillae), anaphylaxis, fever.
4. Administration. 5-FU is given by IV bolus, IV infusion over 15 minutes, continuous IV infusion, arterial infusion, intracavitarily, topically, or orally. The use of ice chips in the mouth 15 minutes before and 15 minutes after IV bolus injections of 5-FU may reduce the incidence and severity of mucositis.
a. Supplied as 500- and 1,000-mg vials
b. Dose modification. Fluorouracil is withheld if the patient has stomatitis, diarrhea, evidence of infection, leukopenia, or thrombocytopenia; drug is resumed (perhaps at reduced dosage) when these problems have resolved.
(1) May be contraindicated in patients with active ischemic heart disease or a history of myocardial infarction within the previous 6 months
(2) Patients who experience unexpected grade 3 or 4 myelosuppression, gastrointestinal and/or neurologic toxicities with initiation of therapy may have an underlying deficiency in dihydropyrimidine dehydrogenase. Further testing to identify this pharmacogenetic syndrome should be considered under these circumstances. If enzyme deficiency is present, therapy with 5-FU must be discontinued immediately.
c. Dose. Fluorouracil is erratically absorbed orally. Several regimens have been used, including the following:
(1) 500 to 600 mg/m2 IV weekly for 6 weeks of every 8 weeks
(2) 425 to 450 mg/m2 IV daily for 5 days every 28 days
(3) 800 to 1,000 mg/m2/d by continuous infusion for 4 to 5 days every 28 days
(4) 200 to 400 mg/m2/d by continuous infusion indefinitely
d. Drug interactions
(1) Toxicity is enhanced by leucovorin (along with antitumor activity), methotrexate, trimetrexate, and phosphonacetyl-L-aspartic acid (PALA).
(2) Allopurinol inhibits activation of 5-FU and may result in decreased effectiveness.
(3) Thymidine and uridine decrease the host toxic effects of 5-FU.
I. Leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate)
1. Indications. Combined with 5-FU in treatment of colorectal and other adenocarcinomas; the rescue agent for antifol toxicity (e.g., methotrexate)
2. Pharmacology
a. Mechanism. Leucovorin is a tetrahydrofolic acid derivative that acts as a cofactor for carbon transfer reactions in the synthesis of purines and pyrimidines. It inhibits the effects of methotrexate and other dihydrofolate reductase antagonists. Leucovorin potentiates the cytotoxic effects of fluorinated pyrimidines (i.e., 5-FU and floxuridine) by increasing the binding of folate cofactor and activated 5-FU to thymidylate synthetase (TS) within the cells.
b. Metabolism. Metabolized intracellularly to the reduced folate, 5, 10-methylenetetrahydrofolate, which forms a ternary complex with the 5-FU metabolite FdUMP and TS. Excreted in urine as metabolites.
3. Toxicity. Potentiates the toxic effects of fluoropyrimidine therapy
4. Administration
a. Supplied as 50-, 100-, 200-, 350-, and 500-mg vials for IV or IM use and as 5- and 15-mg tablets for oral use
b. Dose. Depends on combination regimen
(1) When used as a rescue agent in combination with high-dose methotrexate, leucovorin should be administered 24 hours after methotrexate every 6 hours for up to 12 doses, depending on the serum methotrexate level; continue leucovorin until the methotrexate level falls below 5 × 10−8 M.
(2) When given in combination with 5-FU, leucovorin should be administered at least 30 to 60 minutes before 5-FU to allow sufficient time for intracellular metabolism to take place.
c. Drug interactions. Barbiturates and phenytoin may decrease in their efficacy and increase the risk of seizures. Precipitates when mixed in the same solution as 5-FU.
J. Capecitabine (Xeloda)
1. Indications. Carcinomas of the breast or colon
2. Pharmacology. Capecitabine is a fluoropyrimidine carbamate that is a systemic prodrug of 5′-deoxy-5-fluorouridine (5′-DFUR), which is converted in vivo to 5-FU.
a. Mechanism. See fluorouracil
b. Metabolism. Hepatic. Catabolism predominantly via dihydropyrimidine dehydrogenase, which is present in liver, leukocytes, kidney, and other extrahepatic tissues. More than 90% is cleared in the urine (see 5-fluorouracil).
3. Toxicity. Similar to 5-FU
a. Dose-limiting. Diarrhea (50%), hand–foot syndrome
b. Common. Hand–foot syndrome (palmar–plantar erythrodysesthesia or chemotherapy-induced acral erythema) occurs in 15% to 50% of patients; nausea, vomiting, hematosuppression; fatigue.
c. Occasional. Abnormal LFTs, neurotoxicity; cardiac ischemia in patients with a prior history of coronary artery disease; tear duct stenosis, conjunctivitis, blepharitis; confusion, cerebellar ataxia.
4. Administration. Pyridoxine, 50 mg PO b.i.d. may be used to reduce the incidence and severity of the hand–foot syndrome. Celecoxib (Celebrex), 200-mg b.i.d., or a low-dose nicotine patch may also be effective.
a. Supplied as 150- and 500-mg tablets
b. Dose modification. Use with caution with liver dysfunction and in patients taking coumarin derivatives. Reduce dosage in patients with moderate renal dysfunction. Contraindicated in patients with dihydropyrimidine dehydrogenase deficiency or with severe renal impairment.
c. Dose. 650 to 1,250 mg/m2 PO b.i.d. (approximately every 12 hours) with a glass of water and within 30 minutes of a meal for 14 days every 3 weeks
d. Drug interactions
(1) Patients using warfarin should have dosage monitored closely, even after capecitabine is discontinued.
(2) Phenytoin toxicity can develop; dosage adjustment may be necessary.
(3) Liquid antacids may increase the bioavailability of capecitabine.
(4) Leucovorin enhances the antitumor effect and toxicity of capecitabine.
e. Treatment of hand–foot syndrome. Hand moisturizers; soak hands and feet in cool to tepid water for 10 minutes, then apply petrolatum jelly onto the wet skin. Bag balm or lanolin-containing salves may help.
K. Gemcitabine (Gemzar)
1. Indications. Carcinoma of pancreas, bladder, lung, ovary; soft tissue sarcomas.
2. Pharmacology. A fluorine-substituted deoxycytidine analog
a. Mechanisms. Cell-phase specific, primarily killing cells in S phase and also blocking the progression of cells through the G1 phase to S-phase boundary. Metabolized intracellularly to the active diphosphate and triphosphate. Inhibits ribonucleotide reductase; competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA.
b. Metabolism. Undergoes extensive metabolism by deamination in the liver, plasma, and peripheral tissues. Nearly entirely excreted in urine as active drug and metabolites.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Nausea, vomiting, diarrhea, stomatitis; fever with flu-like symptoms (40%); macular or maculopapular rash; transient LFT elevations; mild proteinuria and hematuria.
c. Occasional. Hair loss, rash, edema.
d. Rare. Hemolytic-uremic syndrome; pulmonary drug toxicity; hypersensitivity reactions; alopecia.
4. Administration. Gemcitabine is a potent radiosensitizer and should be avoided in patients while undergoing radiotherapy.
a. Supplied as vials of 200 and 1,000 mg
b. Dose modification. Use with caution in patients with hepatic or renal insufficiency.
c. Dose. 1,000 mg/m2 over 30 minutes weekly for 7 weeks or until toxicity, followed by 1 week rest; then for 3 of every 4 weeks.
d. Drug interactions. None known
L. Hydroxyurea (hydroxycarbamide, Hydrea, Droxia)
1. Indications. Myeloproliferative disorders, refractory ovarian cancer, sickle cell disease
2. Pharmacology. An analog of urea
a. Mechanism. Antimetabolite. Inhibits DNA synthesis by inhibiting nucleotide reductase, the enzyme that converts ribonucleosides to deoxyribonucleosides. Inhibits DNA repair and thymidine incorporation into DNA. Cell-cycle S-phase–specific, but acts in other phases as well.
b. Metabolism. Crosses the blood–brain barrier. Half of the drug is rapidly degraded into inactive compounds by the liver. Inactive products and unchanged drug (50%) are excreted in urine.
3. Toxicity
a. Dose-limiting. Myelosuppression, which recovers rapidly when treatment is stopped (prominent megaloblastosis)
b. Occasional. Nausea, vomiting, diarrhea; skin rash, facial erythema, hyperpigmentation; azotemia, proteinuria; transient LFT abnormalities; radiation recall phenomenon.
c. Rare. Alopecia, mucositis, diarrhea, constipation; neurologic events; pulmonary edema; flu-like syndrome; painful perimalleolar ulcers; possible acute leukemia in myeloproliferative disorders.
4. Administration
a. Supplied as 500-mg capsules (Hydrea); 200-, 300-, and 400-mg capsules (Droxia)
b. Dose modification. The drug should be given cautiously in the presence of liver dysfunction or when combined with other antimetabolites. Dosages should be reduced for creatinine clearance levels of <50 mL/min and when given with concomitant radiotherapy.
c. Dose. 10 to 30 mg/kg PO daily
d. Drug interactions
(1) Antiretroviral agents: hepatotoxicity and severe neurotoxicity
(2) Didanosine: pancreatitis
(3) 5-Fluorouracil: neurotoxicity
M. 6-Mercaptopurine (6-MP, Purinethol)
1. Indication. Acute lymphoblastic leukemia (maintenance therapy)
2. Pharmacology
a. Mechanism. Purine analog with activity in the S phase of the cell cycle. Inhibits de novo purine synthesis by inhibiting 5-phosphoribosyl-1-pyro-phosphate. The parent drug is inactive. Requires intracellular phosphorylation by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to the monophosphate form, which is eventually metabolized to the triphosphate metabolite. Competes with ribotides for enzymes responsible for conversion of inosinic acid to adenine and xanthine ribotides. Its incorporation into DNA or RNA is of uncertain significance.
b. Metabolism. Mercaptopurine is slowly degraded in the liver, largely by xanthine oxidase. Allopurinol, a xanthine oxidase inhibitor, causes marked increase in its toxicity. Clearance is primarily hepatic with conventional doses.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Mild nausea, vomiting, anorexia (25%); usually reversible cholestasis (30%); dry skin, photosensitivity; immunosuppression.
c. Rare. Stomatitis, diarrhea, dermatitis, fever, hematuria, Budd-Chiarilike syndrome, hepatic necrosis
4. Administration
a. Supplied as 50-mg tablets
b. Dose modification. Dose is reduced by 50% to 75% for patients with hepatic dysfunction.
c. Dose. 70 to 100 mg/m2 PO daily until patient responds or toxic effects are seen; then adjust for maintenance therapy.
d. Drug interactions. If given allopurinol, the 6-MP dose must be reduced by 75%. Dosage may also need to be modified if other hepatotoxic drugs are given. Warfarin dosages may be affected by 6-MP. Bactrim-DS may enhance myelosuppressive effect of 6-MP.
N. Methotrexate (amethopterin, MTX)
1. Indications. A wide variety of conditions
2. Pharmacology
a. Mechanism. Cell cycle–specific antifolate analog active in the S phase of the cell cycle. MTX blocks the enzyme dihydrofolate reductase, preventing formation of reduced (tetrahydro-) folic acid; tetrahydrofolic acid is crucial to the transfer of carbon units in a variety of biochemical reactions (Fig. 4.1). MTX thus blocks formation of thymidylate from deoxyuridylate and prevents synthesis of DNA. The drug also inhibits RNA and protein synthesis and prevents cells from entering the S phase of the cell cycle.
b. Metabolism. MTX is minimally metabolized by the human species. It is converted in the liver and other cells to higher polyglutamate forms. The drug is distributed to body water; patients with significant effusions eliminate the drug much more slowly. Because 50% to 70% of the drug is bound to plasma proteins, displacement by other drugs (e.g., aspirin, sulfonamides) may result in an increase in toxic effects. About 20% of the drug is eliminated in the bile. It is excreted in urine as unchanged drug (80% to 90% within 24 hours). Renal dysfunction results in dangerous blood levels of MTX and possible further renal damage. The half-life of the drug is 8 to 10 hours.
3. Toxicity. Leucovorin can reverse the immediate cytotoxic effects of MTX; generally, 1 mg of leucovorin is given for each 1 mg of MTX.
a. Dose-limiting. Myelosuppression, stomatitis, renal dysfunction
b. High-dose regimens. Nausea, vomiting, renal tubular necrosis, cortical blindness
c. Previously irradiated areas. Skin erythema, pulmonary fibrosis, transverse myelitis, cerebritis
d. Chronic therapy. Liver cirrhosis (reversible hepatic dysfunction occurs with short-term intermittent therapy); osteoporosis (in children).
e. Neurotoxicity. MTX neurotoxicity depends on dose and route of administration. Within a few hours after intrathecal administration, MTX can produce acute aseptic meningitis that is usually self-limited. A subacute encephalopathy and myelopathy can also occur after intrathecal administration.
High-dose systemic administration can cause a reversible encephalopathy of rapid onset and resolution that lasts from minutes to hours (stroke-like episodes). Chronic intrathecal combined with high-dose systemic administration can produce a more serious and irreversible leukoencephalopathy that develops months after treatment, is more likely to occur after brain irradiation, and causes dementia, seizures, spasticity, and ataxia.
f. Occasional. Nausea, vomiting, diarrhea (GI ulceration, hemorrhage, and perforation can occur if therapy is continued after the onset of diarrhea); dermatitis, photosensitivity, altered pigmentation, furunculosis; conjunctivitis, photophobia, excessive lacrimation, cataracts; fever, reversible oligospermia, flank pain (with rapid intravenous infusion).
g. Rare. Alopecia, MTX pneumonitis (see Chapter 29, Section IV.A)
4. Administration
a. Supplied as 2.5-, 5-, 7.5-, 10-, and 15 mg tablets and 20- to 1,000-mg vials
b. Dose modification. The drug must not be administered to any patient with a creatinine clearance level of <60 mL/min (serum creatinine >1.5 mg/dL).
c. Dose. Varies according to regimen
(1) High-dose regimens use supralethal doses of MTX followed by administration of the antidote leucovorin. This treatment is complex and requires experience for the clinician and use of special monitoring techniques.
(2) Intrathecal administration: 5 to 10 mg/m2 (maximum, 15 mg) in 7 to 15 mL of preservative-free saline (3 mL if given using an Ommaya reservoir) every 3 to 7 days
d. Drug interactions
(1) Leucovorin rescues normal tissues from MTX toxicity and may impair its antitumor activity. Folic acid supplements should be discontinued while on therapy.
(2) L-Asparaginase and thymidine also block MTX toxicity and antitumor action.
(3) Aspirin, other nonsteroidal anti-inflammatory agents, penicillins, cephalosporins, phenytoin, and probenecid decrease renal clearance of MTX and increase its toxicity.
(4) Sulfonamides and phenytoin displace MTX from protein-binding sites and may enhance its toxicity.
(5) Trimethoprim is also an inhibitor of dihydrofolate reductase and can enhance MTX toxicity.
(6) Parenteral acyclovir and concomitant intrathecal MTX may result in neurologic abnormalities.
(7) MTX may increase serum levels of warfarin, which is displaced from plasma proteins.
(8) Omeprazole (Prilosec) increases serum MTX levels.
O. Nelarabine (Arranon)
1. Indications. Relapsed or refractory T-cell acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic lymphoma
2. Pharmacology
a. Mechanisms. A prodrug of ara-G, nelarabine is demethylated by adenosine deaminase to ara-G and then converted to ara-GTP, which is incorporated into the DNA of the leukemic blasts, leading to inhibition of DNA synthesis and inducing apoptosis. Ara-GTP accumulates at higher levels in T-cells, which correlates to clinical response.
b. Metabolism. Demethylated and hydrolyzed; drug and metabolites excreted in the urine.
3. Toxicity
a. Dose-limiting. Severe neurotoxicity that may not return to baseline after treatment cessation (discontinue drug for grade ≥ 2)
b. Common. Neurologic (70%; somnolence, confusion, dizziness, ataxia, tremor, peripheral neuropathy; severe neurotoxicity is reported including coma, demyelination, seizures, etc.); hematosuppression; fever, fatigue; nausea, vomiting, diarrhea, constipation; cough, edema
c. Occasional. Myalgia/arthralgia, abdominal pain, limb pain; stomatitis, dyspnea, cough; elevated transaminases or creatinine, hyper-/hypoglycemia
4. Administration.
a. Supplied as 5 mg/mL (50 mL vials)
b. Dose modification: Use with caution with hepatic or renal dysfunction; consider treatment delay for nonneurologic toxicity.
c. Dose (adults): 1,500 mg/m2/dose IV over 2 hours on days 1, 3, and 5; repeat every 21 days.
d. Drug interactions. None known
P. Pemetrexed (multitargeted antifolate, Alimta)
1. Indications. Mesothelioma (with cisplatin) and non–small cell lung cancer (second line)
2. Pharmacology
a. Mechanisms. Pyrrolpyrimidine antifolate analog with activity in the S phase of the cell cycle. Inhibition of the folate-dependent enzyme thymidylate synthetase (TS) is the main site of action. It also inhibits dihydrofolate reductase and two formyltransferases.
b. Metabolism. Metabolized intracellularly to polyglutamates, which are much more potent than the parent monoglutamate. Principally cleared by the kidneys. About 90% of the drug is excreted unchanged in the urine within 24 hours.
3. Toxicity. Patients with insufficient folate intake may be at increased risk for host toxicity. A baseline homocysteine level >10 predicts for the development of grade 3 to 4 toxicity.
a. Dose-limiting. Myelosuppression
b. Common. Skin rash (usually as the hand–foot syndrome), mucositis, nausea, vomiting, diarrhea; mild dyspnea, fatigue; transient elevation of LFTs.
c. Occasional. Myalgia/arthralgia, fever.
4. Administration. All patients are given 350 μg/d PO of folic acid and 1,000 μg of vitamin B12 SC every 3 weeks to reduce drug toxicity. Dexamethasone, 4 mg PO b.i.d. for 3 days before the beginning of treatment, may ameliorate or eliminate the skin rash.
a. Supplied as 500-mg vials
b. Dose modification. Reduce dosage in patients with abnormal renal function
c. Dose. 600 mg/m2 IV every 3 weeks as monotherapy; 500 mg/m2 IV every 3 weeks when used with cisplatin.
d. Drug interactions. Nonsteroidal anti-inflammatory drugs or other agents may inhibit the renal excretion of pemetrexed, resulting in increased drug toxicity. Thymidine rescues against the host toxic effects, and leucovorin decreases the antitumor effect of pemetrexed.
Q. Pentostatin [2′-deoxycoformycin (dCF), Nipent]
1. Indications. Chronic lymphocytic leukemia, hairy cell leukemia, and cutaneous T-cell lymphoma
2. Pharmacology. A fermentation product of Streptomyces antibioticus
a. Mechanism. Antimetabolite. Both cell cycle–specific and cell cycle–nonspecific. Inhibitor of adenine deaminase, an enzyme that is important for the metabolism of purine nucleosides. Also inhibits ribonucleotide reductase (resulting in inhibition of DNA synthesis and function) and S-adenosyl-L-homocysteine hydrolase (resulting in inhibition of one-carbon dependent methylation reactions).
b. Metabolism. Most dCF is excreted unchanged in urine.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Immunosuppression; mild nausea and vomiting, diarrhea, altered taste; fatigue, fever; erythematous, popular, vesiculobullous rashes.
c. Occasional. Chills, myalgia, arthralgia; abnormal LFTs; keratoconjunctivitis, photophobia; cough, renal failure.
d. Rare. Hepatitis; pulmonary infiltrates and insufficiency.
