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Anticancer Agents
Lindsay C. Stansfield and Thomas E. Hughes
Please note that all information has been obtained from current product labeling as of January 31, 2013. Doses listed are those from the package insert and apply when the agent is given alone, unless otherwise noted. Doses are expressed in accordance with nomenclature guidelines from Kohler et al.
ADVERSE REACTIONS
Adverse reactions to anticancer agents involve the following:
■Cardiovascular system (CV)
■Skin and integument system (DERM)
■Electrolyte abnormalities (ELECTRO)
■Endocrine system (ENDO)
■Gastrointestinal system (GI)
■Genitourinary system (GU)
■Hematopoietic system (HEMAT)
■Hepatic system (HEPAT)
■Infusion-related reactions (INFUS)
■Neurologic system, central and peripheral (NEURO)
■Ocular system
■Pulmonary system (PULM)
■Liver function
■Serum creatinine (Cr)
■Creatinine clearance (CrCl)
■Nausea and vomiting (N/V): Classified on a four-level system. Emetogenic potential is based on the incidence of acute emesis in product labeling and/or based on classification by national chemotherapy-induced nausea and vomiting (CINV) guidelines—minimal, <10%; low, 10% to 30%; moderate, 30% to 90%; and high, >90% (see Chapter 38).
ABIRATERONE (ZYTIGA)
Mechanism of Action
■Androgen biosynthesis inhibitor of 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
FDA-Approved Indications
■In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer.
FDA-Approved Dosage
■1,000 mg (four 250 mg tablets) PO once daily in combination with prednisone 5 mg administered PO twice daily. Abiraterone must be taken on an empty stomach, swallowed whole with water. No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose of abiraterone.
Dose Modification Criteria
■Hepatic (moderate, Child–Pugh class B): yes
■Hepatic (severe, Child–Pugh class C): avoid use
■Renal: no
Adverse Reactions
■CV: hypertension
■ELECTRO: hypokalemia, hypernatremia, and hypophosphatemia
■ENDO: adrenal insufficiency, hypercholesterolemia, hyperglycemia, and hypertriglyceridemia
■GI: constipation, diarrhea, and dyspepsia
■GU: hematuria and urinary tract infection
■HEMAT: anemia and lymphopenia
■HEPAT: elevated alkaline phosphatase, elevated bilirubin and elevated LFTs
■PULM: cough, dyspnea, nasopharnygitis, and upper respiratory tract infection
■Other: contusion, edema, fatigue, hot flush, insomnia, joint swelling/discomfort, and muscle discomfort
Comments
■Use abiraterone with caution in patients with a history of CV disease. The safety of abiraterone in patients with LVEF <50% or New York Heart Association (NYHA) class II to IV heart failure was not established in clinical studies. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.
■Monitor for signs and symptoms of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations.
■Abiraterone is an inhibitor of CYP2D6. Avoid coadministration of abiraterone with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). Based on in vitro data, avoid or use with caution with strong CYP3A4 inhibitors or inducers.
■Abiraterone peak concentration (Cmax) and area under the concentration–time curve (AUC) exposure were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone was administered with a meal compared to a fasted state. Patients must be counseled to take abiraterone on an empty stomach.
■Abiraterone is not indicated for use in women. Pregnancy category X: abiraterone can cause fetal harm when administered to a pregnant woman.
ALDESLEUKIN (PROLEUKIN)
Mechanism of Action
■Cellular immunity activation
FDA-Approved Indications
■Metastatic renal cell carcinoma (RCC)
■Metastatic melanoma
FDA-Approved Dosage
■600,000 international units/kg IV over 15 minutes every 8 hours for a maximum of 14 doses
■May be repeated after 9 days of rest for a maximum of 28 doses per course
Dose Modification Criteria
■Withhold or interrupt a dose for toxicity
Adverse Reactions
■CV: hypotension, tachycardia, and arrhythmia
■DERM: rash and pruritis
■GI: diarrhea, N/V (moderate), mucositis, and anorexia
■GU: oliguria and acute renal failure
■HEMAT: myelosuppression
■NEURO: confusion, somnolence, anxiety, and dizziness
■PULM: dyspnea and pulmonary edema
■Other: pain, fever, chills, and malaise
Comments
■Restrict use to patients with normal cardiac and pulmonary function.