4. Administration. Hydration with at least 2 L of D5NSS is required to assure a urine output of 2 L on the day of drug administration.
a. Supplied as 10-mg vials
b. Dose modification. Reduce doses for renal impairment.
c. Dose. 4 mg/m2 IV infusion over 20 minutes every 2 weeks
d. Drug interactions. Pentostatin enhances the toxicity of vidarabine. CNS toxicity may be enhanced with the concomitant use of sedative and hypnotic drugs.
R. Pralatrexate (Folotyn)
1. Indications. Relapsed or refractory peripheral T-cell lymphoma
2. Pharmacology: An antineoplastic folate analog
a. Mechanisms. Competitively inhibits dihydrofolate reductase and polyglutamylation by the enzyme folylpolyglutamyl synthetase
b. Metabolism. Approximately 33% of the drug is excreted unchanged in the urine
3. Toxicity
a. Dose-limiting. Thrombocytopenia, neutropenia and mucositis
b. Common. Anorexia, nausea, vomiting, diarrhea, constipation; fatigue, fever, edema; rash
4. Administration. Supplement with vitamin B12 (1,000 μg IM every 8 to 10 weeks) and folic acid (1.0 to 1.25 mg PO daily)
a. Supplied as 20 mg/1 mL and 40 mg/2 mL vials
b. Dose modification: Use with caution with moderate to severe renal function impairment. Refer to the package insert for dose modifications for mucositis and cytopenias.
c. Dose: 30 mg/m2 IV push over 3 to 5 minutes weekly for 6 weeks in 7-week cycles
d. Drug interactions. Probenecid, nonsteroidal anti-inflammatory drugs, and trimethoprim/sulfamethoxazole may result in delayed renal clearance.
S. Raltitrexed (Tomudex)
1. Indications. Investigational in the United States, but used widely elsewhere for advanced colon cancer, breast cancer, and non–small cell lung cancer
2. Pharmacology
a. Mechanisms. Quinazoline antifolate analog with activity in the S phase of the cell cycle; metabolized intracellularly to higher polyglutamate forms that are 100-fold more potent than the parent compound and are retained within the cell; inhibits the folate-dependent enzyme thymidylate synthetase.
b. Metabolism. Cleared principally by the kidney as unchanged drug
3. Toxicity
a. Dose-limiting. Disabling fatigue and malaise (about 50% of patients)
b. Common. Diarrhea and/or mucositis (usually during the second cycle of treatment), myelosuppression, transient elevations of serum transaminases and bilirubin; mild nausea and vomiting.
4. Administration. Advise patients to avoid strenuous physical activity and activities that require mental alertness. Supplement dietary folate.
a. Supplied as 10-mL vials containing 1 mg/mL
b. Dose modification. Reduce dose with abnormal renal function.
c. Dose. 3 mg/m2 IV every 3 weeks
T. 6-Thioguanine (6-TG, 6-thioguanine, aminopurine-6-thiol-hemihydrate)
1. Indication. Acute myelogenous leukemia
2. Pharmacology
a. Mechanism. Purine analog with cell cycle-specific activity in the S phase. The drug requires intracellular phosphorylation by HGPRT to the cytotoxic monophosphate form, which is eventually metabolized to the triphosphate metabolite (see mercaptopurine). The drug is incorporated extensively into DNA, resulting in miscoding of transcription and DNA replication, and into RNA.
b. Metabolism. Thioguanine is not degraded by xanthine oxidase and, unlike mercaptopurine, can be given in full doses with allopurinol. Clearance of the drug is primarily hepatic, but also renal.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Stomatitis, diarrhea
c. Occasional. Nausea and vomiting, hepatic dysfunction, hepatic venoocclusive disease; decreased vibratory sensation, unsteady gait.
4. Administration
a. Supplied as 40-mg tablets
b. Dose modification. Dose is reduced with impaired liver function.
c. Dose depends on regimen.
U. Trimetrexate (Neutrexin, TMTX)
1. Indications. Approved for treatment of Pneumocystis carinii pneumonia and toxoplasmosis, but investigational in the United States as an anticancer agent; used widely elsewhere for colon cancer, head and neck cancer, and non–small cell lung cancer.
2. Pharmacology
a. Mechanisms. Lipid-soluble, quinazoline antifolate analog with activity in the S phase of the cell cycle; does not undergo polyglutamation (in contrast to MTX); inhibits dihydrofolate reductase, de novo thymidylate synthesis, and de novo purine synthesis.
b. Metabolism. Undergoes extensive metabolism in the liver by the P450 system to inactive forms.
3. Toxicity
a. Dose-limiting. Myelosuppression, mucositis
b. Common. Total alopecia (40%), mild nausea and vomiting, headache; maculopapular rash with pruritus and hyperpigmentation that begins at the neck and upper chest, progresses to the trunk and extremities, develops 5 days after treatment and resolves 7 to 10 days after onset.
4. Administration
a. Supplied as 5- and 30-mL multidose vials; incompatible with chloride-containing solutions.
b. Dose modification. Use with caution with abnormal renal or liver function or with hypoalbuminemia.
c. Dose. 8 to 12 mg/m2 IV for 5 consecutive days every 3 to 4 weeks
d. Drug interactions are possible with other drugs metabolized by the liver P450 system; leucovorin and thymidine rescue the host toxic effects; trimetrexate enhances antitumor activity of 5-FU.
III. ANTITUMOR ANTIBIOTICS
A. General pharmacology of antitumor antibiotics
1. Antitumor antibiotics generally are drugs derived from microorganisms. They usually are cell cycle–nonspecific agents that are especially useful in slow-growing tumors with low growth fractions.
2. They act by a variety of mechanisms. Several of these drugs interfere with DNA through intercalation, a reaction whereby the drug inserts itself between DNA base pairs. Intercalation with DNA prevents DNA replication and messenger RNA production, or both. Other drugs have other actions.
B. Actinomycin D (dactinomycin, Cosmegen)
1. Indications. Trophoblastic neoplasms, sarcomas, testicular carcinoma, Wilms’ tumor
2. Pharmacology
a. Mechanism. Intercalates between DNA base pairs and prevents synthesis of messenger RNA; inhibits topoisomerase II.
b. Metabolism. Unknown; extensively bound to tissues, resulting in long half-life in plasma and tissue. Excreted in bile and urine as unchanged drug.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Nausea and vomiting (often worsening after successive daily doses and lasting several hours); alopecia, acne, erythema, desquamation, hyperpigmentation; radiation-recall reaction. Drug is a vesicant that can cause necrosis if extravasated.
c. Occasional. Stomatitis, cheilitis, glossitis, proctitis, diarrhea; vitamin K antagonism, elevation of LFTs.
d. Rare. Hepatitis, anaphylaxis, hypocalcemia, lethargy
4. Administration. Premedicate patients with antiemetics. Administer through a running intravenous infusion with extravasation precautions.
a. Supplied as 0.5-mg vials
b. Dose modification. Reduce by 50% in the presence of renal or hepatic functional impairment.
c. Dose. 0.25 to 0.45 mg/m2 IV daily for 5 days every 3 to 4 weeks
d. Drug interactions. None known
C. Bleomycin (Blenoxane)
1. Indications. Lymphomas, squamous cell carcinomas, testicular carcinoma, malignant effusions
2. Pharmacology
a. Mechanism. Binds to DNA, thereby inhibiting synthesis of DNA and, to a lesser extent, RNA and proteins. Causes DNA strand cleavage by free radicals and inhibits DNA repair by a marked inhibition of DNA ligase. Cell-cycle G2-phase–specific; also active in late G1, S, and M phases.
b. Metabolism. Activated by microsomal reduction; bound to tissues but not to plasma protein; extensive degradation by hydrolysis in nearly all tissues. Both free drug and metabolic products are excreted into the urine.
3. Toxicity
a. Dose-limiting. Bleomycin pneumonitis with dyspnea, dry cough, fine moist rales, interstitial radiographic changes, reduced diffusing capacity, hypoxia, and hypocapnia may be lethal. Pulmonary fibrosis and insufficiency occur in 1% of patients receiving cumulative doses of <200 U/m2 and in 10% of patients receiving larger doses (see Chapter 29, Section IV.A, for further details). Advanced age, underlying pulmonary disease, prior or concomitant radiotherapy to the chest, and prior exposure to bleomycin predispose patients to pulmonary toxicity.
b. Common
(1) Hypersensitivity reactions with mild to severe shaking chills and febrile reactions are common (25% of patients), frequently occurring within 4 to 10 hours of injection. However, they decrease in incidence and severity with subsequent administrations.
(2) Sensitizes tumor and normal tissues to radiation
(3) Dermatologic (50% of patients): hyperpigmentation of skin stretch areas (e.g., knuckles, elbows), hyperpigmented striae; hardening, tenderness, or loss of fingernails; hyperkeratosis of palms and fingers, scleroderma-like changes; skin tenderness, pruritus, urticaria, erythroderma, desquamation, alopecia.
(4) Anorexia, mucositis; a rancid smell (“like old gym socks”) beginning about 10 seconds after injection.
c. Occasional. Nausea, vomiting, unusual tastes; mild reversible myelosuppression, Raynaud phenomenon, phlebitis, pain at injection site.
d. Rare
(1) Hepatotoxicity, pleuropericarditis, arteritis
(2) Anaphylaxis-like reaction develops in 1% to 7% of patients who have lymphoma, usually after the first or second dose and particularly if the dose is 25 U/m2 or more. This idiosyncratic reaction manifests confusion, faintness, fever, chills, and wheezing that can progress to hypotension, renal failure, and cardiovascular collapse.
4. Administration. A 2-U test dose is given before the first treatment, followed by a 1- to 2-hour observation period to reduce the potential for cardiovascular collapse.
a. Supplied as 15- and 30-U (mg) vials
b. Dose modification. The drug should not be given to patients with symptomatic chronic obstructive lung disease. It must be discontinued in patients who have erythroderma (continued treatment may lead to fatal exfoliative dermatitis). The drug must also be discontinued if there are symptoms or signs of interstitial lung disease. Routine pulmonary function tests are generally not helpful; some authorities recommend monitoring carbon monoxide–diffusing capacity. Dosage should be reduced in patients with renal insufficiency.
c. Dose. Avoid cumulative dosage of >400 U; some physicians limit the total dose to 300 U.
(1) 10 to 20 U/m2 IM, IV, or SC once or twice weekly (twice-weekly doses >20 U each are likely to cause serious toxic reactions of the skin), or
(2) 15 to 20 U/m2 daily for 3 to 7 days by continuous infusion, or
(3) 60 U/m2 dissolved in 100 mL of normal saline for intracavitary therapy
d. Drug interactions
(1) Filgrastim (granulocyte colony stimulating factor) may increase pulmonary toxicity.
(2) Radiation therapy and high oxygen concentrations enhance pulmonary toxicity.
(3) Bleomycin may reduce serum concentrations of digoxin, phenytoin, or zidovudine.
D. Daunorubicin hydrochloride (daunomycin, rubidomycin, Cerubidine). Liposomal daunomycin citrate (DaunoXome) is also available.
1. Indication. Acute leukemias, Kaposi sarcoma
2. Pharmacology. Anthracycline antitumor antibiotic. Essentially the same as doxorubicin. Active metabolite, which is formed in the liver, is daunomycinol. Cell cycle–nonspecific. Excreted through the hepatobiliary system, with renal clearance accounting for <20% of drug elimination.
3. Toxicity. Same as doxorubicin. Daunorubicin may also cause precipitous fatal cardiomyopathy months after therapy has stopped; incidence becomes unacceptable after a total dose of 500 to 600 mg/m2 has been given.
4. Administration. Same as doxorubicin. Use extravasation precautions.
a. Supplied as 20-mg vials
b. Dose modification. Same as doxorubicin
c. Dose. 45 to 60 mg/m2 IV daily for 3 days
d. Drug interactions. Similar to doxorubicin.
E. Doxorubicin (hydroxydaunorubicin, Adriamycin, Rubex)
1. Indications. Effective in a large variety of tumors
2. Pharmacology
a. Mechanism. Anthracycline antitumor antibiotic. Intercalates between DNA base pairs, forms free radicals, alters cell membranes, induces topoisomerase II–dependent DNA damage, inhibits preribosomal DNA and RNA. Cell cycle–phase nonspecific.
b. Metabolism. About 70% of the drug is bound to plasma proteins. Rapidly metabolized by the liver to other compounds, some of which are cytotoxic (including the active metabolite doxorubicinol). The release rate from tissue binding sites is slow compared with the capacity of the liver for metabolism; this results in relatively prolonged plasma levels of drug and metabolites.
c. Excretion. Metabolites and free drug are extensively excreted in the bile; however, known elimination accounts for only half of the drug. The rate of drug elimination and its toxicity thus is rarely limited by liver function. Some chromogens are excreted through the kidney, occasionally imparting a red tinge to the urine.
3. Toxicity
a. Dose-limiting
(1) Myelosuppression, particularly leukopenia
(2) Cardiomyopathy with congestive heart failure, which may become refractory (see Chapter 29, Section VI.D, for further details). Monitor the left ventricular ejection fraction with radionuclide angiography before initiation of treatment, particularly when the cumulative dose exceeds 300 mg/m2, and periodically thereafter. Risks and benefits should be considered at total cumulative doses of 550 mg/m2 (400 mg/m2 with a history of mediastinal irradiation) or for electrocardiographic changes (voltage reduction, significant arrhythmias, ST-T wave changes). Dexrazoxane (see Section X.B), a cardioprotectant, can be considered when the cumulative dose exceeds 300 mg/m2.
b. Common
(1) Alopecia (nearly 100% of patients when administered as a bolus every 3 to 4 weeks, but minimal when the dose is divided and given weekly); nausea and vomiting (mild to severe); stomatitis
(2) Doxorubicin is a vesicant; extravasation of the drug results in severe ulceration and necrosis.
(3) Previously irradiated skin sites may become erythematous and desqua-mate when the drug is started; this radiation-recall reaction can occur years after radiation was given.
c. Occasional. Diarrhea; hyperpigmentation of nail beds and dermal creases, facial flush, flush along injected vein, skin rash; conjunctivitis, lacrimation; red-colored urine.
d. Rare. Activation of fibrinolysis, interstitial pneumonitis, muscle weakness, fever, chills, anaphylaxis
4. Administration. The drug must be slowly pushed through a running intravenous line using extravasation precautions or continuously infused through a central venous line as it is a vesicant.
a. Supplied as multidose vials
b. Dose modification. Doxorubicin should not be given to patients with congestive heart failure from any cause. The package insert recommends reduction of dose by 50% for serum bilirubin of 1.2 to 3.0 mg/dL and by 75% for bilirubin of 3 to 5 mg/dL (but see Section III.E.2.c).
c. Dose. 50 to 75 mg/m2 IV bolus every 3 to 4 weeks or 10 to 20 mg/m2 IV weekly
d. Drug interactions
(1) Dexrazoxane (Zinecard) inhibits doxorubicin’s cardiotoxic effects.
(2) Trastuzumab (Herceptin) and cyclophosphamide potentiate cardiotoxicity.
(3) Barbiturates increase the plasma clearance of doxorubicin, decreasing its therapeutic effect.
(4) Paclitaxel, cyclosporine, and verapamil may increase serum doxorubicin levels.
(5) Digoxin and quinolone antibiotics (e.g., ciprofloxacin) may have reduced oral absorption.
(6) Antiepileptic drugs (e.g., carbamazepine, phenytoin) serum levels may be decreased
F. Doxorubicin, liposomal (Doxil, Caelyx)
1. Indications. Kaposi sarcoma with acquired immunodeficiency syndrome (AIDS), ovarian carcinoma, myeloma
2. Pharmacology. Doxorubicin is encapsulated in long-circulating liposomes (microscopic vesicles composed of a phospholipid bilayer). For mechanisms and metabolism, see doxorubicin. The plasma clearance is slower than standard doxorubicin.
3. Toxicity
a. Dose-limiting. Hematosuppression
b. Common. Fatigue; mucositis, diarrhea, nausea, vomiting; alopecia; infusion reactions (7%; chills, facial swelling, headache, hypotension, shortness of breath), which resolve on interruption of infusion and which do not preclude continued treatment; palmar–plantar erythrodysesthesia (ulceration, erythema, and desquamation on the hands and feet with pain and inflammation).
c. Occasional. Cardiomyopathy at cumulative doxorubicin doses above 400 mg/m2, pain at injection site, radiation-recall reaction; asthenia, pain, fever; red-orange discoloration of urine.
d. Rare. Allergic reaction, hyperglycemia, jaundice, optic neuropathy
4. Administration
a. Supplied as 20- and 50-mg vials
b. Dose modification. Same as for doxorubicin
c. Dose
(1) Kaposi sarcoma in AIDS: 20 mg/m2 IV over 30 minutes every 2 or 3 weeks
(2) Ovarian carcinoma: 40 to 50 mg/m2 IV over 1 to 2 hours every 4 weeks
d. Drug interactions. Similar to doxorubicin.
G. Epirubicin (4′-epidoxorubicin, pidorubicin, Ellence) is the 4′-epimer of doxorubicin and is a semisynthetic derivative of daunorubicin. An epimer is one of a pair of isomers that differ only in the position of the H- and OH- attached to one asymmetric carbon atom.
1. Indication. Breast and gastric cancers
2. Pharmacology. Anthracycline antitumor antibiotic. For mechanisms and metabolism, see doxorubicin.
3. Toxicity. Same as doxorubicin, but with more nausea and vomiting. The risk of developing cardiomyopathy increases substantially after a total dose of 900 mg/m2 (without mediastinal radiation or treatment with other anthracyclines).
4. Administration. Intravenously over 5 minutes using extravasation precautions
a. Supplied as 50- and 200-mg vials
b. Dose modification. Same as for doxorubicin
c. Dose. 50 to 100 mg/m2 IV every 3 weeks in combination chemotherapy regimens
d. Drug interactions. Cimetidine increases plasma levels of epirubicin and should be discontinued upon starting epirubicin. Others are similar to doxorubicin.
H. Idarubicin (4-demethoxydaunorubicin, Idamycin)
1. Indication. Acute leukemia
2. Pharmacology. Anthracycline antitumor antibiotic; an analog of daunorubicin. More lipophilic and better cell uptake than other anthracycline antibiotics; otherwise similar to doxorubicin. The active metabolite is 13-epirubicinol.
3. Toxicity. Similar to doxorubicin. Myelosuppression is expected. Although idarubicin is less cardiotoxic than doxorubicin and daunorubicin, the same monitoring criteria apply.
4. Administration. Intravenously over 15 minutes using extravasation precautions.
a. Supplied as 5-, 10-, and 20-mg vials
b. Dose modification. Same as doxorubicin
c. Dose. 12 mg/m2 IV daily for 3 days with induction therapy
d. Drug interactions. Similar to doxorubicin.
I. Mitomycin (mitomycin C, Mutamycin)
1. Indications. Adenocarcinomas of the stomach or pancreas
2. Pharmacology
a. Mechanism. Antitumor antibiotic. After intracellular activation, functions as an alkylating agent; DNA cross-linking, DNA depolymerization, and free-radical formation.
b. Metabolism. Metabolized predominantly in the liver by the P450 system and DT-diaphorase. Excreted mainly through the hepatobiliary system.
3. Toxicity
a. Dose-limiting. Cumulative myelosuppression, which may be severe and prolonged (particularly thrombocytopenia)
b. Common. Mild nausea and vomiting, anorexia; alopecia, desquamation; a vesicant drug that can cause necrosis if injected subcutaneously (skin erythema and ulceration can occur weeks to months after administration and may appear at a site distant from the site of injection)
c. Occasional. Alopecia, stomatitis, skin rashes, photosensitivity, pain at site of injection, phlebitis; congestive heart failure; hemolytic-uremic–like syndrome (HUS)
d. HUS usually occurs after 6 months of therapy or cumulative doses of at least 60 mg. The course may be chronic or fulminant. Blood transfusions may worsen symptoms. Plasmapheresis may be indicated for treatment.
e. Rare. Hepatic and renal (cumulative) dysfunction, paresthesias, blurred vision, fever; acute interstitial pneumonitis
4. Administration. Administer through a running intravenous infusion using extravasation precautions as the drug is a vesicant.
a. Supplied as 5-, 20-, and 40-mg vials
b. Dose modification. Reduce dose by 50% to 75% for patients who were previously treated with extensive irradiation or who developed a white blood cell count of <2,000/μL with prior doses of mitomycin. Also reduce dose for liver dysfunction.
c. Dose
(1) Single agent: 10 to 20 mg/m2 IV every 6 to 8 weeks, or
(2) In combination: 5 to 10 mg/m2 IV every 5 weeks
d. Drug interactions.
(1) Use of vinca alkaloids in patients who have previously or simultaneously received mitomycin has resulted in acute shortness of breath and bronchospasm.
(2) Anthracycline-induced cardiomyopathy is increased with mitomycin.
J. Mitoxantrone (Novantrone, dihydroxyanthracenedione)
1. Indications. Breast and prostate cancer, lymphoma, acute leukemia
2. Pharmacology. Mitoxantrone is in the anthracenedione class of compounds, which are analogs to the anthracyclines. Its mechanism of action and routes of metabolism are similar but not identical to doxorubicin.
a. Mechanism. DNA intercalation, single- and double-strand DNA breakage, inhibition of topoisomerase II
b. Metabolism. Metabolized by the liver’s P450 system; <1% of the drug is excreted in the urine.
3. Toxicity. Compared with the anthracyclines, mitoxantrone is associated with less cardiotoxicity, less nausea and vomiting, and decreased potential for extravasation injury.
a. Dose-limiting. Myelosuppression (nadir at 10 to 14 days)
b. Common. Mild nausea and vomiting, mucositis; alopecia (usually mild); edema, fatigue; blue discoloration of urine, sclerae, fingernails, and over venous site of injection that may last 48 hours.
c. Occasional. Cardiomyopathy (most well defined for patients who have previously received other anthracyclines, cyclophosphamide, or mediastinal radiation or have preexisting cardiovascular disease); appears to be less cardiotoxic than doxorubicin. Pruritus, LFT abnormalities, allergic reactions.
d. Rare. Jaundice, seizures, pulmonary toxicity, anaphylaxis
4. Administration as a 30-minute infusion; rarely causes extravasation injury if infiltrated.
a. Supplied as multidose vials
b. Dose modification. Hematologic
c. Dose. 10 to 12 mg/m2 IV given every 3 weeks for solid tumors
d. Drug interactions. Cyclosporine may increase mitoxantrone levels. Quinolone antibiotics (e.g., ciprofloxacin) oral absorption may be decreased.
IV. MITOTIC SPINDLE AGENTS
A. General pharmacology of mitotic spindle agents. Mitotic spindle inhibitors are classically represented by vincristine and vinblastine. These drugs bind to microtubular proteins, thus inhibiting microtubule assembly (M phase of the cell cycle) and resulting in dissolution of the mitotic spindle structure. Taxanes (paclitaxel and docetaxel) not only bind to microtubules but also promote microtubule assembly and resistance to depolymerization, resulting in the production of nonfunctional microtubules.
B. Paclitaxel (Taxol)
1. Indications. Carcinomas of the breast, ovary, lung, esophagus, and other sites; AIDS-associated Kaposi sarcoma.
2. Pharmacology. Isolated from the bark of the Pacific yew tree, Taxus brevifolia
a. Mechanism. Plant alkaloid (antimicrotubule agent); see Section IV.A.
b. Metabolism. Extensively metabolized by the hepatic P450 microsomal system. More than 75% of the drug is excreted in the feces.
3. Toxicity
a. Dose-limiting
(1) Neutropenia, particularly in patients who were previously heavily treated or who received cisplatin just before paclitaxel
(2) Hypersensitivity (up to 40%) is manifested by cutaneous flushing, hypotension, bronchospasm, urticaria, diaphoresis, pain, or angioedema. Reactions usually develop within 10 minutes of starting the treatment; 90% of hypersensitivity reactions develop after the first or second dose. Anaphylaxis occurs in about 3% of patients. Reactions may be caused by Cremophor EL or by the drug itself.
(3) Peripheral neuropathy, particularly in the higher dosage schedules and in patients with concomitant etiologies for peripheral neuropathy. Neurotoxicity occurs less frequently when infused over 24 hours (5%) than when infused over 3 hours (25% to 75%). The distribution typically is “stocking-glove” and consists of dysesthesias, paresthesias, and loss of proprioception which usually resolve within a few months.
b. Common. Alopecia (90%; usually total and sudden, within 3 weeks of treatment); thrombocytopenia (usually not severe); transient arthralgias and myalgias within 3 days of treatment and lasting for about 1 week (ameliorated by nonsteroidal anti-inflammatory agents and prednisone); diarrhea, transient bradycardia (usually asymptomatic)
c. Occasional. Nausea, vomiting, taste changes, mucositis (cumulative), diarrhea; atrioventricular conduction defects, ventricular tachycardia, cardiac angina; necrosis when extravasated; intoxication when infused over 1 hour (because of high alcohol content in the preparation); onycholysis, elevated LFTs
d. Rare. Paralytic ileus, generalized weakness, seizures; myocardial infarction, interstitial pneumonia
4. Administration. Paclitaxel should be given before cisplatin in combination with regimens in which both are administered. Cardiac monitoring is recommended for patients with a history of cardiac disease. Use with caution in patients who have a history of myocardial infarction within the previous 6 months or who are on medications known to alter cardiac conduction. Administer with extravasation precautions; the drug is a vesicant.
a. Supplied as multidose vials formulated in polyoxyethylated castor oil (Cremophor EL) and alcohol
b. Dose modification. Hematologic and with hepatic dysfunction. Use with caution with diabetes mellitus, or prior therapy with neurotoxic drugs, such as cisplatin.
c. Dose
(1) Premedications: Dexamethasone, 20 mg PO or IV is given 12, 6, and 0.5 hours before paclitaxel; diphenhydramine, 50 mg IV, and ranitidine, 50 mg IV, given 30 minutes before administering paclitaxel.
(2) Every 3 to 4 weeks: 135 to 175 mg/m2 infused over 3 to 24 hours
(3) Weekly: 80 to 100 mg/m2 for 3 weeks with 1 week rest
d. Drug interactions. Paclitaxel is a radiosensitizing agent.
(1) Barbiturates, phenytoin, and other drugs that the liver’s cytochrome P450 CYP3A4 and CYP2C enzymes may affect paclitaxel metabolism (see Section VI.A).
(2) Carboplatin, cisplatin, or cyclophosphamide decrease paclitaxel’s clearance and thus increase myelosuppression; they should be administered after paclitaxel.
C. Paclitaxel, protein-bound (nab-paclitaxel, albumin-bound paclitaxel, Abraxane)
1. Indications. Metastatic breast cancer
2. Pharmacology. This injectable suspension contains paclitaxel protein-bound particles.
a. Mechanisms. See paclitaxel
b. Metabolism. See paclitaxel
3. Toxicity
a. Dose-limiting. Neutropenia
b. Common. Hematosuppression, sensory neuropathy, arthralgias/myalgia (usually transient), gastrointestinal disturbances, alopecia, fatigue
c. Occasional. Abnormal liver function tests, fluid retention
4. Administration. Premedication with corticosteroids to prevent hypersensitivity reactions is not required for Abraxane. Administer IV over 30 minutes.
a. Supplied as vials containing 100-mg of paclitaxel and 900 mg of albumin
b. Dose modification. For neutropenia, hepatic dysfunction, and sensory neuropathy
c. Dose. 260 mg/m2 IV over 30 minutes every 3 weeks
D. Cabazitaxel (Jevtana)
1. Indications. Hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen
2. Pharmacology
a. Mechanisms. A microtubule inhibitor binds to tubulin and promotes its assembly into microtubules, while simultaneously inhibiting disassembly, resulting in the inhibition of mitotic and interphase cellular functions.
b. Metabolism. Extensively metabolized in the liver, mainly by the CYP3A4/5 isoenzyme. Excreted mainly in the feces as numerous metabolites (renal excretion is <5%).
3. Toxicity
a. Dose-limiting. Severe hypersensitivity reactions (do not give to patients with a history of hypersensitivity reactions to other drugs formulated with polysorbate 80), severe neutropenia
b. Common. Pancytopenia (>90%); diarrhea, nausea, vomiting, abdominal pain; peripheral neuropathy, dysgeusia; fever, fatigue, alopecia (10%), dyspnea, arthralgia
c. Occasional. Renal failure, arrhythmia, mucositis
4. Administration. Premedicate with antihistamine (e.g., diphenhydramine 25 mg), corticosteroid (e.g., dexamethasone 8 mg), H2 antagonist (e.g., ranitidine 50 mg), and antiemetic.
a. Supplied as 60 mg/1.5 mL vial
b. Dose modification: Do not administer if neutrophils are ≤1,500/μL or if there is hepatic impairment. Reduce dose to 20 mg/m2 for prolonged grade ≥3 neutropenia or grade ≥3 diarrhea, febrile neutropenia.
c. Dose: 25 mg/m2 IV over 1 hour every 3 weeks plus prednisone (10 mg daily) throughout cabazitaxel treatment
d. Drug interactions. Strong inducers or inhibitors of CYP3A are expected to affect the pharmacokinetics of cabazitaxel (see Section VI.A.).
E. Docetaxel (Taxotere)
1. Indications. Cancers of the breast, lung, stomach, esophagus, and head and neck; hormone-refractory prostate cancer
2. Pharmacology. The drug is prepared by semisynthesis beginning with a precursor extracted from the needles of the European yew tree.
a. Mechanisms. Inhibitor of microtubular depolymerization (see Section IV.A). The binding of docetaxel to microtubules does not alter the number of protofilaments in the bound microtubules, which differs from most spindle poisons currently in clinical use.
b. Metabolism. Extensively metabolized by the hepatic P450 microsomal system. More than 75% is excreted in feces and a small percentage in urine.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Alopecia (80% except with the weekly schedule), maculopapular rash and dry itchy skin, discoloration of finger nails; mucositis, diarrhea; fatigue, fever
c. Occasional
(1) Severe hypersensitivity reactions (<5%) despite premedications
(2) Fluid retention that is cumulative in incidence and severity (especially after a cumulative dose of 705 mg/m2) is reversible (usually within 8 months); the fluid retention usually affects the lower extremities but can also result in ascites or pleural or pericardial effusions.
(3) GI upset, severe nail reactions; hypotension; transiently elevated liver function tests
(4) Peripheral neuropathy, which is less common than with paclitaxel, is mainly sensory, but motor or autonomic neuropathy and CNS effects are also seen.
d. Rare. Cardiac events
4. Administration
a. Supplied as 20- and 80-mg vials in polysorbate 80, which is less allergenic than Cremophor EL, which is used for paclitaxel
b. Dose modification. Patients with elevated serum bilirubin or significantly elevated liver enzymes should generally not receive docetaxel.
c. Dose
(1) 60 to 100 mg/m2 IV over 1 hour every 3 weeks; give dexamethasone, 4 mg PO b.i.d. on the day before, the day of, and the day after docetaxel administration to reduce the incidence and severity of fluid retention and hypersensitivity reactions.
(2) 35 mg/m2 weekly for 3 weeks of a 4-week cycle (the weekly schedule is associated with less hematologic toxicity and no hair loss; it requires a maximum of 4 mg dexamethasone on the morning and evening of dosing)
d. Drug interactions. Docetaxel is a radiosensitizing agent. Barbiturates, phenytoin, and other drugs that the liver’s cytochrome P450 CYP3A4 enzyme may affect docetaxel metabolism (see Section VI.A). St. John’s wort may lower docetaxel concentrations.
F. Eribulin (Halaven)
1. Indications. Metastatic breast cancer
2. Pharmacology
a. Mechanisms. A nontaxane microtubule inhibitor which is a halichondrin B analog. It inhibits formation of mitotic spindles causing arrest of the cell cycle at the G2/M phase; suppresses microtubule polymerization without affecting depolymerization.
b. Metabolism. Negligible; more than 80% excreted in the feces as unchanged drug.
3. Toxicity
a. Dose-limiting. Hematosuppression; peripheral neuropathy
b. Common. Neutropenia (>80%), anemia; nausea, vomiting, stomatitis, constipation, diarrhea, ALT elevation; alopecia (45%); fatigue, fever, headache; peripheral neuropathy which may be prolonged (35%), arthralgia/myalgias, bone pain, limb pain; QT interval prolongation
c. Occasional. Rash, lacrimation, dysgeusia
d. Rare. Pharyngolaryngeal pain.
4. Administration. Infuse IV over 2 to 5 minutes
a. Supplied as 2 mL vial containing 0.5 mg/mL
b. Dose modification: Dose reduction is required for mild to moderate hepatic impairment or renal impairment
c. Dose: 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. Use 1.1 mg/m2 for creatinine clearance 30 to 50 mL/min or for Child-Pugh class A hepatic impairment; 0.7 mg/m2 for Child-Pugh class B hepatic impairment.
d. Drug interactions.
(1) May enhance the QT prolonging effect of antiarrhythmic agents and may decrease the absorption of cardiac glycosides
(2) May increase the serum concentration of CYP3A4 substrates
G. Estramustine (Emcyt, Estracyte)
1. Indication. Progressive prostate cancer
2. Pharmacology. Structurally, estramustine is a combination of estradiol phosphate and nornitrogen mustard.
a. Mechanism. Cell cycle–specific agent with activity in the mitosis (M) phase by binding to microtubule-associated proteins. Although initially designed as an alkylating agent, it has no alkylating activity.
b. Metabolism. Rapidly dephosphorylated in GI tract and metabolized primarily in the liver. About 20% of the drug is excreted in the urine.
3. Toxicity. Similar to estrogens
a. Dose limiting. Thromboembolism
b. Common. Diarrhea; nausea and vomiting (usually mild); skin rash. Gynecomastia in up to 50% of patients (can be prevented by prophylactic irradiation).
c. Rare. Myelosuppression, cardiovascular complications
4. Administration. Contraindicated in patients with active thrombophlebitis or thromboembolic disorders
a. Supplied as 140-mg capsules
b. Dose. 600 mg/m2/d in three divided doses; taken with water 1 hour before meals or 2 hours after meals. Calcium-rich foods may impair drug absorption.
H. Ixabepilone (Ixempra)
1. Indications. Refractory locally advanced or metastatic breast cancer either as monotherapy or in combination (e.g., with capecitabine)
2. Pharmacology. The drug is an epothilone B analog.
a. Mechanisms. Binds to the β-tubulin subunit of the microtubule, thus arresting the cell cycle at the G2/M phase and inducing apoptosis
b. Metabolism. Extensive hepatic metabolism via CYP3A4 into inactive metabolites. Excreted mostly in the feces, <10% as unchanged drug. The drug has minimal renal excretion.
3. Toxicity. Cognitive impairment (due to ethanol content of diluent) or hypersensitivity reactions (related to the Cremophor in the diluent) may occur.
a. Dose-limiting. Myelosuppression (particularly neutropenia; grade 4 in 15% to 25%) and peripheral neuropathy (60%)
b. Common. Alopecia (50%), headache, fatigue, mucositis, GI disturbance, myalgia/arthralgia (50%)
c. Occasional. Edema, fever, dizziness, palmar–plantar dysesthesia (hand–foot syndrome), skin and nail disorders, hyperpigmentation, motor neuropathy, dysgeusia, increased lacrimation, dyspnea
4. Administration. Premedicate with an H1-antagonist drug (e.g., diphenhydramine, 50 mg) and an oral H2-antagonist (e.g., ranitidine, 150 to 300 mg). Premedicate with corticosteroids for those with hypersensitivity reactions. The drug is classified as an irritant.
a. Supplied as 15 and 45 mg as a powder (diluent contains ethanol and purified polyoxyethylated castor oil [Cremophor® EL])
b. Dose modification. With hepatic dysfunction, reduce dosage when given as monotherapy and do not use in combination with capecitabine. Reduce dose for neuropathy or for severe or prolonged neutropenia or thrombocytopenia. Use with caution in patients with a history of cardiovascular disease.
c. Dose. 40 mg/m2 IV over 3 hours every 3 weeks (maximum 88 mg)
d. Drug interactions. CYP3A4 inducers and inhibitors may decrease or increase the levels or effects of ixabepilone, respectively (see Section VI.A). If concurrent use of a strong CYP3A4 inhibitor cannot be avoided, reduce dosage to 20 mg/m2; if the inhibitor is discontinued, allow about 1 week before the ixabepilone dose is increased. Avoid St. John’s wort and grape juice. Ixabepilone is contraindicated in patients with hypersensitivity to Cremophor EL or drugs containing this excipient (e.g., injectable paclitaxel, cyclosporine, teniposide).
I. Vinblastine (vinca leukoblastine, Velban, Vlb)
1. Indications. Lymphomas, testicular carcinoma, Kaposi sarcoma
2. Pharmacology
a. Mechanism. Periwinkle plant alkaloid; see Section IV.A. Binds to micro-tubular proteins. Inhibits RNA synthesis by affecting DNA-dependent RNA polymerases. Cell cycle–phase specific; it arrests cells at the G2-phase and M-phase interface.
b. Metabolism. Highly bound to plasma proteins and to formed blood elements, especially platelets. Metabolized by the hepatic P450 microsomal system to active and inactive metabolites. Predominantly excreted in bile. Minimal free drug is recovered in urine.
3. Toxicity
a. Dose-limiting. Neutropenia
b. Common. Cramps or severe pain in jaw, pharynx, back, or limbs after injection
c. Occasional. Thrombocytopenia, anemia, alopecia (10%); SIADH, hypertension, Raynaud phenomena, neuropathy
d. Rare. Nausea, vomiting, diarrhea, mucositis, abdominal cramps, GI hemorrhage; acute interstitial pneumonitis (especially when administered with mitomycin C); ischemic cardiotoxicity
4. Administration. Administered by rapid infusion through the tubing of a running intravenous line with extravasation precautions because vinblastine is a vesicant
a. Supplied as 10-mg vials
b. Dose modification. Decrease dose by 50% for patients with serum bilirubin >3.0 mg/dL and by 75% for 3 to 5 mg/dL.
c. Dose. 5 mg/m2 IV every 1 or 2 weeks
d. Drug interactions
(1) Phenobarbital, calcium channel blockers, cimetidine, metoclopramide, and other drugs that inhibit the liver’s P450 system (see Section VI.A) may lead to increased production of metabolites. Vbl should be used cautiously in patients receiving these medications.
(2) Phenytoin levels are decreased with vinblastine treatment.
(3) Mitomycin C given within 2 weeks of Vbl may result in severe bronchospasm.