■Monitor for capillary leak syndrome.
■Associated with impaired neutrophil function; consider antibiotic prophylaxis for patients with indwelling central lines.
■Withhold in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.
ALEMTUZUMAB (CAMPATH)
Mechanism of Action
■Humanized monoclonal antibody directed against the cell surface protein CD52. The CD52 antigen is expressed on the surface of normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and a subpopulation of granulocytes. The proposed mechanism of action is antibody-dependent lysis of leukemic cells following cell-surface binding.
FDA-Approved Indication
■B-cell chronic lymphocytic leukemia (CLL)
FDA-Approved Dosage
■Alemtuzumab is dose escalated in a stepwise format to a maintenance dose of 30 mg.
■The initial recommended dose is 3 mg IV over 2 hours daily. When this dose is tolerated (infusion-related toxicities ≤ grade 2), the daily dose should be escalated to 10 mg IV over 2 hours daily and continued until tolerated. When the 10 mg dose is tolerated, the maintenance dose of 30 mg may be initiated. The maintenance dose is 30 mg IV over 2 hours administered three times per week (i.e., Monday, Wednesday, and Friday) for up to 12 weeks. In most patients, escalation to 30 mg can be accomplished in 3 to 7 days. If therapy is interrupted for 7 or more days, alemtuzumab should be reinitiated with gradual dose escalation.
■Single doses of Campath >30 mg or cumulative doses >90 mg per week should not be administered because these doses are associated with a higher incidence of pancytopenia.
■Premedicate patients with an antihistamine (e.g., diphenhydramine 50 mg oral or IV) and acetaminophen (650 mg oral) 30 minutes prior to alemtuzumab to ameliorate or avoid infusion-related toxicity. Antiemetics, meperidine, and corticosteroids have also been used to prevent or treat infusion-related toxicities.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■CV: hypotension and edema/peripheral edema
■DERM: rash, urticaria, and pruritus
■GI: N/V (minimal), diarrhea, anorexia, and mucositis/stomatitis
■HEMAT: myelosuppression and lymphopenia
■INFUS: rigors, fever, chills, N/V, hypotension, dyspnea, bronchospasm, headache, rash, and urticaria
■NEURO: headache, dysthesias, and dizziness
■PULM: dyspnea, cough, bronchitis, pneumonia, and bronchospasm
■Other: opportunistic infections, sepsis, fatigue, asthenia, and pain
Comments
■Alemtuzumab (Campath®) was removed from the commercial market in September 2012. The Campath Distribution Program was developed to ensure continued access to alemtuzumab for appropriate patients. Drug supplies are provided free of charge, but in order to receive drug, the healthcare provider is required to document and comply with certain requirements. For additional information, refer to www.campath.com or contact the Campath Distribution Program (1-877-422-6728).
■Alemtuzumab-treated patients are at risk for opportunistic infections due to profound lymphopenia. Anti-infective prophylaxis is recommended upon initiation of therapy and for a minimum of 2 months following the last dose of alemtuzumab or until the CD4 count is ≥200 cells/μL. Prophylaxis directed against Pneumocystis pneumonia (PCP) (e.g., trimethoprim/sulfamethoxazole) and herpesvirus infections (e.g., famciclovir or equivalent) should be utilized.
■Do not administer as an intravenous push or bolus.
■Careful monitoring of blood pressure and hypotension is recommended especially in patients with ischemic heart disease and in patients on antihypertensive medications.
■Patients who have recently received alemtuzumab should not be immunized with live viral vaccines.
ALTRETAMINE (HEXALEN)
Mechanism of Action
■Unknown, but like an alkylating agent in structure
FDA-Approved Indications
■Ovarian cancer: second-line, palliative treatment of persistent or recurrent ovarian cancer
FDA-Approved Dosage
■65 mg/m2 orally four times daily; total daily dose: 260 mg/m2 for 14 or 21 consecutive days every 28 days
Dose Modification Criteria
■Myelosuppression: yes
■Nonhematologic toxicity (GI intolerance and progressive neurotoxicity): yes
Adverse Reactions
■GI: N/V (moderate)
■HEMAT: myelosuppression (WBC, RBC, and platelets)
■NEURO: peripheral sensory neuropathy, mood disorders, ataxia, and dizziness
Comments
■Monitor for neurologic toxicity
ANASTRAZOLE (ARIMIDEX)
Mechanism of Action
■Selective, nonsteroidal aromatase inhibitor
FDA-Approved Indications
■Breast cancer
•Adjuvant treatment: postmenopausal women with hormone receptor-positive early breast cancer
•First-line therapy: postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer
•Second-line therapy (after tamoxifen) in postmenopausal women with advanced breast cancer
FDA-Approved Dosage
■1 mg orally daily (no requirement for glucocorticoid or mineralocorticoid replacement)
Dose Modification Criteria
■Renal: no
■Hepatic (mild-to-moderate impairment): no
■Hepatic (severe impairment): unknown
Adverse Reactions
■CV: hot flashes/flushing
■GI: N/V (low) and diarrhea
■HEPAT: elevated liver function tests (LFTs) (in patients with liver metastases)
■NEURO: headache
■PULM: dyspnea
■Other: asthenia, pain, back pain, and vaginal bleeding
Comments
■Patients with estrogen receptor (ER)-negative disease and patients who do not respond to tamoxifen rarely respond to anastrazole
ARSENIC TRIOXIDE (TRISENOX)
Mechanism of Action
■The mechanism is not completely defined.
■Induces apoptosis in NB4 human promyelocytic leukemia cells in vitro and causes damage or degradation of the fusion protein PML/RAR-α.
FDA-Approved Indications
■Acute promyelocytic leukemia (APL): Second-line treatment for the induction of remission and consolidation of APL patients who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.
FDA-Approved Dosage
■APL induction: 0.15 mg/kg IV over 1 to 2 hours daily until bone marrow remission. Total induction dose should not exceed 60 doses.
■APL consolidation: 0.15 mg/kg IV over 1 to 2 hours daily × 25 doses over a period up to 5 weeks. Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy.
Dose Modification Criteria
■Renal: no data, use with caution
■Hepatic: no data
Adverse Reactions
■CV: QT interval prolongation, complete atrioventricular block, torsades de pointes-type ventricular arrhythmia, atrial dysrhythmias, tachycardia, hypotension, and edema
■DERM: rash, dermatitis, dry skin, and pruritus
■ENDO: hyperglycemia, hypokalemia, and hypomagnesemia
■GI: N/V (moderate), diarrhea, abdominal pain, anorexia, and constipation
■HEMAT: leukocytosis and myelosuppression
■HEPAT: elevated LFTs
■NEURO: headache, dizziness, and paresthesias
■PULM: dyspnea and cough
■Other: fatigue, arthralgia, myalgia, pain, and APL differentiation (RA-APL) syndrome (RA-APL syndrome—fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusion)
Comments
■The APL differentiation syndrome (RA-APL syndrome) has occurred in some patients treated with arsenic trioxide. Early recognition and high-dose corticosteroids (dexamethasone 10 mg IV every 12 hours × 3 days or until the resolution of symptoms) have been used for management.
■Prior to stating arsenic trioxide, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed; preexisting electrolyte abnormalities should be corrected. Avoid concomitant drugs that may prolong the QT interval. During therapy with arsenic trioxide, monitor and maintain normal potassium and magnesium concentrations (see package insert).
■Risk factors for QT prolongation and subsequent arrhythmias include other QT prolonging drugs, a history of torsades de pointes, preexisting QT prolongation, congestive heart failure (CHF), administration of potassium wasting diuretics, or other drugs or conditions that result in hypokalemia or hypomagnesemia.