J. Vincristine (leurocristine, Oncovin, Vcr)
1. Indications. A wide variety of malignancies
2. Pharmacology
a. Mechanism. Same as vinblastine
b. Metabolism. Same as vinblastine
3. Toxicity
a. A dose-dependent peripheral neuropathy universally develops. Cranial nerves and the autonomic system may also be involved. The neuropathies usually reverse within several months. Jaw, throat, or anterior thigh pain occurring within hours of injection disappears within days and usually does not recur.
(1) Dose-limiting. Severe paresthesias, ataxia, foot-drop (slapping gait), muscle-wasting cranial nerve palsies, paralytic ileus, obstipation, abdominal pain, optic atrophy, cortical blindness, seizures
(2) Not dose-limiting. Mild hypoesthesia, mild paresthesias, transient jaw pain (and similar syndromes), loss of deep tendon reflexes, constipation
b. Common. Alopecia (20% to 50%)
c. Occasional. Mild leukopenia (does not have significant effect on erythrocytes or platelets), rash; polyuria, urinary retention; acute jaw or joint pain, optic nerve atrophy
d. Rare. Nausea, vomiting, pancreatitis; fever. SIADH
4. Administration. Patients receiving Vcr should be given bulk laxatives routinely. Administered by rapid infusion using extravasation precautions because Vcr is a vesicant.
a. Supplied as 1- and 2- mg vials
b. Dose modification. Hepatic dysfunction; same as for vinblastine
c. Dose. 1.0 to 1.4 mg/m2 IV every 1 to 4 weeks (often limited to 2 mg per dose in adults); continuous infusion regimens involve 0.4 to 0.5 mg/d for 4 days.
d. Drug interactions
(1) Barbiturates, calcium channel blockers, cimetidine, metoclopramide, and other drugs that inhibit the liver’s P450 system (see Section VI.A) may lead to increased production of metabolites. Vcr should be used cautiously in patients receiving these medications.
(2) Phenytoin and digoxin blood levels are decreased with Vcr treatment.
(3) Ototoxic agents (e.g., aminoglycosides, cisplatin, erythromycin, furosemide) increase risk for auditory and vestibular toxicity when given concomitantly with Vcr.
(4) Filgrastim (Neupogen), when used concurrently with Vcr, may result in severe atypical neuropathy.
(5) L-asparaginase should be given 12 to 24 hours after Vcr because that drug inhibits Vcr clearance.
(6) Mitomycin C given within 2 weeks of Vcr may result in severe bronchospasm.
K. Vindesine (desacetylvinblastine amide sulfate, Eldisine)
1. Indications. Experimental for lung cancer, leukemias, and others
2. Pharmacology. Same as vinblastine
3. Toxicity. Same as vinblastine, but alopecia is more common with vindesine. Neurotoxicity is same as for vincristine but is generally less severe.
4. Administration. Same as vinblastine
a. Supplied as 10-mg vials
b. Dose modification. Necessary for patients with hepatic dysfunction; same as for vinblastine
c. Dose. 3 to 4 mg/m2 IV every 7 to 14 days
L. Vinorelbine (Nvb, Navelbine)
1. Indications. Non–small cell lung cancer, ovarian cancer, breast cancer, and lymphoma
2. Pharmacology. A semisynthetic alkaloid derived from vinblastine
a. Mechanisms. Inhibits tubular polymerization, disrupting formation of tubules during mitosis (see Section IV.A)
b. Metabolism. The majority of the drug is metabolized in the liver by the cytochrome P450 microsomal system. Drug and metabolites are excreted in bile.
3. Toxicity
a. Dose-limiting. Myelosuppression, especially neutropenia
b. Common. Fatigue; mild to moderate peripheral neuropathy; nausea, vomiting, constipation, diarrhea
c. Occasional. Stomatitis; jaw pain, myalgias/arthralgias; allergic-type pulmonary reactions; nausea, vomiting, transient abnormalities in LFTs
d. Rare. Thrombocytopenia; hemorrhagic cystitis, SIADH, interstitial pneumonia
4. Administration. Same as vinblastine
a. Supplied as 10- and 50-mg vials
b. Dose modification. Reduce dose for hyperbilirubinemia (similar to vinblastine) or neutropenia
c. Dose. 15 to 30 mg/m2 IV weekly
d. Drug interactions
(1) Barbiturates, calcium channel blockers, cimetidine, metoclopramide, and other drugs that inhibit the liver’s P450 system (see Section VI.A) may lead to increased production of metabolites.
(2) Paclitaxel potentiates neuropathy.
(3) Cisplatin increases the incidence of granulocytopenia.
(4) Mitomycin C given within 2 weeks of Nvb may result in severe bronchospasm.
V. TOPOISOMERASE INHIBITORS
A. General pharmacology of topoisomerase inhibitors. DNA is attached at regular intervals to the nuclear matrix at sites called domains, which are wound together with their paired DNA molecules. DNA topoisomerases are enzymes that alter DNA topology by causing and resealing DNA strand breaks. Topoisomerases bind to DNA domains, forming a “cleavable complex,” which allows DNA to unwind in preparation for cell division. Topoisomerase I relaxes supercoiled DNA for a variety of crucial cellular processes. Topoisomerase II catalyzes the double-stranded breaking and resealing of DNA, thereby allowing the passage of one double helical segment of DNA through another. They relax superhelical turns, interconvert knotted rings, and intertwist complementary viral sequences into DNA. Topoisomerases are essential for such events as transcription, replication, and mitosis.
Of all the topoisomerases, groups I and II are the targets of cytotoxic agents. Camptothecin derivatives (irinotecan, topotecan) exert their cytotoxic effect by inhibiting topoisomerase I. Epipodophyllotoxin derivatives (etoposide, teniposide) inhibit topoisomerase II. Drugs from other classes (e.g., amsacrine and the anthracyclines) also inhibit topoisomerases as part of their mechanism of action. Inhibition of topoisomerase interferes with transcription and replication by causing DNA damage, inhibition of DNA replication, failure to repair strand breaks, and, then, cell death.
B. Etoposide (VP-16, VePesid, Toposar; oral form is etoposide phosphate [Etopophos])
1. Indications. Testicular carcinoma, small cell lung cancer, lymphoma, and other malignancies
2. Pharmacology. An epipodophyllotoxin extracted from the Podophyllum peltatum mandrake plant
a. Mechanisms. A topoisomerase II inhibitor (see Section V.A); cell cycle–phase specific at G2, late S, and M phases
b. Metabolism. Highly bound to plasma proteins (mainly albumin); decreased albumin levels result in potentially greater host toxicity. Metabolized by the liver via glucuronidation to less active metabolites. Excreted in urine (40%) as intact and degraded drug; excretion of the remaining 60% is uncertain.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Nausea and vomiting (with oral dosing, but uncommon with intravenous dosing); alopecia (usually mild); hypotension if rapidly infused; malaise, metallic taste during drug infusion
c. Occasional. Anemia, thrombocytopenia, pain at injection site, phlebitis, abnormal LFTs, diarrhea, chills, fever
d. Rare. Stomatitis, dysphagia, diarrhea, constipation, parotitis, rash, radiation-recall reaction, hyperpigmentation; anaphylaxis, transient hypertension, arrhythmias; somnolence, vertigo, transient cortical blindness; peripheral neuropathy, anaphylactoid reaction
4. Administration. Administer slowly over 30 to 60 minutes when given intravenously to avoid hypotension.
a. Supplied as 50-mg capsules and multidose vials
b. Dose modification. Administer with caution in the presence of renal dysfunction; reduce doses by 25% or 50% for creatinine clearance levels of <50 and <10 mL/min, respectively. Dose reduction is also recommended for patients with abnormal liver function (hyperbilirubinemia).
c. Dose
(1) 50 to 100 mg/m2 PO daily for 3 to 7 days every 2 to 6 weeks, or
(2) 30 to 50 mg/m2 IV daily for 3 to 5 days, depending on the regimen
d. Drug interactions
(1) Drugs that affect CYP3A4 (see Section VI.A.) affect VP-16 concentration and effect.
(2) Calcium-channel antagonists, such as verapamil, or methotrexate may increase cytotoxicity of etoposide.
(3) The prothrombin time may be prolonged by etoposide in patients taking warfarin.
(4) Carmustine may increase the risk of Hepatotoxicity.
(5) Cyclosporine may reduce VP-16 clearance, causing increased toxicity.
(6) St. John’s wort may lower VP-16 concentration.
C. Irinotecan (camptothecin-11, Camptosar, CPT-11)
1. Indications. Colorectal cancer, lung cancer
2. Pharmacology. A water-soluble analog of camptothecin that is a relatively inactive prodrug, which is converted to the active agent
a. Mechanisms. Inhibits topoisomerase I; see Section V.A; cell cycle-phase specific.
b. Metabolism. Conversion to the active metabolite, SN-38, occurs mainly in the liver, but also in the plasma and intestinal mucosa. The major route of elimination is the bile and feces, with renal clearance playing only a minor role.
The active form of the drug is metabolized by the polymorphic enzyme UGT1A1. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele and have reduced UGT1A1 activity and are at increased risk of experiencing grade 4 neutropenia.
3. Toxicity
a. Dose-limiting. Profuse diarrhea (especially in patients 65 years of age and older) and myelosuppression
b. Common. Neutropenia; mild nausea, vomiting, abdominal cramps; flushing during administration; mild alopecia; weakness, sweating
c. Occasional. LFT abnormalities, headache, fever, dyspnea, back pain
d. Rare. Anaphylactoid reaction, acute renal failure
4. Administration. Administer as a 90-minute infusion with antiemetic agents once weekly for 4 weeks in 6-week cycles. If diarrhea, abdominal cramps, or diaphoresis (mostly cholinergic in nature) develops during the infusion of the drug, administer atropine, 0.25 to 1.0 mg IV. For the first poorly formed stool preceding delayed diarrhea, administer loperamide (Imodium), 4 mg PO, then 2 mg every 2 hours (4 mg PO every 4 hours at night) until the patient is free of diarrhea for 12 hours.
a. Supplied as 40- and 100-mg vials
b. Dose modification. Use with caution for hepatic insufficiency; reduce dose for hyperbilirubinemia. A diagnostic test is available to detect genetic polymorphism on allele 18 of UDP-glucuronesyl transferase in peripheral blood. UGT1A1*1 is the normal allele and, UGT1A1*28 the variant; a lower starting dose is recommended for patients with the variant allele.
c. Dose. Start at 125 mg/m2 IV weekly for 4 weeks followed by a 2-week rest.
d. Drug interactions.
(1) Anticonvulsants increase metabolism of CPT-11’s active metabolite, possibly decreasing CPT-11’s concentration and efficacy.
(2) Medications with laxative or dehydrating effects are additive with CPT-11.
(3) Prochlorperazine increases the incidence of akathisia.
D. Teniposide (VM-26, Vumon)
1. Indication. Acute lymphoblastic leukemia
2. Pharmacology
a. Mechanism. Plant alkaloid; topoisomerase II inhibitor (see Section V.A).
b. Metabolism. Virtually all of the drug is bound to protein. Systemic metabolism is significant, but metabolites have not been identified. Renal excretion is only a small fraction of its clearance.
3. Toxicity
a. Dose-limiting. Neutropenia
b. Common. Thrombocytopenia, hypotension with too rapid an infusion
c. Occasional. Nausea and vomiting, alopecia, abnormal LFTs, phlebitis
d. Rare. Diarrhea, stomatitis; rash, anaphylaxis; azotemia; fever; paresthesias, seizures
4. Administration. The drug is administered by slow intravenous infusion over at least 30 minutes.
a. Supplied as 50-mg vials with alcohol and Cremophor EL
b. Dose modification. The manufacturer advises reducing the dose by 50% for the first cycle of treatment in patients with Down syndrome. Dose reduction is also advised for renal or hepatic dysfunction.
c. Dose. 150 to 250 mg/m2 once or twice weekly
d. Drug interactions. Anticonvulsants increase clearance of teniposide.
E. Topotecan (Hycamtin)
1. Indications. Ovarian cancer after failure to respond to previous (cisplatin-based) therapies; cervical cancer in combination with cisplatin; relapsed small cell lung cancer.
2. Pharmacology
a. Mechanisms. A derivative of camptothecin, it inhibits topoisomerase I activity; see Section V.A; cell cycle–phase specific. It exerts its cytotoxic effect by blocking DNA repair.
b. Metabolism. Rapid conversion in plasma to the active lactone form. About 60% of the drug is excreted in urine. Metabolism in the liver appears to be minimal and is mediated by the microsomal P450 system.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Nausea and vomiting; diarrhea, constipation, abdominal pain; alopecia; headache, fatigue, fever; arthralgias and myalgias
c. Occasional. Transient elevation of LFTs; paresthesia; rash; microscopic hematuria (30%)
4. Administration. The drug is a mild vesicant, and a free-flowing IV site is necessary.
a. Supplied as 4-mg vials and 0.25- and 1-mg capsules
b. Dose modification. None for impaired hepatic function. Reduce dosage by 50% for creatinine clearance levels of 20 to 40 mL/min.
c. Dose. Usual dose is 1.25 to 1.50 mg/m2 IV over 30 minutes for 5 consecutive days every 3 weeks; 2.3 mg/m2 PO for 5 days of 21-day cycle for small cell lung cancer.
VI. TYROSINE KINASE (TK) INHIBITORS
A. Drug interactions with cytochrome P450 (CYP). Cytochrome P450 families of more than 100 enzymes are located on the endoplasmic reticulum. Although present in all tissues, the highest concentrations are found in the liver and small intestine. These enzymes detoxify ingested substances, including drugs. The four major enzyme families involved in the metabolism of drugs are CYP1, CYP2, CYP3, and CYP4.
1. CYP3A is a subfamily of the CYP3 enzymes; they are the most abundant cytochrome enzymes in humans, accounting for 30% of the cytochrome enzymes in the liver and 70% of those in the gut. CYP3A3 and CYP3A4 are nearly identical. The relative contribution to drug metabolism in decreasing order of magnitude is CYP3A4 (50%), CYP2D6 (25%), and CYP2C8/9 (15%).
Many chemotherapeutic agents are metabolized by CYP3A4, particularly among the TK inhibitors. Other related hepatic enzymes also may be operative. Concomitantly prescribed drugs, particularly antimicrobial agents and antiseizure medications, can inhibit or induce CYP3A4 and related enzymes in the liver. Drugs that inhibit CYP3A4 can result in higher levels of the chemotherapeutic agent in the plasma; conversely, drugs that induce CYP3A4 can result in lower levels of the drug in the plasma and indicate higher prescribed dosages of the anticancer drug.
2. Inhibitors of CYP3A4 (resulting in higher-than-expected plasma levels of the chemotherapeutic agent and possibly indicating a decrease in dosage):
a. Antifungal agents: Ketoconazole (Nizoral), clotrimazole (Mycelex), fluconazole (Diflucan), itraconazole (Sporanox), voriconazole (Vfend)
b. Antibiotics: Clarithromycin (Biaxin), erythromycin, telithromycin (Ketek); metronidazole (Flagyl), norfloxacin (Noroxin)
c. Protease inhibitors: Atazanavir (Reyataz), delavirdine (Rescriptor), indinavir (Crixivan), nefazodone (Serzone), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Fortovase)
d. Gastrointestinal agents: Cimetidine (Tagamet), omeprazole (Prilosec)
e. Cardiovascular agents: Diltiazem (Cardizem), nifedipine (Procardia), verapamil (Calan)
f. Psychotropic agents: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), nefazodone (Serzone)
g. Miscellaneous: Grapefruit juice, propoxyphene (Darvon), zafirlukast (Accolate)
3. Inducers of CYP3A4 (resulting in lower-than-expected plasma levels of the chemotherapeutic agent and possibly indicating an increase in dosage):
a. Corticosteroids: Dexamethasone (Decadron), prednisone
b. Antiseizure drugs: Phenytoin (Dilantin), carbamazepine (Tegretol), barbiturates
c. Antibiotics: Rifampin (Rifadin), rifabutin (Mycobutin), nafcillin, isoniazid, griseofulvin
d. Nonclassified agents: St. John’s wort, modafinil (Provigil)
4. TK inhibitors may affect the concentration and efficacy of the following drugs:
a. Drugs metabolized by CYP2B6 include bupropion (Wellbutrin), propofol (Diprivan); cyclophosphamide and ifosfamide.
b. Drugs that are metabolized by CYP2C8 include amiodarone (Cordarone), pioglitazone (Actos), repaglinide (Prandin), rosiglitazone (Avandia) and paclitaxel.
c. Drugs that are metabolized by CYP2C9 include fluvastatin (Lescol), rosuvastatin (Crestor), glimepiride (Amaryl), glyburide (DiaBeta), phenytoin (Dilantin), some NSAIDs, and warfarin.
d. Drugs that are metabolized by CYP2D6 include tramadol (Ultram), some β-adrenergic blockers, propafenone (Rythmol), codeine, hydrocodone, oxycodone; some SSRIs, thioridazine (Mellaril), and tricyclic antidepressants.
e. Drugs that are metabolized by P-glycoprotein include loperamide (Imodium), fexofenadine (Allegra), loratadine (Claritin), ritonavir (Norvir), sirolimus (Rapamune), tacrolimus (Prograf), cyclosporine, and digoxin.
5. Drugs that inhibit P-glycoprotein and may increase TK inhibitor concentrations include amiodarone (Cordarone), felodipine (Plendil), nicardipine (Cardene), propafenone (Rythmol), quinidine; tacrolimus (Prograf), cyclosporine, tamoxifen, and testosterone.
B. Crizotinib (Xalkori)
1. Indications. Metastatic or locally advanced ALK-positive non–small cell lung cancer (NSCLC)
2. Pharmacology
a. Mechanisms. TK receptor inhibitor, which inhibits anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), and Recepteur d’Origine Nantais (RON). ALK gene abnormalities may result in expression of oncogenic fusion proteins (e.g., ALK fusion protein). Approximately 5% of patients with NSCLC have the abnormal echinoderm microtubule-associated protein-like 4, or EML4-ALK gene. This gene has a higher prevalence in patients with adenocarcinoma and in never smokers or light smokers. Crizotinib selectively inhibits ALK TK and reduces proliferation of cells expressing the genetic alteration.
b. Metabolism. Metabolized in the liver via CYP3A4/5
3. Toxicity
a. Dose-limiting. Hematosuppression
b. Common. Visual disturbances (60%); nausea, vomiting, diarrhea, constipation, esophageal disorders; lymphocytopenia, abnormal LFTs; edema, fatigue, dizziness, neuropathy
c. Occasional. Neutropenia, bradycardia, headache, rash (10%), arthralgia, cough
d. Rare. Thrombocytopenia, QTc prolongation
4. Administration. May be taken with or without food. Avoid grapefruits.
a. Supplied as 200 and 250 mg capsules
b. Dose modification: Use with caution in patients with hepatic or severe renal function impairment.
c. Dose: 250 mg PO b.i.d.
d. Drug interactions. Inducers or inhibitors of CYP3A4 may respectively decrease or increase plasma concentrations of crizotinib (see Section VI.A).
C. Dasatinib (Sprycel)
1. Indications. Chronic, accelerated or blast phase of CML
2. Pharmacology
a. Mechanisms. An inhibitor of multiple TK, including BCR-ABL
b. Metabolism. Metabolized in the liver and excreted in the feces
3. Toxicity
a. Dose-limiting. Hematosuppression; bleeding events related to thrombocytopenia but also possibly to drug-induced platelet dysfunction
b. Common. Dose-related fluid retention (which can be severe), diarrhea, various dermatoses, headache, fatigue, rash, dyspnea; hypocalcemia, hypophosphatemia
c. Occasional. Neurologic and muscular disorders, prolongation of QT-interval, fever, arthralgia/myalgia
4. Administration. Avoid the use of antacids, H2 blockers, and proton pump inhibitors because the drug has pH-dependent solubility and these agents can reduce dasatinib absorption.
a. Supplied as 20-, 50-, 70-, and 100-mg tablets
b. Dose modification. Increase or decrease dose in 20-mg increments per dose based on individual tolerability and blood cell counts.
c. Dose. 100 mg once daily initially
d. Drug interactions. Inducers or inhibitors of CYP3A4 may respectively decrease or increase plasma concentrations of dasatinib (see Section VI.A).
(1) Anticoagulants or drugs that inhibit platelet function may increase the risk of bleeding complications.
(2) Drugs that prolong the QT interval or cause electrolyte abnormalities may have additive effects and cause life-threatening cardiac dysrhythmias.
(3) Grapefruit juice reduces dasatinib elimination and may increase dasatinib serum levels. St. John’s wort may lower dasatinib serum levels and reduce the antineoplastic effect. Avoid concomitant use of these agents.
D. Erlotinib (Tarceva)
1. Indications. Non–small cell lung cancer (NSCLC) refractory to at least one prior chemotherapy regimen and pancreatic cancer (in combination with gemcitabine). Erlotinib is not recommended in patients with NSCLC with KRASmutations (or EGFR gene amplification) as they are not likely to benefit from erlotinib treatment. EGFR mutations, specifically exon 19 deletions and exon 21 mutations (L858R), are associated with better response to erlotinib in patients with NSCLC.
2. Pharmacology
a. Mechanisms. A selective small molecule inhibitor of the epidermal growth factor receptor (EGFR) TK that results in inhibition of proliferation, growth metastasis, and angiogenesis
b. Metabolism. Metabolized in the liver primarily by the CYP3A4 microsomal enzyme and, to a lesser extent, by CYP1A2. More than 90% of the drug metabolites are excreted in the bile.
3. Toxicity
a. Dose-limiting. Diarrhea (55%) and rash (75%)
b. Common. Pustular, acneiform rash (oral or gel forms of clindamycin, 2% erythromycin topical gel b.i.d., or minocycline, 100 mg b.i.d. for 5 days, may help); mild dyspnea, cough
c. Occasional. Interstitial lung disease (<1% of patients), keratoconjunctivitis
d. Rare. Interstitial lung disease, microangiopathic hemolytic anemia when combined with gemcitabine
4. Administration. Give on an empty stomach (1 hour before or 2 hours after meals).
a. Supplied as 25-, 100-, and 150-mg tablets
b. Dose modification see package insert for management of skin reactions
c. Dose. 150 mg/d taken 1 hour before or 2 hours after food
d. Drug interactions. Inducers or inhibitors of CYP3A4 may respectively decrease or increase plasma concentrations of erlotinib (see Section VI.A).
(1) Drugs that reduce gastric acid may reduce erlotinib absorption; administer these drugs 2 hours before or after erlotinib.
(2) Drugs that induce CYP1A2 (e.g., barbiturates, carbamazepine, rifampin) may reduce erlotinib concentrations and efficacy.
(3) Warfarin effect is increased.
(4) Grapefruit juice reduces dasatinib elimination and may increase erlotinib serum levels. St. John’s wort and smoking may lower erlotinib serum levels and reduce the antineoplastic effect. Avoid concomitant use of these agents.
E. Imatinib (Gleevec)
1. Indications. Chronic myelogenous leukemia (CML); gastrointestinal stromal tumors (GIST) expressing c-kit TK; consider use in other conditions expressing c-kit or platelet-derived growth factor receptor-β (PDGFR-β) activation. Imatinib is also approved by treatment of dermatofibrosarcoma protuberans (DFSP), myelodysplastic/myeloproliferative diseases (MDS/MPD), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), and relapsed/refractory Philadelphia chromosome positive acute lymphoblastic leukemias (Ph+ ALL).
2. Pharmacology
a. Mechanisms. BCR-ABL encodes a protein, P210BCR-ABL. Imatinib occupies the ATP binding site of the BCR-ABL protein and other related TKs and thus results in subsequent inhibition of substrate phosphorylation. Imatinib is a potent selective inhibitor of the P210BCR-ABL TK, resulting in inhibition of clonogenicity and tumorigenicity and induction of apoptosis of BCR-ABL and Ph+ cells. It also inhibits other activated ABL TKs (including P185BCR-ABL) and other receptor TKs for PDGFR, stem cell factor (SCF), and c-kit.
b. Metabolism. Eliminated mainly in feces. The half-life of the parent drug is 18 hours and of the main metabolites is 40 hours.
3. Toxicity
a. Dose-limiting. Myelosuppression
b. Common. Transient ankle and periorbital edema that is usually mild to moderate; nausea, vomiting (especially when not taken with food), diarrhea; fatigue, headache, rash, musculoskeletal pain, fever
c. Occasional. Fluid retention with pleural effusion, pulmonary edema, ascites (especially in older patients); night sweats, abnormal LFTs, cough
d. Rare. Severe dermatologic reactions
4. Administration. Drug should be taken with food and a large glass of water.
a. Supplied as 100-mg capsules
b. Dose modification. Reduce dose for severe liver dysfunction (bilirubin > 3 mg/dL).
c. Dose
(1) For CML, 400 mg/d in the chronic phase and 600 mg/d for the accelerated phase
(2) For GIST, 600 mg/d
(3) For HES/CEL, 400 mg/d; for HES/CEL with demonstrated FIPLIPDGFR alpha fusion kinase, starting dose 100 mg/d
(4) For Ph+ ALL, 600 mg/d
(5) For unresectable, recurrent, or metastatic DFSP, 800 mg/d
(6) For MDS/MPD associated with PDGFR gene rearrangements, 400 mg/d
(7) For ASM associated with eosinophilia, starting dose 100 mg/d; for ASM without the D816V c-kit mutation or with unknown c-kit mutational status, 400 mg/d
d. Drug interactions. Drugs that stimulate or inhibit liver microsomal CYP3A4 affect plasma levels of the drug). Imatinib also inhibits CYP2C9 and CYP2D6 (see Section VI.A).
(1) Warfarin effect is increased.
(2) Acetaminophen results in increased risk of hepatotoxicity.
(3) Digoxin absorption may be reduced.
(4) Grapefruit products may increase imatinib concentrations and toxicity. St. John’s wort may decrease imatinib concentration and activity. Avoid concomitant use of these agents.
F. Lapatinib (Tykerb)
1. Indications. In combination with capecitabine for the treatment of patients with advanced or metastatic breast cancers that overexpress human epidermal receptor type 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Also, in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
2. Pharmacology
a. Mechanisms. Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular TK domains of both EGFR (ErbB1) and of HER2 (ErbB2). In vitro studies showed an additive effect with 5-FU, the active metabolite of capecitabine.
b. Metabolism. Lapatinib undergoes extensive metabolism, primarily by CYP3A4, CYP3A5, and P-glycoprotein. There is negligible real excretion.
3. Toxicity of lapatinib plus capecitabine
a. Dose-limiting. Diarrhea, serious adverse events
b. Common. Diarrhea (65%), nausea, vomiting; fatigue, palmar–plantar erythrodysesthesia (50%, due to capecitabine), rash; elevated LFTs (40%); hematosuppression (20%); prolonged QT interval
c. Occasional. Decreased left ventricular ejection fraction (LVEF, 2%)
d. Rare. Pulmonary toxicity, hepatotoxicity (including fatalities)
4. Administration. Administration with food increases absorption of the drug up to fourfold. Give on an empty stomach (1 hour before or 2 hours after meals).
a. Supplied as 250 mg tablets (tablets are not to be crushed or chewed)
b. Dose modification is required for LVEF <50%; reduce dose to 750 mg with known pre-existing hepatic dysfunction (Child-Pugh classes B and C).
c. Dose.
(1) HER2 positive metastatic breast cancer. Lapatinib, 1,250 mg (five tablets), is taken PO once daily at least 1 hour before or 1 to 2 hours after a meal. Capecitabine, 1,000 mg/m2 PO, is taken every 12 hours on days 1 to 14 of repeating 21-day cycles; capecitabine is taken with or within 30 minutes of eating food.
(2) HER2 positive, hormone receptor positive metastatic breast cancer. Lapatinib, 1,500 mg (six tablets), is taken once daily at least 1 hour before or 1 to 2 hours after a meal in combination with letrozole (2.5 mg PO daily).
d. Drug interactions. Drugs that induce or inhibit CYP3A4 can result in decreased or increased plasma levels of lapatinib, respectively (see Section VI.A).
(1) Drugs that prolong the QT interval or cause electrolyte imbalance may have additive effects and cause life-threatening cardiac dysrhythmias.
(2) Drugs (which are many) that inhibit P-glycoprotein may increase plasma concentrations of lapatinib. Lapatinib may result in increased levels of drugs metabolized by P-glycoprotein or CYP2C8 (see Section VI.A).
(3) Grapefruit products may increase lapatinib concentrations and toxicity. St. John’s wort may decrease lapatinib concentration and activity. Avoid concomitant use of these agents.
G. Nilotinib (Tasigna)
1. Indications. Philadelphia chromosome positive CML
2. Pharmacology
a. Mechanisms. An inhibitor of multiple TKs, including BCR-ABL
b. Metabolism. Metabolized extensively in the liver by CYP3A4 and P-glycoprotein and excreted in the feces
3. Toxicity. Electrocardiograms should be obtained to monitor the QTc at baseline, 7 days after initiation of therapy, and periodically thereafter, as well as following any dose adjustment. Electrolytes, divalent cations, and other chemistries as suggested below should be followed periodically.
a. Dose-limiting. Myelosuppression. Prolongation of the QT interval, which can result in a type of ventricular tachycardia called Torsades de pointes, which may result in syncope, seizure, or sudden death.
b. Common. Prolongation of QT-interval; rash, pruritus; fatigue, headache; musculoskeletal pain; nausea, vomiting, constipation, diarrhea; insomnia, dizziness; hypomagnesemia, hyperkalemia, hyperglycemia; abnormal LFTs; elevated serum lipase/amylase.
c. Occasional. Hypophosphatemia, hypokalemia, hyponatremia, hypocalcemia; hyperthyroidism; interstitial lung disease; pancreatitis; urinary urgency; gynecomastia
4. Administration. Food increases blood levels of nilotinib; for the dose should be given at least 1 hour before and 2 hours after meals.
a. Contraindications. Patients with long QT syndrome or with hypokalemia or hypomagnesemia (which should be corrected before starting the drug and monitored thereafter)
b. Supplied as 150- and 200-mg capsules
c. Dose modification. Use with caution in patients with hepatic impairment or with a history of pancreatitis. Avoid drugs known to prolong the QT interval. Consider dose reduction in patients receiving a strong CYP3A4 inhibitor concurrently. Dose increase or alternative therapy should be considered in patients who have undergone total gastrectomy due to reduced exposure to the drug.
d. Dose. 300 mg every 12 hours for newly diagnosed CML and 400 mg every 12 hours for resistant CML
e. Drug interactions. Inducers or inhibitors of CYP3A4 may respectively decrease or increase plasma concentrations of nilotinib (see Section VI.A). Conversely, nilotinib may affect the elimination of agents metabolized by CYP3A4, CYP2C8, CYP2C9, CYP2D6, CYP2B6, or P-glycoprotein.
(1) Drugs that prolong the QT interval or cause electrolyte imbalance may have additive effects and cause life-threatening cardiac dysrhythmias.
(2) Drugs (which are many) that inhibit P-glycoprotein may increase plasma concentrations of nilotinib. Nilotinib may result in increased levels of drugs metabolized by P-glycoprotein or CYP2C8 (see Section VI.A).
(3) Grapefruit products may increase nilotinib concentrations and toxicity. St. John’s wort may decrease nilotinib concentration and activity. Avoid concomitant use of these agents.
(4) Warfarin metabolism is affected by nilotinib.
H. Pazopanib (Votrient)
1. Indications. Advanced renal cell carcinoma
2. Pharmacology
a. Mechanisms. Pazopanib is a multiple TK inhibitor of VEGFR, PDGFR, fibroblast growth factor receptor, cytokine receptor, and others.
b. Metabolism. The drug is extensively metabolized in the liver by CYP3A4 and eliminated primarily in the feces; <4% is eliminated in the urine.
3. Toxicity
a. Dose-limiting. Hepatotoxicity, QT prolongation and Torsades de Pointes, gastrointestinal perforation, hemorrhagic events, arterial thrombotic events,
b. Common. Elevated serum transaminases (18%, particularly during the first 4 months of treatment); anorexia, nausea, vomiting, diarrhea; hypertension (40%); fatigue; hair color change; hematosuppression (about 33%), hypomagnesemia
c. Occasional. Alopecia, palmar–plantar dysesthesia, rash; dysgeusia, dyspepsia; QT prolongation and Torsades de Pointes (<2%), hemorrhagic events (13%), arterial thrombotic events, delayed wound healing, gastrointestinal perforation (1%); hypothyroidism, proteinuria
4. Administration.
a. Supplied as 200 and 400 mg tablets
b. Dose modification: Reduce dose to 200 mg for moderate hepatic impairment; use with caution in patients with prolonged QTc or who are taking other drugs that prolong the QT interval.
c. Dose: 800 mg once daily at least 1 hour before or 2 hours after a meal; do not chew or crush tablets.
d. Drug interactions: Consider dose modification with concomitant use of other drugs affecting CYP3A4 or P-glycoprotein (see Section VI.A).
I. Sorafenib (Nexavar)
1. Indications. Metastatic renal cell carcinoma; unresectable hepatocellular carcinoma
2. Pharmacology
a. Mechanisms. A multiple TK inhibitor
b. Metabolism. Metabolized by CYPA34 and hepatic UGT1A9 glucuronidation. Approximately 80% of the drug and its metabolites are excreted in the feces and 20% in the urine.
3. Toxicity
a. Dose-limiting. Skin reactions or unacceptable toxicities
b. Common. Rash/desquamation, hand–foot skin reaction; hypertension; diarrhea, alopecia, anemia; fatigue
c. Occasional. Granulocytopenia, thrombocytopenia; bleeding events, vomiting, myocardial ischemia, increased serum lipase or amylase; sensory neuropathy, headache; arthralgia/myalgia
d. Rare. Hypothyroidism, pancreatitis
4. Administration
a. Supplied as 200-mg tablets
b. Dose modification for severe hepatic dysfunction (no dosage adjustment is necessary for mild or moderate dysfunction)
c. Dose. 400 mg b.i.d. taken at least 1 hour before or 2 hours after eating
d. Drug interactions. Inducers or inhibitors of CYP3A4 may respectively decrease or increase plasma concentrations of sorafenib (see Section VI.A).
J. Sunitinib malate (Sutent)
1. Indications. Metastatic renal cell carcinoma; GIST after progression while on imatinib; progressive pancreatic neuroendocrine tumors
2. Pharmacology
a. Mechanisms. Inhibition of multiple TK receptors which are implicated in tumor growth, pathologic angiogenesis, and metastasis
b. Metabolism. The drug and its active metabolite are metabolized primarily by the p450 enzyme CYP3A4. More than 80% of the drug is eliminated via feces.
3. Toxicity
a. Dose-limiting. Hematosuppression, bleeding
b. Common. Bleeding events (epistaxis and elsewhere); hypertension; anorexia, diarrhea, mucositis, nausea/vomiting; fatigue; altered taste; yellow skin discoloration (one-third of patients), rash.
c. Occasional. Peripheral neuropathy, anorexia, periorbital edema, lacrimation; prolonged QT interval on electrocardiogram, left ventricular dysfunction, deep vein thrombosis; hypothyroidism, adrenal insufficiency, hypoglycemia, hypocalcemia, hypophosphatemia, hyponatremia, hypernatremia, hypokalemia, hyperkalemia, elevated serum lipase or amylase levels; musculoskeletal pain, reversible hair depigmentation, alopecia; fever.
d. Rare. Adrenal insufficiency, severe hemorrhage, microangiopathic hemolytic anemia (with bevacizumab)
4. Administration
a. Supplied as 12.5, 25-, and 50-mg capsules
b. Dose modification. Dose changes should be done in 12.5-mg increments. Modification may be considered for severe hepatic dysfunction (no dosage adjustment is necessary for mild or moderate dysfunction).
c. Dose. 50-mg once daily for 4 weeks on treatment and 2 weeks off treatment, a 6-week schedule. The drug may be taken with or without food.
d. Drug interactions. Inducers or inhibitors of CYP3A4 may respectively decrease or increase plasma concentrations of sunitinib (see Section VI.A).
(1) Drugs that prolong the QT interval or cause electrolyte imbalance may have additive effects and cause life-threatening cardiac dysrhythmias.
(2) Grapefruit products may increase sunitinib concentrations and toxicity. St. John’s wort may decrease sunitinib concentration and activity. Avoid concomitant use of these agents.
VII. MONOCLONAL ANTIBODIES
A. Monoclonal antibodies have the advantage of relative selectivity for tumor tissue and relative lack of toxicity. Both technical problems and the development of human antimouse antibodies are major problems in using monoclonal antibodies for therapy.
1. Biological effects. Monoclonal antibodies can attack certain cells directly (e.g., malignant lymphocytes exposed to a selective monoclonal antibody are lysed in the presence of complement). Various radioactive and chemotherapeutic agents can be conjugated to monoclones, which deliver these agents specifically to cancer cells. Plant toxins (e.g., ricin, abrin), bacterial toxins (Pseudomonas endotoxin A, diphtheria toxin), or ribosome-inactivating protein can also be conjugated to monoclonal antibodies as immunotoxins. Growth factors (e.g., interleukins, epidermal growth factor, tumor growth factor) can sometimes be used as carriers for toxins; these constructs are called oncotoxins.
2. Clinical uses
a. Imaging of tumors using radioisotope-labeled monoclones
b. Selectively purging bone marrow of cancer cells
c. Treatment of specific tumors
3. An infusion-related cytokine release syndrome (IRCRS) develops frequently during infusion of monoclonal antibodies, particularly during the first infusion. Manifestations can include fever or chills, hypotension, bronchospasm with dyspnea, and angioedema. Nausea, vomiting, fatigue, headache, rhinitis, pruritus, urticaria, and flushing also can occur. These symptoms generally develop 30 minutes to 2 hours after beginning the infusion. Symptoms generally respond to slowing the infusion rate or stopping the infusion, which can be resumed at a slower rate after symptoms resolve. Slowing the infusion rate, diphenhydramine and acetaminophen, bronchodilators, or saline infusion may be useful for treating the IRCRS, which must be distinguished clinically from true hypersensitivity and which becomes progressively less of a problem with subsequent infusions.
B. Alemtuzumab (Campath-1H)
1. Indications. T-cell prolymphocytic leukemia; relapsed or refractory B-cell chronic lymphocytic leukemia
2. Pharmacology
a. Mechanisms. This recombinant humanized monoclonal antibody is directed against the cell-surface glycoprotein CD52 that is expressed on most normal and malignant B and T lymphocytes, NK cells, monocytes, and macrophages.
b. Metabolism. The half-life is about 12 days with minimal clearance by the liver and kidneys. Steady-state levels are reached by the sixth week. CD4+ and CD8+ counts may take more than 1 year to return to normal.