ASPARAGINASE (ELSPAR, ERWINAZE)
Mechanism of Action
■Asparaginase depletes asparagine, an amino acid required by some leukemic cells
FDA-Approved Indications
■Elspar (asparaginase derived from Escherichia coli): acute lymphoblastic leukemia (ALL) induction therapy (component of multiagent chemotherapeutic regimen)
■Erwinaze (asparaginase derived from Erwinia chrysanthemi): ALL induction therapy for patients who have developed hypersensitivity to E. coli–derived asparaginase
FDA-Approved Dosage
■Consult current literature for doses.
■Elspar: ALL induction therapy—6,000 international units/m2 IM or IV three times a week.
■Erwinaze: ALL induction therapy—25,000 international units/m2 intramuscularly substituting for each planned dose of either pegaspargase or E. coli–derived asparaginase.
Dose Modification Criteria
■None available
Adverse Reactions
■DERM: skin rash
■ENDO: hyperglycemia
■GI: N/V (minimal) and pancreatitis
■GU: prerenal azotemia
■HEMAT: coagulopathy
■HEPAT: increased LFTs, hyperbilirubinemia, and decreased serum albumin
■NEURO: variety of mental status changes
■Other: hypersensitivity, anaphylactic reactions, and hyperthermia
Comments
■Contraindicated in patients with active pancreatitis or history of pancreatitis.
■Hypersensitivity and anaphylactic reactions can occur.
■Consult package insert regarding test doses and desensitization schedules.
■Intramuscular administration has a lower incidence of hypersensitivity reactions compared to intravenous administration.
■Intravenous infusions should be over at least 30 minutes.
AXITINIB (INLYTA)
Mechanism of Action
■Inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3
FDA-Approved Indications
■Advanced RCC after failure of one prior systemic therapy
FDA-Approved Dosage
■5 mg orally twice should be administered daily. Swallow whole with a glass of water. Administer axitinib doses approximately 12 hours apart with or without food.
Dose Modification Criteria
■Hepatic (mild, Child–Pugh class A): no
■Hepatic (moderate, Child–Pugh class B): yes
■Hepatic (severe, Child–Pugh class C): not studied
■Renal (mild, moderate, and severe): no
■End-stage renal disease (CrCl <15 mL/minute): use caution
■Tolerability/toxicity: yes
Adverse Reactions
■CV: hypertension
■DERM: dry skin, palmar-plantar erythrodysesthesia, and rash
■ELECTRO: decreased bicarbonate, hyperkalemia, hypernatremia, hypocalcemia, hyponatremia, and hypophosphatemia
■ENDO: hyperglycemia, hypoglycemia, and hypothyroidism
■GI: abdominal pain, anorexia, constipation, diarrhea, dysgeusia, N/V (minimal to low), and stomatitis
■GU: proteinuria
■HEMAT: anemia, leukopenia, lymphopenia, and thrombocytopenia
■HEPAT: hypoalbuminemia, hyperbilirubinemia, increased alkaline phosphatase, and increased LFTs
■NEURO: headache
■PULM: cough and dyspnea
■Other: asthenia, arterial and venous thromboembolic events, dysphonia, fatigue, hemorrhage, pain in extremity, and weight decreased
Comments
■Blood pressure should be well controlled prior to starting axitinib, and should be monitored regularly during treatment.
■Use with caution in patients who are at an increased risk for arterial and venous thrombotic events, as these events have been observed.
■Hemorrhagic events have been reported. Axitinib has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in these patients.
■Gastrointestinal perforation and fistula have occurred.
■Hypothyroidism requiring thyroid hormone replacement has been reported. Thyroid function should be monitored prior to and throughout treatment.
■Stop axitinib at least 24 hours prior to scheduled surgery. The decision to resume axitinib after surgery should be based on clinical judgment of adequate wound healing.
■Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed. Permanently discontinue axitinib if signs or symptoms of RPLS, such as headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances, occur.
■Monitor for proteinuria before initiation of, and periodically throughout, treatment with axitinib.