3. Toxicity
a. Dose-limiting. Significant immunosuppression with increased incidence of opportunistic infections; myelosuppression
b. Common. IRCRS (see Section VII.A.3) usually occurs within the first week of therapy. Hypertension, rash, fever, rigors
c. Occasional. Pancytopenia, supraventricular tachycardia; nausea, vomiting, diarrhea
d. Rare. Anaphylaxis
4. Administration. Premedicate with acetaminophen and diphenhydramine.
a. Supplied as 30-mg vials
b. Dose modification. Contraindicated in patients with active systemic infections or underlying immunodeficiency. Discontinue if severe infection, profound hematosuppression, or other serious adverse event develops. Permanently discontinue if autoimmune hemolytic anemia or thrombocytopenia develop.
c. Dose. Initiate therapy with 3 mg over 2 hours and then increase the dose to 10 mg if the 3-mg dose is tolerated. The maintenance dose is 30 mg/d IV three times weekly for 4 to 12 weeks.
d. Prophylactic antibiotics should include Bactrim DS, one tablet b.i.d. 3 days per week, and famciclovir, 250 mg PO b.i.d. (or equivalent). Fluconazole can also be given to reduce the occurrence of fungal infections.
e. Drug interactions. None known
C. Brentuximab vedotin (Adcetris)
1. Indications. Refractory Hodgkin lymphoma and refractory systemic anaplastic large cell lymphoma
2. Pharmacology
a. Mechanisms. An antibody drug conjugate consisting of a CD30-specific chimeric IgG1 antibody, a microtubule-disrupting agent (monomethylauristatin E, MMAE), and a protease cleavable dipeptide linker that covalently binds MMAE to the antibody. MMAE disrupts the cellular microtubule network and induces cell cycle arrest at the G2/M phase.
b. Metabolism. Minimally metabolized, primarily in the liver via oxidation by CYP3A4/5.
3. Toxicity
a. Dose-limiting. Neutropenia, neuropathy
b. Common. Hematosuppression; infusion reactions; fatigue, fever; peripheral sensory neuropathy, arthralgia/myalgia, headache, dizziness, insomnia, anxiety; anorexia, nausea, vomiting, diarrhea, constipation; upper respiratory tract infections; rash, pruritus.
c. Occasional. Peripheral motor neuropathy, oropharyngeal pain; alopecia; chills, shortness of breath; supraventricular arrhythmia, edema; antibrentuximab antibody formation.
d. Rare. Anaphylaxis, progressive multifocal leukoencephalopathy, Stevens–Johnson syndrome, tumor lysis syndrome.
4. Administration. Infuse IV over 30 minutes.
a. Supplied as 50 mg powder for reconstitution.
b. Dose modification: The effects of hepatic or renal impairment are undetermined.
c. Dose: 1.8 mg/kg (maximum dose 180 mg) IV every 3 weeks until disease progression, unacceptable toxicities, or a maximum of 16 cycles.
d. Drug interactions. Concomitant use with psychotropic agents may have additive effects.
D. Bevacizumab (rHuMAb-VEGF, Avastin)
1. Indications. Advanced colorectal cancer, breast cancer, nonsquamous non–small cell lung cancer
2. Pharmacology. Bevacizumab is a humanized monoclonal antibody from genetically engineered cells designed to block the action of vascular endothelial growth factor (VEGF). VEGF is a protein that is secreted from malignant and nonmalignant hypoxic cells and stimulates new blood vessel formation by binding to specific receptors. Metabolism of bevacizumab has not been characterized.
3. Toxicity
a. Dose-limiting. Thromboembolism (e.g., transient ischemic attack, stroke, angina pectoris, myocardial infarction), gastrointestinal perforation, wound dehiscence
b. Common. Hypertension (severe in 15%), proteinuria, bleeding (especially epistaxis or GI), IRCRS (see Section VII.A.3), fatigue, abdominal pain, impaired wound-healing, constipation, diarrhea
c. Occasional. Leukopenia, thrombocytopenia, hypersensitivity, taste disorders, sensory neuropathy
d. Rare. Bowel perforation, reversible posterior leukoencephalopathy syndrome (RPLS), nephrotic syndrome, hypertensive crisis
4. Administration. Bevacizumab should be given at 4 weeks after any surgical and/or invasive procedure.
a. Supplied as 100- and 400-mg vials
b. Dose modification. Use with caution in patients over 65 years of age.
c. Dose. 5 to 10 mg/kg IV every 2 weeks or 15 mg/kg every 3 weeks in combination with other chemotherapeutic drugs
d. Drug interactions.
(1) Irinotecan: Severe diarrhea or neutropenia
(2) Sorafenib: Increased risk of hand–foot syndrome
(3) Sunitinib: Microangiopathic hemolytic anemia (avoid this combination)
(4) Anthracyclines: Increased risk of cardiomyopathy
E. Cetuximab (monoclonal epidermal growth factor receptor [EGFR] antibody, Erbitux)
1. Indications. EGFR-expressing metastatic colon cancer after failure of both irinotecan- and oxaliplatin-based regimens; squamous cell carcinoma of the head and neck. Metastatic colorectal cancer trials have not shown a benefit with EGFR inhibitor treatment in patients whose tumors have KRAS mutations (codons 12 or 13); use of cetuximab is not recommended in these patients. Similar findings and conclusions pertain to BRAF gene point mutation V600E and EGFR gene amplification.
2. Pharmacology
a. Mechanisms. Monoclonal antibody that binds to the EGFR (HER1, ErbB-1), which is a transmembrane glycoprotein of the TK growth factor receptor family, and thus inhibits ligand-induced TK autophosphorylation, which affects multiple mechanisms of action (cell growth, apoptosis, production of vascular endothelial growth factor, production of matrix metalloproteinase). There is no evidence to indicate that the level of EGFR expression can predict for the drug’s clinical activity.
b. Metabolism. Metabolism of cetuximab has not been characterized. In steady state, the mean half-life of cetuximab in the serum is approximately 5 days.
3. Toxicity
a. Dose-limiting. Severe IRCRS (see Section VII.A.3) characterized by rapid onset of airway obstruction, hypotension, and/or cardiac arrest (particularly during the first infusion); mild or moderate reactions are managed by slowing the infusion rate in subsequent doses. Severe reactions require the immediate and permanent discontinuation of cetuximab therapy. An acneiform rash develops in 90% of patients (severe in 12%), usually within 2 weeks of starting therapy. Treatment of the rash involves topical and oral antibiotics, but not topical corticosteroids.
b. Common. Asthenia/malaise; skin drying and fissuring; abdominal pain, diarrhea, nausea, vomiting; hypomagnesemia (with accompanying hypokalemia and hypocalcemia) during or following infusions; headache
c. Occasional. Stomatitis, fever, mild anemia, depression
d. Rare. Interstitial lung disease, severe IRCRS (up to 3%)
4. Administration. Premedicate with antihistamines (e.g., diphenhydramine, 50 mg IV). Monitor for hypomagnesemia, including for several weeks after treatment is completed.
a. Supplied as 100-mg vials
b. Dose modification. For mild or moderate infusion-related reactions, reduce the infusion rate by 50%. Severe acneiform rash may require dosage delay or reduction.
c. Dose. 400 mg/m2 IV over 2 hours initially and then 250 mg/m2 IV over 1 hour weekly
d. Drug interactions. None known
F. Gemtuzumab ozogamicin (Mylotarg)
1. Indications. Mylotarg® was withdrawn from the US market in June 2010 after results from a postapproval clinical trial failed to demonstrate a clinical benefit. Additionally, postmarketing data showed an increased incidence of a serious and potentially fatal hepatic veno-occlusive disease.
2. Pharmacology. The drug is composed of a semisynthetic derivative of calicheamicin covalently linked to a recombinant humanized monoclonal antibody directed against the cell-surface glycoprotein CD33. Calicheamicin is a cytotoxic antibiotic that binds to DNA, resulting in double-strand breaks and inhibition of DNA synthesis. CD33 antigen is expressed on normal myeloid cells, on more than 90% of the leukemia cells in AML, but not on stem cells or nonmyeloid tissues.
G. Ipilimumab (Yervoy)
1. Indications. Unresectable or metastatic melanoma in adults
2. Pharmacology. A recombinant human IgG1 immunoglobulin monoclonal antibody that binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), which is a down-regulator of T-cell activation pathways. Blocking CTLA-4 allows for enhanced T-cell activation and proliferation.
3. Toxicity.
a. Dose-limiting. Severe and fatal immune-mediated adverse effects due to T-cell activation may occur and involve any organ. Reactions generally occur during treatment, although some reactions have occurred weeks to months after treatment discontinuation. Common severe effects include dermatitis, endocrine disorders, enterocolitis, hepatitis, and neuropathy. Corticosteroid treatment is recommended for immune-mediated reactions.
b. Common. Fatigue; pruritus, rash; anorexia, nausea, vomiting, diarrhea, constipation, abdominal pain
c. Occasional. Headache, fever, enterocolitis; anemia, eosinophilia; hepatotoxicity; nephritis; hypopituitarism, hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency (≤2% each); ophthalmic toxicity (episcleritis, irits, uveitis)
d. Rare. Postmarketing and/or case reports include but are not limited to acute respiratory distress syndrome, Guillain–Barré syndrome, motor or sensory neuropathy, leukocytoclastic vasculitis, myasthenia gravis, myelofibrosis.
4. Administration. Infuse over 90 minutes through a low protein-binding inline filter.
a. Supplied as 50- and 200-mg vials
b. Dose modification: Temporarily withhold scheduled dosing for moderate immune-mediated reactions or symptomatic endocrine disorders. Discontinue treatment for severe or life-threatening adverse reactions or inability to reduce prednisone dosage to 7.5 mg/d (or equivalent).
c. Dose: 3 mg/kg IV every 3 weeks for four doses
d. Drug interactions. May interact with digoxin and warfarin metabolism
H. Ofatumumab (Arzerra)
1. Indications. Chronic lymphocytic leukemia (CLL) refractory to fludarabine
2. Pharmacology. A CD20-directed cytolytic monoclonal antibody generated via transgenic mouse and hybridoma technology
a. Mechanisms. Binds specifically to both the small and large extracellular loops of the CD20 molecule, which is expressed in normal and CLL B-cells
b. Metabolism. The mean half-life is approximately 14 days after the first three doses.
3. Toxicity
a. Dose-limiting. Prolonged severe neutropenia (40%) and thrombocytopenia
b. Common. IRCRS (see Section VII.A.3) occurs in 40% of patients on the first infusion, 30% on the second infusion and less frequently thereafter. Fever, cough, upper respiratory infections, dyspnea; nausea, diarrhea, rash.
c. Occasional. Activation of hepatitis B virus (HBV)—closely monitor carriers of HBV for 1 year; bowel obstruction
d. Rare. Progressive multifocal leukoencephalopathy
4. Administration. Premedicate with 1,000 mg acetaminophen PO or antihistamine IV, plus IV corticosteroid (100 mg prednisolone or equivalent)
a. Supplied as 100-mg vial
b. Dose modification: Discontinue treatment with the development or reactivation of viral hepatitis
c. Dose: IV infusion of 300 mg as the initial dose, followed 1 week later by 2,000 mg weekly for seven doses, followed 4 weeks later by 2,000 mg every 4 weeks for four doses (no dosage adjustment is recommended based on body weight)
d. Drug interactions. None known
I. Panitumumab (rHuMAb-EGFR, Vectibix)
1. Indications. Metastatic colorectal cancer that expresses EGFR and that has progressed with 5-FU-, oxaliplatin-, and irinotecan-containing regimens. Panitumumab is not effective for tumors that have KRAS mutations in codon 12 or 13 and is not indicated for use in these patients. Similar findings and conclusions pertain to BRAF gene point mutation V600E.
2. Pharmacology. Panitumumab is a recombinant human monoclonal EGFR antibody that is produced in genetically engineered mammalian cells.
a. Mechanisms. Panitumumab binds specifically to EGFR on normal and tumor cells and competitively inhibits the binding of ligands for EGFR. The interaction of EGFR with its ligands activates a series of intracellular TKs.
b. Metabolism. Panitumumab concentrations reach a steady state by the third infusion. Its half-life is about 1 week.
3. Toxicity
a. Dose-limiting. IRCRS (see Section VII.A.3); severe dermatologic toxicity (potentially complicated by infection and septic death); pulmonary infiltrates
b. Common. Skin toxicities (90% of patients, severe in 15%), paronychia, fatigue, abdominal pain; nausea, diarrhea, constipation; hypomagnesemia/hypocalcemia; ocular toxicity (conjunctivitis, irritation)
c. Occasional. Mucositis
d. Rare. Pulmonary fibrosis (<1%)
4. Administration. Patients should limit sun exposure while receiving panitumumab as skin reactions could be exacerbated by sunlight.
a. Supplied as 100-, 200-, and 400-mg single-dose vials
b. Dose modification. Discontinue the drug for severe IRCRS, pulmonary infiltration, and severe dermatologic reactions. See manufacturer’s recommendations on dosage adjustment for skin reactions.
c. Dose. 6 mg/kg given as a 1-hour intravenous infusion every 2 weeks; reduce infusion rate by 50% for mild IRCRS and permanently discontinue the drug for severe reactions.
d. Drug interactions. Unknown
J. Rituximab (anti-CD20 antibody, Rituxan, MabThera)
1. Indications. CD20-positive, B-cell non-Hodgkin lymphoma
2. Pharmacology
a. Mechanisms. The rituximab antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. CD20 is expressed on more than 90% of all B-cell non-Hodgkin lymphomas. CD20 is not expressed on early pre-B cells, plasma cells, normal bone marrow stem cells, or antigen-presenting dendritic reticulum cells.
In vitro, the Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate complement- and antibody-dependent B-cell lysis.
b. Metabolism. Rituximab has been detectable in the serum 3 to 6 months after completion of treatment. Administration results in a rapid and sustained depletion of circulating and tissue-based B cells. B-cell levels return to normal by 12 months after completion of treatment.
3. Toxicity
a. Dose-limiting. Hypersensitivity reactions, serious cardiac arrhythmias
b. Common. IRCRS (see Section VII.A.3) occurs in 50%, particularly during the first infusion (decreasing in occurrence substantially on subsequent infusions).
c. Occasional. Severe granulocytopenia or thrombocytopenia; arthralgia/myalgia, malaise, headache; diarrhea, dyspepsia, taste perversion; hypertension, hypotension, tachycardia, bradycardia, dyspnea; lacrimation, paresthesia, hypesthesia, agitation, insomnia; hyperglycemia, hypocalcemia; pain in chest, back, abdomen or tumor site; rash, night sweats, angioedema, tumor lysis syndrome
d. Rare. Arrhythmias, angina; aplastic anemia, hemolytic anemia; mucocutaneous reactions (e.g., Stevens–Johnson syndrome); pneumonia; progressive multifocal leukoencephalopathy related to Jakob–Creutzfeldt virus infections up to 1 year after treatment, reactivation of hepatitis B virus infection
4. Administration. During the first infusion, the initial rate should be 50 mg/h or less; if hypersensitivity or infusion-related events do not occur, increase the infusion rate in 50-mg/h increments up to a maximum of 400 mg/h. Subsequent infusions can be started at 100 mg/h and escalated by 100 mg/h at 30-minute intervals. Corticosteroids, epinephrine, and antihistamines should be available for immediate use in event of a severe hypersensitivity reaction during administration. Watch for tumor lysis syndrome in patients with a high tumor burden.
a. Supplied as 100- and 500-mg vials
b. Dose modification. Infusion-related reactions respond to stopping the infusion and then resuming at a slower rate. Use with caution in patients with pre-existing heart disease.
c. Dose. 375 mg/m2 IV weekly for 2 to 4 weeks or with each cycle of combination chemotherapy
K. Trastuzumab (Herceptin, anti-HER2 antibody)
1. Indications. Cancers of the breast (adjuvant or metastatic) and metastatic adenocarcinomas of the stomach or gastroesophageal junction (GEJ) that overexpress the HER2 protein
a. Adjuvant breast indication: In combinations for ER/PR-negative or high risk ER/PR-positive (tumor size > 2 cm, or age < 35 years, or tumor grade >1) breast cancers
b. Metastatic breast indication: As a single agent or in combinations
c. Metastatic gastric/GEJ adenocarcinoma indication: In combination with cisplatin and capecitabine or 5-FU for patients who have not received prior treatment for metastatic disease
2. Pharmacology. The HER2 (HER2/neu, c-erb-B2) proto-oncogene encodes a transmembrane receptor protein that is structurally related to EGFR. Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of HER2. The humanized IgG-κ antibody against HER2 is produced by a mammalian cell (Chinese hamster ovary) suspension culture. It inhibits the proliferation of tumor cells that overexpress HER2. The metabolism of trastuzumab is not well characterized.
3. Toxicity. During pregnancy, it can result in oligohydramnios and oligohydramnios sequence.
a. Dose-limiting. Cardiomyopathy
b. Common. IRCRS (see Section VII.A.3) occurs in 40% during the first infusion (reactions can be serious).
c. Occasional. Asthenia, headache, rash, nausea and vomiting, arthralgia, pain, fever
d. Rare. Anemia, leukopenia; severe pulmonary toxicity, hypersensitivity reaction, nephritic syndrome (4 to 18 months after treatment)
4. Administration. Monitor left ventricular ejection fraction in these patients during ongoing therapy (every 3 months during and upon completion of trastuzumab; every 6 months for at least 2 years thereafter).
a. Supplied as 440-mg vial
b. Dose modification. Use with extreme caution in patients with pre-existing cardiac dysfunction or prior cardiotoxic therapy.
c. Dose
(1) Adjuvant for breast cancer. Initial dose 4 mg/kg over 90 minutes; maintenance dose 2 mg/kg/wk or 6 mg/kg every 3 weeks, given over 30 to 90 minutes
(2) Metastatic breast cancer. Initial dose 4 mg/kg over 90 minutes; subsequent doses 2 mg/kg/wk given over 30 minutes
(3) Metastatic gastric/GEJ adenocarcinoma. Initial dose 8 mg/kg over 90 minutes; subsequent doses 6 mg/kg every 3 weeks given over 30 to 90 minutes. Chemotherapies are given for 6 cycles with trastuzumab, which is continued as monotherapy until disease progression.
d. Drug interactions. Increased risk of cardiotoxicity when used in combination with anthracyclines or cyclophosphamide, increased anticoagulant effect with warfarin
VIII. MISCELLANEOUS AGENTS
A. Anagrelide (Agrylin)
1. Indications. Thrombocytosis in myeloproliferative disorders
2. Pharmacology
a. Mechanisms. Anagrelide reduces the platelet count by uncertain mechanisms. It does not affect the leukocyte count and does not affect DNA synthesis.
b. Metabolism. The drug is extensively metabolized by CYP1A2 and also inhibits this enzyme; <1% is excreted in the urine as unaltered drug.
3. Toxicity. Adverse effects are treated symptomatically and usually abate on continuation of therapy. Cardiovascular complications that occur are usually related to underlying diseases.
a. Dose-limiting. Thrombocytopenia (platelet counts return to normal 4 days after discontinuing the drug.
b. Common. Headache (45%), asthenia, palpitations, tachycardia, fluid retention, diarrhea, bloating, abdominal pain, asthenia, dizziness
c. Occasional. Nausea, vomiting, other GI disturbances; dyspnea, chest pain, paresthesia, rash, pruritus, fever, malaise
4. Administration. Platelet counts should be monitored every 2 to 7 days until maintenance dosage is attained. Propranolol can be helpful for induced arrhythmias.
a. Supplied as 0.5- and 1-mg capsules
b. Dose modification. None for renal dysfunction. Avoid the drug in patients with severe hepatic impairment; reduce dose for patients with moderate hepatic impairment.
c. Dose. Start at 0.5 mg q.i.d. or 1 mg b.i.d. PO; increase dosage weekly by 0.5 mg/d until the desired platelet count is achieved. Maximum recommended dosages are 10 mg/d or 2.5 mg/dose.
d. Drug interactions. Drugs that induce, inhibit, or are metabolized by CYP1A2 may affect anagrelide concentrations and vice versa.
B. Arsenic trioxide (Trisenox)
1. Indications. Refractory or relapsed acute promyelocytic leukemia (APL) that is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
2. Pharmacology
a. Mechanisms. The mechanism of action is not understood.
b. Metabolism. Involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsonic acid by methyltransferases, which appear to be mostly in the liver. Trivalent arsenic is mostly methylated and excreted in urine.
3. Toxicity. A litany of side effects is associated with this drug; refer to the package insert for details. The following are the most important:
a. Dose-limiting. QT interval prolongation can lead to torsades de points and complete heart block and occurs in 40% of patients.
b. Common. Leukocytosis, GI disturbances, fatigue, fever, edema, cough, dyspnea, hypotension; rash, pruritus; headaches, insomnia, paresthesia dizziness; arthralgias, myalgias; hypokalemia, hyperkalemia, hypomagnesemia, hyperglycemia
c. APL differentiation syndrome occurs in about 25% of patients and is characterized by fever, dyspnea, pulmonary infiltrates, pleural or pericardial effusions, and weight gain, with or without leukocytosis (this topic is further discussed in Chapter 25, Acute Leukemia). High dose dexamethasone is administered when clinical signs develop.
4. Administration. The drug is an irritant. Serum potassium, calcium, magnesium, and creatinine (as well as CBC and coagulation profile) should be monitored at least twice weekly and abnormalities corrected; if possible, drugs that are known to prolong the QT interval should be discontinued; absolute QT intervals >500 ms should be addressed immediately.
a. Supplied as 10 mg/10 mL ampules
b. Dose modification: Use caution with renal dysfunction.
c. Dose: 0.15 mg/kg IV daily over 1 to 2 hours (or up to 4 hours if vasomotor reactions are observed) until bone marrow remission occurs (≤60 doses). Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy; 0.15 mg/kg IV daily for 25 doses over a period up to 5 weeks.
d. Drug interactions. Drugs that cause blood glucose concentrations, electrolyte abnormalities or prolongation of the QT interval
C. Asparaginase (L-asparaginase, Elspar)
1. Indication. Acute lymphoblastic leukemia
2. Pharmacology. The drug is purified from Escherichia coli and/or Erwinia chrysanthemi.
a. Mechanism. This enzyme hydrolyzes asparagine into aspartic acid and, to a lesser extent, glutamine into glutamic acid. Leads to inhibition of protein synthesis. Kills cells that cannot synthesize asparagine by destroying extracellular asparagine stores. Cell cycle–specific for postmitotic G1 phase.
b. Metabolism. Plasma half-life (8 to 30 hours) is independent of dose. Metabolism is independent of hepatic and renal function. Only trace amounts are recovered in urine.
3. Toxicity
a. Dose-limiting.
(1) Allergic reactions (including chills, urticaria, skin rashes, fever, laryngeal constriction, asthma, and anaphylactic shock) are the most frequent. Allergic reactions develop within 1 hour of dosing and are most likely to occur after several doses are given, particularly if the last dose was given more than 1 month previously and if the drug is administered intravenously rather than intramuscularly. Patients who respond to E. coli asparaginase but develop allergic reactions may be treated relatively safely with another source of the enzyme (e.g., pegaspargase, Erwinia source).
(2) Coagulation defects associated with decreased synthesis of fibrinogen, factor V, factor VIII, protein C, antithrombin III, and variably factors VII and IX. Manifestations are usually subclinical but may result in overt CNS thrombosis or pulmonary embolism,
(3) Acute pancreatitis (15%)
b. Common
(1) Immediate effects (50% to 60%): Fever, chills, nausea, vomiting, abdominal cramps
(2) Encephalopathy in 25% to 50% of patients. Lethargy, somnolence, and confusion tend to occur within the first few days of therapy, reverse after completion of therapy, and are rarely a cause for discontinuing treatment. Hemorrhagic and thrombotic CNS events occur later and are associated with induced imbalances in the coagulation and fibrinolytic systems.
(3) Hepatitis: Abnormal LFTs in more than 50% of treated patients, but is rarely severe
(4) Prerenal azotemia (65%); a rise in blood urea nitrogen and blood ammonia levels not evidence of toxicity
(5) Hyperglycemia
(6) Interferes with thyroid function tests for up to 1 month, probably due to marked reduction of thyroxine-binding globulin
c. Rare. Mild to moderate myelosuppression, diarrhea, severe renal failure, hyperthermia, Parkinsonian symptoms, serum ammonia increase
4. Administration. Administer a small (2-U) intradermal test dose to check for hypersensitivity, particularly when the dose is being repeated more than 1 week from the immediately previous dose; however, false negative rates of up to 80% are reported. Epinephrine (1 mg, 1:1,000), hydrocortisone (100 mg), and diphenhydramine (50 mg) should be readily available to treat anaphylaxis each time the drug is given. An asparaginase desensitization scheme is available.
For IM, volumes > 2 mL should be divided and administered at two separate sites. For IV (greatly increases the risk of allergic reactions and should be avoided if possible), administer over at least 30 to 60 minutes.
a. Supplied as 10,000-IU vials
b. Dose modification. None for renal dysfunction. Use with caution for moderate hepatic dysfunction. Contraindicated in the presence of pancreatitis.
c. Dose. Usually administered in combination with other chemotherapeutic agents at a dose of 6,000 U/m2 IM or IV every 3 days (or three times weekly) for six to nine doses or 1,000 U/kg/d IV for 10 days
d. Drug interactions
(1) Asparaginase blocks the action of methotrexate and thus rescues the patient from methotrexate toxicity. Give asparaginase 24 hours after methotrexate
(2) Vincristine should be administered 12 to 24 hours before asparaginase, which inhibits the clearance of that drug.
D. Asparaginase, pegylated (PEG-L-asparaginase, polyethylene glycol-L-asparaginase, pegaspargase, Oncaspar)
1. Indications. Acute lymphoblastic leukemia (particularly in patients who have had hypersensitivity reactions to native asparaginase). Pegaspargase is contraindicated in patients with a history of any of the following with prior L-asparaginase treatment: pancreatitis, serious hemorrhagic events, serious thrombosis.
2. Pharmacology. See asparaginase above. The drug is purified from E. coli.
3. Toxicity. IV administration is associated with higher incidences of adverse effects than IM administration.
a. Dose-limiting. Allergic reactions (particularly when given IV), 1% to 10% with no prior asparaginase hypersensitivity; 32% with prior asparaginase hypersensitivity
b. Common. Edema, fever, malaise, rash; coagulopathy (7%); increased transaminases (10%)
c. Occasional (1% to 5%). Hypotension, tachycardia, thrombosis; GI upset, pancreatitis (1 to 2%); headache, seizure, CNS thrombosis or hemorrhage (3%), paresthesias; hyperglycemia, hypoglycemia; arthralgias, myalgias
4. Administration. Be prepared to treat anaphylaxis at each administration
a. Supplied as 750 U/mL in 5 mL vials
b. Dose modification: None for moderate hepatic or renal dysfunction
c. Dose: for adults, 2,500 U/m2 deep IM (do not exceed 2 mL per injection site) or slow IV over 1 to 2 hours as part of a combination chemotherapy regimen. Administer at intervals of at least 14 days.
d. Drug interactions. Methotrexate (give pegaspargase 24 hours after methotrexate)
E. Bexarotene (Targretin)
1. Indication. Cutaneous T-cell lymphoma that is refractory to at least one prior systemic therapy
2. Pharmacology
a. Mechanisms. Selectively binds and activates retinoic X receptors (RXRs), which form heterodimers with various other receptors, including retinoic acid receptors (RARs), vitamin D receptors, and thyroid receptors. The activated receptors function as transcription factors, which then regulate the expression of various genes involved in controlling cell differentiation, growth, and proliferation.
b. Metabolism. Extensively metabolized by the hepatic P450 microsomal system to both active and inactive metabolites. Primarily eliminated through the hepatobiliary system and in feces.
c. Toxicity
(1) Photosensitivity, dry skin, rash, exfoliative dermatitis
(2) Hypothyroidism (up to 50% of patients), hypoglycemia, hypertriglyceridemia, hypercholesterolemia
(3) Ocular problems: Retinal complications, cataracts, xerophthalmia, conjunctivitis, blepharitis, periorbital edema
(4) Headache, asthenia
(5) Mild, dose-related leukopenia
d. Administration. Patients should avoid exposure to sunlight and should be advised to limit vitamin A supplementation to <1,500 IU/d to avoid potential additive toxic effects.
(1) Supplied as 75-mg capsules and 1% gel (60 g tube) for topical use
(2) Dose modification. Use with caution in patients with liver dysfunction, diabetes (particularly those on hypoglycemic agents), or lipid disorders.
(3) Dose. 300 mg/m2 PO daily with food as a single dose. An initial dose of 150 to 225 mg has also been used.
(4) Drug interactions. Use with caution in patients who are also taking drugs that inhibit or induce the cytochrome P450 system, such as phenytoin, phenobarbital, and rifampin (see Section VI.A). The efficacy of hypoglycemic agents may be potentiated by bexarotene.
F. Bortezomib (Velcade)
1. Indication. Multiple myeloma, mantle cell lymphoma
2. Pharmacology. Bortezomib is a modified dipeptidyl boronic acid.
a. Mechanisms. Reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, which is a large protein complex that degrades ubiquitinated proteins, which are involved in regulating the intracellular concentration of specific proteins. Disruption of this pathway affects multiple signaling pathways within the cell, leading to cell death. Down-regulates the NK-κB pathway, leading to inhibition of cell growth.
b. Metabolism. Metabolized via hepatic P450 3A4 (CYPEA4) enzymes. Elimination is not well characterized.
3. Toxicity
a. Dose-limiting. Peripheral neuropathy (predominantly sensory), hematosuppression (especially dose-related thrombocytopenia with nadir at day 11)
b. Common. Fatigue, fever (up to 40%), headache; gastrointestinal disturbance (anorexia, nausea, vomiting, diarrhea, constipation); arthralgia
c. Occasional. Hypotension (10%); motor neuropathy, blurred vision, myalgia; congestive heart failure; toxic epidermal necrolysis
d. Rare. Interstitial pneumonia and acute respiratory distress syndrome, reversible posterior leukoencephalopathy syndrome, acute hepatic failure
4. Administration
a. Supplied as 3.5-mg vials
b. Dose modification. Use with caution with hepatic dysfunction.
c. Dose. 1.3 mg/m2 IV bolus or subcutaneously on days 1, 4, 8, and 11 of each 21-day cycle (weekly regimens are also used)
d. Drug interactions
(1) Patients who are concomitantly receiving inhibitors of cytochrome P450 (see Section VI.A.) should be closely monitored for toxicities or reduced efficacy.
(2) Patients receiving oral hypoglycemics require close monitoring of blood glucose levels.
(3) Medications that cause peripheral neuropathy (e.g., antivirals) may potentiate neuropathy.
G. Denileukin diftitox (Ontak, DAB389IL-2) is a recombinant fusion protein composed of amino acid sequences of human interleukin-2 (IL-2) and the enzymatic and translocation domains of diphtheria toxin. This protein binds specifically to the CD25 component of the IL-2 receptor and is then internalized via endocytosis. Cellular protein synthesis is inhibited, and apoptosis occurs on release of diphtheria toxin into the cytosol.
1. Indications. Persistent or recurrent cutaneous T-cell lymphomas whose malignant cells express the CD25 component of the IL-2 receptor (must be confirmed on tumor biopsy)
2. Toxicity
a. Infusion reactions are observed in 70% of patients within 24 hours and resolving within 48 hours of the last infusion of a course. Serious hypersensitivity reactions occur in about 8% of patients.
b. Common. A capillary leak syndrome characterized by edema, hypotension, and/or hypoalbuminemia is usually a self-limited process but can be serious and even result in death (the onset may occur up to 2 weeks after infusion); asthenia, mild, transient flu-like symptoms; rash, diarrhea (may be prolonged), abnormal LFTs; hypoalbuminemia (85% with nadir at 2 weeks).
c. Occasional. Loss of visual acuity, usually with loss of color vision, has been reported and may be persistent; hyperthyroidism; nausea, vomiting, constipation; tachycardia, chest pain; paresthesia, confusion; arthralgia/myalgias; hematosuppression.
3. Administration. Premedicate with nonsteroidal anti-inflammatory agents and antihistamines. Patients should be monitored closely throughout the entire treatment. Resuscitative medications (epinephrine, corticosteroids) and equipment should be available at bedside before treatment.
a. Supplied as 300 μg in 2-mL vials
b. Dose. 9 or 18 μg/kg/d IV over 30 to 60 minutes on days 1 to 5 every 21 days for 8 cycles
c. Dose modification. Withhold administration if serum albumin levels are <3.0 g/dL.
d. Drug interactions. Antihypertensives may exacerbate hypotension.
H. Everolimus (Afinitor)
1. Indications. Advanced renal cell carcinoma refractory to sunitinib or sorafenib; progressive pancreatic neuroendocrine tumors
2. Pharmacology
a. Mechanisms. Inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the P13K/AKT pathway. Everolimus binds to an intracellular protein resulting in a complex that inhibits mTOR kinase activity and downstream effectors of mTOR involved in protein synthesis. Additionally, the drug reduces expression of hypoxia-inducible factors (HIF-1) and of VEGF.
b. Metabolism. Extensively metabolized in the liver by CYP3A4. Metabolites are excreted in the feces.
3. Toxicity
a. Dose-limiting. Immunosuppression resulting in bacterial or fungal infections
b. Common. Stomatitis, gastrointestinal disturbance; fatigue; hematosuppression; hyperglycemia, hyperlipidemia, hypophosphatemia, transaminase elevation; fever; peripheral edema; nephrotoxicity; cough, dyspnea
c. Occasional. Epistaxis, interstitial pneumonia, nail disorders, hand–foot syndrome; hypertension, headache, tremor
4. Administration.
a. Supplied as 2.5, 5 and 10 mg tablets
b. Dose modification: For patients with Child-Pugh class B hepatic impairment, reduce dose to 5 mg once daily; do not use for Child-Pugh class C. If moderate inhibitors of CYP3A4 (see Section VI.A. are required, reduce dose to 2.5 mg once daily.
c. Dose: 10 mg once daily with or without food (reduction to 5 mg once daily may be needed to manage adverse reactions); do not crush or chew tablets
d. Drug interactions. Consider dose modification with concomitant use of other drugs affecting CYP3A4 (see Section VI.A) or P-glycoprotein.
I. Hexamethylmelamine (altretamine, hexetidine, Hexalen)
1. Indication. Recurrent ovarian carcinoma
2. Pharmacology
a. Mechanism is unknown. It structurally resembles an alkylating agent but does not have alkylating agent activity.
b. Metabolism. Rapidly demethylated and hydroxylated in the liver by the microsomal P450 system. Excreted in urine and hepatobiliary tract as metabolites.
3. Toxicity
a. Dose-limiting. Nausea and vomiting, which may worsen with continued therapy
b. Common. Neurotoxicity (25%), including paresthesias, hypoesthesia, hyperreflexia, motor weakness, agitation, confusion, hallucinations, lethargy, depression, coma; myelosuppression (mild) with nadir blood cell counts occurring 3 to 4 weeks after starting treatment; nausea and vomiting
c. Occasional. abnormal LFTs, flu-like syndrome; abdominal cramps, diarrhea.
d. Rare. Alopecia, skin rashes, cystitis
4. Administration
a. Supplied as 50-mg capsules
b. Dose modification. Give cautiously to patients with hepatic or renal dysfunction.
c. Dose. 200 to 260 mg/m2 PO daily in 4 divided doses for 14 to 21 days of a 28-day schedule when recovery permits
d. Drug interactions. Cimetidine may inhibit metabolism. Barbiturates may enhance metabolism. Tricyclic antidepressants may result in severe orthostatic hypotension.
J. Lenalidomide (IMiD3, Revlimid)
1. Indications. Myeloma; myelodysplastic syndrome (MDS) with deletion 5q abnormality, myelofibrosis
2. Pharmacology
a. Mechanisms. Lenalidomide is a thalidomide analogue with immunomodulatory, antiangiogenic, and antineoplastic properties.
b. Metabolism. The majority of the drug is excreted unchanged in the urine.
3. Toxicity. Lenalidomide is an analogue of thalidomide, which is a known human teratogen that causes life-threatening human birth defects.
a. Dose-limiting. Neutropenia and thrombocytopenia
b. Common. Diarrhea, other gastrointestinal disturbances; rash, pruritus, fatigue
c. Occasional. Deep vein thrombosis; myalgia/arthralgias, peripheral neuropathy, dizziness, headache, fever; hypokalemia, hypomagnesemia; hypertension, hypothyroidism
4. Administration. The capsules are taken with water and should not be opened, broken, or chewed.
a. Supplied as 5-, 10-, 15-, and 25-mg capsules
b. Dose modification. Dosage reduction is necessary in patients with impaired renal function, particularly with creatinine clearance <30 mL/min.
c. Dose. For MDS, the starting dose is 10 mg daily. For myelofibrosis, the dose is 5 to 10 mg daily. For myeloma, the starting dose is 25 mg daily for 21 days of each 28-day cycle.
d. Drug interactions. Hypotensive agents may increase risk for hypotension. Concomitant antineoplastic agents or dexamethasone increase risk for thromboembolic events in myeloma patients.
K. Temsirolimus (Torisel)
1. Indications. Advanced renal cell carcinoma
2. Pharmacology
a. Mechanisms. Inhibitor of mTOR (mammalian target of rapamycin) that controls cell division, resulting in growth arrest in the G1 phase of the cell cycle and reduced levels of hypoxia-inducible factors (HIF-1 and HIF-2) and of VEGF
b. Metabolism. Extensively metabolized via the cytochrome P450 3A4 hepatic microsomal pathway into metabolites, including sirolimus (the principle active metabolite). Elimination is primarily through the feces.
3. Toxicity
a. Dose-limiting. Hypersensitivity reactions or end-organ damage (see below)
b. Common. Myelosuppression, anorexia; dysgeusia; mucositis, diarrhea, constipation; rash, asthenia, edema; delayed wound healing; hyperglycemia, hyperlipidemia (may require cholesterol-lowering agents), hypokalemia, hypophosphatemia, elevated serum creatinine, abnormal LFTs
c. Occasional. Interstitial lung disease, headache, lacrimation, arthralgia/myalgias, chest pain, intracerebral hemorrhage (with brain metastasis or anticoagulant therapy)
d. Rare. Fatal interstitial lung disease, bowel perforation, or acute renal failure
4. Administration. Premedicate with 25 to 50 mg diphenhydramine IV alone or with an IV histamine H2 antagonist (e.g., ranitidine 50 mg).
a. Supplied as 30-mg vial plus diluent
b. Dose modification. Consider dose modification with concomitant use of other drugs affecting CYP3A4.
c. Dose. 25 mg IV over 30 to 60 minutes weekly; dose modifications for renal cell carcinoma are as follows (see package insert for recommendations for mantle cell lymphoma):
(1) Reduce dose to 20 mg weekly on first occurrence of neutrophils <1,000/μL, or platelets <75,000/μL, or other toxicities are grade 3 to 4.