■Concomitant use of strong CYP3A4/5 inhibitors should be avoided. If coadministration is necessary, decrease the axitinib dose by half.
■Pregnancy category D: Axitinib may cause fetal harm when administered to a pregnant woman.
AZACITIDINE (VIDAZA)
Mechanism of Action
■Antimetabolite is a pyrimidine nucleoside analog of cytidine. Azacitidine causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow.
FDA-Approved Indications
■Myelodysplastic syndrome (MDS): The specific subtypes of MDS for which azacitidine is indicated include refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.
FDA-Approved Dosage
■First treatment cycle: The recommended starting dose for all patients regardless of baseline hematology laboratory values is 75 mg/m2 SC or IV, daily for 7 days.
■Subsequent treatment cycles: A cycle should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after two treatment cycles and if no toxicity other than N/V has occurred.
■Duration: Minimum duration of four treatment cycles is recommended; complete or partial response may take more than four treatment cycles; may be continued as long as the patient continues to benefit.
Dose Modification Criteria
■Renal: no data (use with caution)
■Hepatic: no data (use with caution)
■Myelosuppression: yes
■Nonhematologic toxicity (renal tubular acidosis, renal toxicity): yes
Adverse Reactions
■DERM: injection site erythema or pain, ecchymosis, rash, and pruritus
■ELECTRO: renal tubular acidosis (alkaline urine, fall in serum bicarbonate, and hypokalemia)
■GI: N/V (moderate), diarrhea, constipation, anorexia, abdominal pain, and hepatotoxicity
■GU: increased Cr and BUN, renal failure, and renal tubular acidosis
■HEMAT: anemia, neutropenia, and thrombocytopenia
■NEURO: headache and dizziness
■PULM: cough and dyspnea
■Other: fever, rigors, fatigue, weakness, and peripheral edema
Comments
■Teratogenic (pregnancy category D): Women of childbearing potential should be advised to avoid becoming pregnant while receiving azacitidine. Men should be advised to not father a child while receiving azacitidine.
■Use caution in patients with liver disease. Azacitidine is potentially hepatotoxic in patients with preexisting hepatic impairment.
■Azacitidine is contraindicated in patients with advanced malignant hepatic tumors.
■Azacitidine and its metabolites are primarily cleared renally. Patients with renal impairment should be closely monitored for toxicity. Renal toxicity has been reported rarely with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditions.
BCG LIVE (INTRAVESICAL) [THERACYS, TICE BCG]
Mechanism of Action
■Local inflammatory and immune response
FDA-Approved Indications
■Treatment and prophylaxis of carcinoma in situ of the urinary bladder and for the prophylaxis of primary or recurrent-stage Ta and/or T1 papillary tumors following transurethral resection (TUR)
FDA-Approved Dosage
■TheraCys: Vial contains 81 mg (dry weight) or 10.5 ± 8.7 × 108 colony-forming units with accompanying 3 mL diluent vial.
•One reconstituted vial (81 mg/3 mL), diluted in 50 mL sterile, preservative-free normal saline (0.9% sodium chloride injection, USP), instilled into bladder for as long as possible (up to 2 hours) once weekly for 6 weeks (induction therapy) followed by one treatment at 3, 6, 12, 18, and 24 months after initial treatment (maintenance therapy)
■TICE Bacillus Calmette–Guérin (BCG): Vial contains 50 mg (wet weight) or 1 to 8 × 108 colony-forming units.
•One reconstituted vial (50 mg/1 mL), diluted in a total volume of 50 mL preservative-free normal saline (0.9% sodium chloride injection, USP), instilled into bladder for as long as possible (up to 2 hours) once weekly for 6 weeks followed by once monthly for 6 to 12 months
Dose Modification Criteria
■Withhold on any suspicion of systemic infection
Adverse Reactions
■GU: irritative bladder symptoms
■Other: malaise, fever, and chills; infectious complications (uncommon)
Comments
■TheraCys and TICE BCG are not bioequivalent products and may not be used interchangeably.
■May complicate tuberculin skin test interpretation.
■BCG live products contain live, attenuated mycobacteria. Because of the potential risk of transmission, it should be prepared, handled, and disposed of as a biohazard material.
BENDAMUSTINE HYDROCHLORIDE (TREANDA)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■CLL
■Indolent B-cell non-Hodgkin lymphoma (NHL): Disease progression during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
FDA-Approved Dosage
■CLL: 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to six cycles
■NHL: 120 mg/m2 IV over 60 minutes on days 1 and 2 of a 21-day cycle, up to eight cycles
Dose Modification Criteria
■Myelosuppression: yes
■Nonhematologic toxicity: yes
■Renal: No data; use with caution in patients with mild-to-moderate renal impairment, avoid in patients with CrCL <40 mL per minute.
■Hepatic: No data; use with caution in patients with mild hepatic impairment, avoid in patients with moderate to severe hepatic impairment.
Adverse Reactions
■DERM: rash, pruritis, toxic skin reactions, and bullous exanthema
■GI: N/V (moderate), diarrhea, and mucositis
■INFUS: fever, chills, pruritis, rash, anaphylaxis, or anaphylactoid reactions
■PULM: cough
■Other: tumor lysis syndrome, asthenia, and infections
Comments
■Infusion reactions occurred commonly in clinical trials. Monitor clinically and discontinue drug for severe reactions (grade 3 or worse). Measures to prevent severe reactions (e.g., antihistamines, antipyretics, and corticosteroids) should be considered in subsequent cycles in patients who have previously experienced grade 1 or 2 infusion reactions.
■Monitor for tumor lysis syndrome, particularly with the first treatment cycle, and utilize allopurinol during the first 1 to 2 weeks of therapy in patients at high risk.
■Severe skin reactions have been reported necessitating drug therapy to be withheld or discontinued.
■Bendamustine hydrochloride is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. Some metabolism via cytochrome P450 1A2 (CYP1A2) occurs forming active metabolites; thus, potential drug interactions with CYP1A2 inhibitors or inducers should be considered.
■Pregnancy category D: Bendamustine may cause fetal harm when administered to a pregnant woman.
BEVACIZUMAB (AVASTIN)
Mechanism of Action
■Recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF).
FDA-Approved Indications
■Metastatic colorectal cancer: First- or second-line treatment of patients with metastatic carcinoma of the colon or rectum; in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy. Second-line treatment of metastatic colorectal carcinoma (in combination with fluoropyrimidine–irinotecan-based or fluoropyrimidine–oxaliplatin-based therapy) in patients who have progressed on a first-line bevacizumab-containing regimen.
■Nonsquamous, non–small cell lung cancer (NSCLC): First-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC; in combination with carboplatin and paclitaxel.
■Glioblastoma: Second-line single-agent therapy in patients with progressive disease following prior therapy.
■Metastatic RCC: In combination with interferon-α.
FDA-Approved Dosage
■Metastatic colorectal cancer: Administered as an intravenous infusion (5 mg/kg or 10 mg/kg) every 2 weeks when used in combination with intravenous fluorouracil-based chemotherapy.
•5 mg/kg IV every 2 weeks when used in combination with bolus-IFL
•10 mg/kg IV every 2 weeks when used in combination with FOLFOX4
•5 mg/kg IV every 14 days or 7.5 mg/kg IV every 3 weeks when used in combination with a fluoropyrimidine–irinotecan-based or fluoropyrimidine–oxaliplatin-based chemotherapy regimen in patients who have progressed on a first-line bevacizumab-containing regimen.
■Nonsquamous NSCLC: 15 mg/kg intravenous infusion every 3 weeks in combination with carboplatin and paclitaxel.
■Glioblastoma: 10 mg/kg intravenous infusion every 2 weeks.
■Metastatic RCC: 10 mg/kg intravenous infusion every 2 weeks in combination with interferon-α.
■Do not administer as an intravenous push or bolus. The initial bevacizumab dose should be delivered over 90 minutes as an IV infusion following chemotherapy. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.