(2) Reduce dose to 15 mg weekly on second occurrence of the above.
(3) Discontinue drug on third occurrence of the above.
d. Drug interactions. Consider dose modification with concomitant use of other drugs affecting CYP3A4 (see Section VI.A). Also consider dose modification for hepatic dysfunction.
L. Thalidomide (α-[N-phthalimido]glutarimide, Thalomid)
1. Indications. Myeloma; myelodysplastic syndromes
2. Pharmacology
a. Mechanisms. Incompletely understood; inhibits TNF-α, down-modulates certain surface adhesion molecules, may exert an antiangiogenic effect
b. Metabolism. Not well defined
3. Toxicity. Thalidomide’s teratogenic effect is its most serious toxicity. All women of childbearing age should have a baseline β-human chorionic gonadotrophin before starting therapy with thalidomide. Women should practice two forms of birth control throughout treatment: one highly effective form (intrauterine device, hormonal contraception, partner’s vasectomy) and one additional barrier method. Men taking the drug must use latex condoms for every sexual encounter with a woman of childbearing potential, because the drug may be in the semen.
a. Dose-limiting. Neurologic side effects (70% and dose-related), including fatigue, sensory and motor neuropathy, sedation, dizziness, confusion, tremor, agitation, orthostatic hypotension, etc. Manifestations may resolve slowly or be irreversible.
b. Common. Constipation, anorexia, skin rash (maculopapular or urticarial), venous thromboembolism, edema
c. Occasional. Leukopenia, hypersensitivity, fever, hypotension, LFT abnormalities
d. Rare. Stevens–Johnson syndrome
4. Administration
a. Supplied as 50-, 100-, 150-, and 200-mg capsules
b. Dose modification. Therapy should be discontinued if a rash develops and can be restarted with caution if the rash was not suggestive of a serious skin condition.
c. Dose. 50 to 200 mg PO at bedtime for myeloma with dexamethasone
d. Drug interactions.
(1) Antineoplastic agents and dexamethasone increase the risk of thromboembolic events.
(2) IV bisphosphonates risk of nephrotoxicity may be increased.
(3) Neurotoxic medications may increase the risk of peripheral neuropathy.
M. Tretinoin (all-trans-retinoic acid [ATRA], Vesanoid)
1. Indication. Acute promyelocytic leukemia
2. Pharmacology
a. Mechanisms. On entry into cells, tretinoin binds to cellular retinoic acid binding protein. This complex is transported to the nucleus, where it binds to retinoic acid receptors (RARs) and/or retinoic X receptors (RXRs, see Section VIII.E.). This process induces differentiation of acute promyelocytic cells to normal myelocytes and induces apoptosis by mechanisms that have not been fully elucidated.
b. Metabolism. Extensively metabolized by the hepatic P450 microsomal system. Excreted both in feces and urine.
3. Toxicity
a. Vitamin A toxicity (nearly all patients): headache (which improves after the first week), fever, dryness of skin and mucous membranes, skin rash, mucositis, conjunctivitis, and fluid retention.
b. Retinoic acid syndrome (25% of patients): Fever, leukocytosis, dyspnea, diffuse pulmonary infiltrates, pleural and/or pericardial effusions, and weight gain. The syndrome usually occurs during the first month of therapy and can be dose-limiting. Development of these manifestations mandates discontinuance of the drug and treatment with dexamethasone (10 mg IV q12 h for 3 days or until the syndrome has completely resolved). Therapy can be resumed in most cases once the syndrome has completely resolved.
c. Other common events. Fatigue and weakness, hyperlipidemia (60%), gastrointestinal symptoms; bone pain, myalgia, chest discomfort, arrhythmias, flushing, abnormal LFTs (50%), ear discomfort (25%), visual disturbances
d. Occasional. Alopecia, photosensitivity; cardiac ischemia or failure, myocarditis, pericarditis, hypertension, pulmonary hypertension; renal dysfunction; central nervous system toxicity in various forms including encephalopathy
e. Rare. Venous or arterial thrombosis, vasculitis, genital ulceration
4. Administration. Monitor patients closely for retinoic acid syndrome during the first month of therapy. Take with food.
a. Supplied as 10-mg capsules
b. Dose modification. Use with caution in patients who have pre-existing hypertriglyceridemia, diabetes mellitus, obesity, or alcoholism. Dosage adjustment may be necessary for hepatic or renal impairment, but no specific guidelines are available.
c. Dose. 45 mg/m2 PO divided in two or three daily doses for 45 to 90 days (for 30 days after achieving a complete remission)
d. Drug interactions.
(1) Use with caution in patients who are also taking drugs that inhibit or induce the cytochrome P450 system (see Section VI.A.).
(2) Oral contraceptive efficacy may be reduced.
(3) Tetracycline antibiotics may increase pseudotumor cerebri (seen in the pediatric population).
(4) Avoid vitamin A; increases vitamin A toxicity associated with ATRA.
IX. HORMONAL AGENTS
A. Adrenocorticosteroids
1. Indications. Broad variety of oncologic problems that include the following:
a. Component of combination chemotherapy regimens for lymphoproliferative disorders and plasma cell dyscrasias
b. Symptomatic lymphangitic lung carcinomatosis; bronchial obstruction by tumor.
c. Symptomatic brain metastases with or without cerebral edema; spinal cord compression
d. Painful liver metastases
e. Immune-mediated cytopenias
f. Prevention of chemotherapy-induced vomiting
g. Appetite stimulant and mood elevator in patients with terminal cancer
2. Toxicity and side effects (usually associated with long-term therapy)
a. Peptic ulcer disease
b. Sodium retention (edema, heart failure, hypertension)
c. Potassium wasting (hypokalemia, alkalosis, muscle weakness)
d. Glucose intolerance, accumulation of fat on trunk and face, weight gain
e. Proximal myopathy
f. Personality changes, including euphoria and psychosis
g. Osteoporosis, aseptic hip necrosis
h. Thinning and fragility of the skin
i. Suppression of the pituitary–adrenal axis
j. Susceptibility to infection
3. Administration. Patients receiving high doses of corticosteroids are given prophylactic oral antacid therapy. Methylprednisolone is preferred for patients with severe hepatic dysfunction. Dexamethasone is preferred for peritumoral edema. These drugs are supplied in a wide variety of dosages, as follows:
a. Prednisone: 1.0-, 2.5-, 5.0-, 10-, 20-, 25-, and 50-mg tablets and 1- and 5-mg/mL oral solutions
b. Methylprednisolone (Medrol): 2-, 4-, 8-, 16-, 24-, and 32-mg tablets
c. Dexamethasone (Decadron): 0.5-, 0.75-, 1.0-, 1.5-, 2.0-, 4.0-, and 6.0-mg tablets and 0.5 mg/5 mL to 1.0 mg/mL solutions
B. Adrenal inhibitors: Mitotane (o,p’-DDD, Lysodren)
1. Indications. Adrenal carcinoma, ectopic Cushing syndrome
2. Pharmacology
a. Mechanism. Causes adrenal cortical atrophy; the exact mechanism is unknown. Blocks adrenocorticosteroid synthesis in normal and malignant cells. Aldosterone synthesis is not affected.
b. Metabolism. Degraded slowly in the liver and extensively distributed in fatty tissues. Its action is antagonized by spironolactone; the two drugs should not be administered together. Metabolites are excreted in the bile and urine.
3. Toxicity
a. Dose-limiting. Nausea and vomiting; adrenocortical insufficiency
b. Common. Depression, lethargy, maculopapular rash
c. Occasional. Orthostatic hypotension; diarrhea, abnormal LFTs; headache, irritability, confusion, tremors; diplopia, retinopathy, lens opacity; myalgia; hemorrhagic cystitis, fever
d. Rare. Long-term (>2 years) use may lead to brain damage or functional impairment.
4. Administration. Initiate treatment in a hospital until a stable dosage is achieved. Do not give mitotane with a fatty meal, which may impair absorption. Plasma cortisol levels should be monitored periodically to assess the effectiveness of treatment and the possible development of adrenal insufficiency. Glucocorticoid and mineralocorticoid replacement therapy may be necessary; some suggest replacement therapy with the initiation of mitotane treatment.
a. Supplied as 500-mg tablets
b. Dose modification. Reduce dose for patients with hepatic impairment.
c. Dose. 2 to 10 g PO daily in three or four divided doses
d. Drug interactions
(1) Warfarin doses usually have to be increased when mitotane is given.
(2) Mitotane alters the liver’s P450 system and thus may affect the levels of other drugs that are metabolized by this system.
C. Androgens
1. Indications. Breast carcinoma, short-range anabolic effect, stimulation of erythropoiesis
2. Toxicity and side effects vary among preparations. Virilization, fluid retention, and hepatotoxicity, which is characterized by abnormal LFTs or cholestasis and is usually reversible, are frequent with certain preparations. May cause hypercalcemia in immobilized patients.
3. Administration. Use with caution in patients with cardiac, hepatic, or renal disease.
a. Fluoxymesterone (Halotestin and others): 10 to 40 mg/d in two to four divided doses (supplied as 2-, 5-, and 10-mg tablets)
b. Methyltestosterone (Android and others): 50 to 200 mg/d in two or three divided doses (supplied as 10- and 25-mg tablets)
D. Antiandrogens (bicalutamide, flutamide, nilutamide)
1. Indications. Prostate cancer in combination with medical therapy or orchiectomy that reduces testicular but not adrenal androgen production
2. Pharmacology. Nonsteroidal antiandrogens bind to cytosol androgen receptors and competitively inhibit the uptake or binding of androgens in target tissues. The drugs are almost totally metabolized.
3. Toxicity (may be contributed to by the combined therapeutic component)
a. Common. Impotence, gynecomastia, and other manifestations of hypogonadism; diarrhea
b. Occasional. Nausea and vomiting, myalgia, depression; mild hypertension or pulmonary disorder (bicalutamide, nilutamide)
c. Rare. Hepatitis, including cholestatic jaundice (all three), hemolytic anemia or methemoglobinemia (flutamide), iron-deficiency anemia (bicalutamide), interstitial pneumonitis, or visual disturbances (nilutamide)
4. Administration. Usually given in combination with gonadotropin-releasing hormone (GnRH) agonist analogs. Use with caution in patients with hepatic dysfunction.
a. Bicalutamide (Casodex): 50 mg PO once daily (supplied as 50-mg tablets)
b. Flutamide (Eulexin): 250 mg t.i.d. PO (supplied as 125-mg capsules)
c. Nilutamide (Nilandron): 300 mg once daily PO for 30 days, then 150 mg daily (supplied as 50-mg tablets)
d. Abiraterone acetate (Zytiga): 1,000 mg once PO daily on empty stomach with prednisone 5 mg b.i.d. for metastatic castration-resistant prostate cancer in patients who have received chemotherapy containing docetaxel (supplied as 250-mg tablets)
E. Estrogens [diethylstilbestrol (DES)]
1. Indication. Breast carcinoma
2. Toxicity. Nausea, uterine bleeding; hypercalcemic “flare”; thromboembolic disorders; abnormal LFTs, cholestatic jaundice (rare); chloasma, optic neuritis, retinal thrombosis; rash, pruritus; fluid retention, hypertension, headache, dizziness, hypertriglyceridemia
3. Administration
a. Supplied as 0.25-, 0.5-, 1.0-, and 5.0-mg tablets
b. Dose. 1 to 15 mg PO daily in divided doses
F. Antiestrogens (tamoxifen, toremifene, fulvestrant)
1. Indication. Breast carcinoma
2. Pharmacology. Tamoxifen and toremifene are nonsteroidal agents that bind to estrogen receptors and may exert antiestrogenic, estrogenic, or both activities. Fulvestrant is an estrogen receptor antagonist without known agonist effects.
3. Toxicity (derived from tamoxifen, which is associated with the largest experience)
a. Common. Hot flashes, menstrual changes, vaginal discharge, uterine bleeding; lowered serum cholesterol (especially low-density cholesterol); thrombocytopenia (mild and transient)
b. Occasional. Retinopathy or keratopathy (reversible), cataracts; leukopenia, anemia; nausea, vomiting; hair loss (mild), rash; “flare” in first month of therapy of patients with bone metastases; thrombophlebitis or thromboembolism, particularly in patients with cofactors for thrombosis (e.g., inheritance of factor VLeiden)
c. Rare. Abnormal LFTs; altered mental state; slightly increased occurrence of endometrial adenocarcinoma on prolonged use
d. Toxicity of fulvestrant includes transient pain at injection site, gastrointestinal symptoms, headache, back pain, and vasodilatation.
4. Administration
a. Tamoxifen (Nolvadex): 20 mg PO once daily (supplied as 10- and 20-mg tablets)
b. Toremifene (Fareston): 60 mg PO once daily (supplied as 60-mg tablets)
c. Fulvestrant (Faslodex): 500 mg (10 mL) by slow IM injection on days 1, 15, and 29 and once monthly thereafter; 250 mg (5 mL) by slow IM injection on days 1, 15, and 29 and once monthly thereafter for moderate hepatic impairment (Child-Pugh class B)
G. Aromatase inhibitors (anastrozole, letrozole, exemestane, aminoglutethimide)
1. Indication. Breast cancer in postmenopausal women
2. Pharmacology. These nonsteroidal inhibitors interfere with aromatase, the enzyme that converts androgens from the adrenals and peripheral tissues to estrogens. Anastrozole and letrozole are competitive inhibitors, whereas exemestane permanently binds to and irreversibly inactivates aromatase. None of these agents inhibit adrenal corticosteroid or aldosterone biosynthesis. All are significantly more potent inhibitors of aromatase than aminoglutethimide (Cytadren), which also inhibits corticosteroid or aldosterone biosynthesis, requires q.i.d. dosing with hydrocortisone, is more toxic than the newer alternatives, and is no longer recommended.
3. Toxicity. Antiestrogen effects, peripheral edema, thromboembolism, osteopenia, vaginal bleeding
4. Dose
a. Anastrozole (Arimidex): 1 mg PO daily (supplied as 1-mg tablets)
b. Letrozole (Femara): 2.5 mg PO daily (supplied as 2.5-mg tablets)
c. Exemestane (Aromasin): 25 mg PO daily (supplied as 25-mg tablets)
H. Gonadotropin-releasing hormone (GnRH) agonists
1. Indications. Prostate and breast cancer
2. Pharmacology. GnRH agonist analogs are potent inhibitors of gonadotropin secretion. Continuous administration decreases serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and result in castration levels of testosterone in men and of estradiol in women within 2 to 4 weeks of treatment.
3. Toxicity and side effects. A small but statistically significant increased risk of diabetes mellitus and/or cardiovascular disease has been observed in men receiving GnRH agonist therapy.
a. Common. Hot flushes, decreased libido; impotence and gynecomastia in men; amenorrhea and uterine bleeding in women; osteoporosis, depression
b. Occasional. Hypercholesterolemia, local discomfort at site of injection
c. Rare. GI upset, rash, hypertension, azotemia, headache, depression
4. Administration. Antiandrogens are recommended beginning 7 days before and for 5 weeks after starting GnRH-agonist therapy.
a. Leuprolide (Lupron, Eligard)
(1) Supplied as 7.5-, 22.5-, and 30-mg vials
(2) Dose. 7.5-, 22.5-, or 30-mg IM every 1, 3, or 4 months, respectively
b. Goserelin (Zoladex)
(1) Supplied as 3.6- and 10.8-mg pellets in prefilled syringe
(2) Dose. 3.6 mg SC monthly or 10.8 mg every 3 months
c. Buserelin (Suprefact). Available in Canada
(1) Supplied as 6.3- and 9.45-mg implants
(2) Dose. 6.3- and 9.45-mg every 2 or 3 months, respectively
I. Progestins
1. Indications. Endometrial and breast carcinomas; or as an appetite stimulant in malignant cachexia; or for hot flashes in patients with breast carcinoma
2. Toxicity and side effects
a. Menstrual changes, uterine bleeding, hot flashes, gynecomastia, galactorrhea
b. Fluid retention, thrombophlebitis, thromboembolism
c. Nervousness, somnolence, depression, headache
3. Administration
a. Medroxyprogesterone acetate injectable (Depo-Provera)
(1) Supplied as vials containing 150 or 400 mg/mL
(2) Dose for hot flashes, 150 mg IM every 3 months
(3) Dose for endometrial carcinoma. 1 g IM weekly for six doses and then monthly
b. Megestrol (Megace)
(1) Supplied as 20- and 40-mg tablets and 40 mg/mL suspension
(2) Dose for breast cancer. 40 mg PO q.i.d.
(3) Dose for endometrial cancer. 20 to 80 mg q.i.d.
(4) Dose for appetite stimulation. 400 to 800 mg PO daily as a single dose
X. CYTOPROTECTIVE AGENTS
A. Amifostine (ethiofos, Ethyol)
1. Indications. Protection against cumulative nephrotoxicity from cisplatin-based therapies. Reduction of xerostomia in patients undergoing postoperative radiation therapy for head and neck cancer.
2. Pharmacology
a. Mechanisms. It is a prodrug that is dephosphorylated in tissues to an active free thiol metabolite that acts as a potent scavenger of oxygen-free radicals and superoxide anions to inactivate the reactive species of cisplatin and radiation.
b. Metabolism. Rapidly metabolized to an active free thiol metabolite, which is further converted to a less active disulfide metabolite. The estimated plasma half-life is 8 minutes.
3. Toxicity
a. Dose-limiting. Hypotension (>60% of patients) is treated with fluid infusion and changes in posture.
b. Common. Hypotension, nausea, and vomiting
c. Occasional. Hypocalcemia, hiccups; infusion-related reaction with flushing, chills, dizziness, somnolence, and sneezing
d. Rare. Transient loss of consciousness, allergic reaction
4. Administration. Patients should be well hydrated before amifostine is administered. Antiemetics, including dexamethasone and a serotonin receptor antagonist, should be administered before amifostine.
a. Supplied as 500-mg vials
b. Dose modification. The infusion should be interrupted if systolic blood pressure decreases significantly.
c. Dose.
(1) 910 mg/m2 over 15 minutes, starting 30 minutes before chemotherapy (740 mg/m2 if hypotension does not correct itself 5 minutes after interrupting the infusion)
(2) 200 mg/m2 once daily 15 to 30 minutes before radiation therapy
d. Drug interactions. Drugs that could potentiate hypotension should not be administered in conjunction with amifostine.
B. Dexrazoxane (Zinecard, Totect)
1. Indications. Zinecard is approved to reduce the incidence and severity of anthracycline cardiotoxicity. Totect is approved as an orphan drug to treat anthracycline extravasation.
2. Pharmacology. The drug is converted to a chelating agent that interferes with iron-mediated free-radical generation that is thought to be responsible, in part, for anthracycline-induced cardiomyopathy.
3. Toxicity. Added myelosuppression that is usually mild and reversible; pain at injection site
4. Administration
a. Cardioprotectant dose. The Zinecard dose is 10 times the doxorubicin dose, which is given within 30 minutes of starting dexrazoxane. This drug can be begun when the patient has received 300 mg/m2 of doxorubicin and is expected to be continued on that therapy.
b. Extravasation dose. Totect should be given within 6 hours of anthracycline extravasation at a dose of 1,000 mg/m2 every 24 hours twice and then 500 mg/m2 24 hours later once (maximum body surface area is 2 m2).