Dose Modification Criteria
■Renal: no
■Hepatic: no
■Myelosuppression: no
■Nonhematologic toxicity: yes
Adverse Reactions
■CV: hypertension, hypertensive crisis, and CHF
■GI: N/V (minimal), diarrhea, abdominal pain, gastrointestinal perforation, and wound dehiscence
■GU: proteinuria and nephrotic syndrome
■INFUS: fever, chills, wheezing, and stridor
■NEURO: headache
■PULM: dyspnea and wheezing stridor
■Other: epistaxis and other mild-to-moderate hemorrhagic events; serious hemorrhagic events; wound healing complications; deep vein thrombosis or other thromboembolic events; asthenia
Comments
■Bevacizumab can result in the development of gastrointestinal perforation and wound dehiscence and other wound healing complications. The appropriate interval between termination of bevacizumab and subsequent elective surgery required to avoid the risks of wound healing/wound dehiscence has not been determined. Product labeling suggests that bevacizumab should not be initiated for at least 28 days following major surgery and the surgical incision should be fully healed.
■Bleeding complications secondary to bevacizumab occur in two distinct patterns: minor hemorrhage (most commonly grade 1 epistaxis) and serious, and in some cases, fatal hemorrhagic events. Patients with squamous cell NSCLC appear to be at higher risk for serious hemorrhagic events. The risk of CNS bleeding in patients with CNS metastases receiving bevacizumab has not been evaluated.
■Blood pressure monitoring should be conducted every 2 to 3 weeks during therapy and more frequently in patients who develop hypertension.
■Monitor urinalysis serially for proteinuria; patients with a 2+ or greater urine dipstick reading should undergo further assessment (e.g., a 24-hour urine collection).
■Pregnancy category C: Angiogenesis is critical to fetal development and bevacizumab has been shown to be teratogenic in rabbits.
BEXAROTENE (TARGRETIN)
Mechanism of Action
■A retinoid that selectively binds and activates retinoid X receptor subtypes (RXRs).
■Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation.
FDA-Approved Indications
■Cutaneous T-cell lymphoma (CTCL): second-line treatment of the cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy
FDA-Approved Dosage
■300 mg/m2 orally daily with a meal
Dose Modification Criteria
■Renal: no (caution due to possible protein binding alterations)
■Hepatic: use with caution
■Toxicity: yes
Adverse Reactions
■CV: peripheral edema
■DERM: dry skin, photosensitivity, rash, and pruritus
■ENDO: hypothyroidism and hypoglycemia (diabetic patients)
■GI: nausea, pancreatitis, and abdominal pain
■HEMAT: leukopenia and anemia
■HEPAT: elevated LFTs
■NEURO: headache
■Ocular: cataracts
■Other: lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol, and decreased HDL cholesterol), asthenia, and infection
Comments
■Monitor fasting blood lipid tests prior to initiation of bexarotene and weekly until the lipid response is established (usually occurs within 2 to 4 weeks) and then at 8-week intervals thereafter.
■Monitor LFTs prior to initiation of bexarotene and then after 1, 2, and 4 weeks of treatment, and if stable, at least every 8 weeks thereafter during treatment.
■Monitor complete blood count (CBC) and thyroid function tests at baseline and periodically thereafter.
■Bexarotene is a teratogen (category X) and may cause fetal harm when administered to a pregnant woman. Bexarotene must not be given to a pregnant woman or a woman who intends to become pregnant. A negative pregnancy test in female patients of childbearing potential should be obtained within 1 week prior to starting bexarotene therapy and then repeated at monthly intervals while the patient remains on therapy. Effective contraception (two reliable forms used simultaneously) must be used for 1 month prior to initiation of therapy, during therapy, and for at least 1 month following discontinuation of therapy. Bexarotene may induce the metabolism of hormonal contraceptives and reduce their effectiveness; thus one form of contraception should be nonhormonal.
BICALUTAMIDE (CASODEX)
Mechanism of Action
■Antiandrogen
FDA-Approved Indications
■Prostate cancer: palliation of advanced prostate cancer (stage D2) in combination therapy with a luteinizing hormone-releasing hormone (LHRH) agonist
FDA-Approved Dosage
■50 mg orally daily
Dose Modification Criteria
■Renal: no
■Hepatic (mild-to-moderate impairment): no
■Hepatic (severe impairment): use with caution
Adverse Reactions
■ENDO: loss of libido, hot flashes, and gynecomastia
■GI: N/V, diarrhea, and constipation
■GU: impotence
Comments
■Monitor LFTs prior to treatment, at regular intervals for the first 4 months, and periodically thereafter.
BLEOMYCIN (BLENOXANE)
Mechanism of Action
■Unknown, but may inhibit DNA and RNA synthesis
FDA-Approved Indications
■Squamous cell cancers, NHL, testicular cancer, Hodgkin disease, malignant pleural effusions
FDA-Approved Dosage
■The product labeling recommends a test dose (2 units or less) for the first two doses in lymphoma patients.
■From 0.25 to 0.50 units/kg (10 to 20 units/m2) IV or IM or SC weekly or twice weekly.
■Malignant pleural effusions: 60 units as single intrapleural bolus dose.
Dose Modification Criteria
■Renal: yes
Adverse Reactions
■DERM: erythema, rash, striae, vesiculation, hyperpigmentation, skin tenderness, alopecia, nail changes, pruritus, and stomatitis
■PULM: pulmonary fibrosis (increases at cumulative doses >400 units, but can happen at lower total doses), and pneumonitis
■Other: fever and chills; idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in 1% of lymphoma patients; local pain with intrapleural administration
Comments
■Risk factors for bleomycin-induced pulmonary toxicity include age (>70 years old), underlying emphysema, prior thoracic radiotherapy, high cumulative doses (e.g., >450 units), and high single doses (>30 units).
■Patients who have received bleomycin may be at increased risk of respiratory failure during the postoperative recovery period after surgery. Use the minimal tolerated concentration of inspired oxygen and modest fluid replacement to prevent pulmonary edema.
BORTEZOMIB (VELCADE)
Mechanism of Action
■Bortezomib is a reversible inhibitor of the 26S proteosome, a large protein complex that degrades ubiquinated proteins. Inhibition of the 26S proteosome prevents targeted proteolysis, which can effect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.
FDA-Approved Indications
■Multiple myeloma: first-line therapy in combination with melphalan and prednisone and in relapsed disease as a single agent
■Mantle cell lymphoma: second-line therapy in mantle cell lymphoma patients who have received at least one prior therapy
FDA-Approved Dosage
■General dosing guidelines: The recommended starting dose for bortezomib is 1.3 mg/m2. Bortezomib may be administered intravenously at a concentration of 1 mg/mL or subcutaneously at a concentration of 2.5 mg/mL. When administered intravenously, bortezomib is administered as a 3- to 5-second bolus intravenous injection.
■Multiple myeloma (first-line therapy in combination with melphalan and prednisone): 1.3 mg/m2 IV or SC twice weekly on a 6-week treatment cycle on days 1, 4, 8, 11, 22, 25, 29, and 32 for cycles 1 to 4. In cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22, and 29 of a 6-week treatment cycle (note that week 3 and week 6 of cycle are rest periods.)
■Multiple myeloma (relapsed disease) and mantle cell lymphoma: 1.3 mg/m2 IV or SC administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12 to 21). For extended therapy of more than eight cycles, bortezomib may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (days 1, 8, 15, and 22) followed by a 13-day rest period (days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib.
Dose Modification Criteria
■Renal: no data (use caution)
■Hepatic: yes (moderate or severe hepatic impairment)
■Myelosuppression: yes
■Nonhematologic toxicity (e.g., neuropathy and neuropathic pain): yes
Adverse Reactions
■CV: hypotension (including orthostatic hypotension and syncope) and edema
■DERM: rash
■GI: N/V (low), diarrhea, anorexia, and constipation
■HEMAT: myelosuppression (thrombocytopenia > anemia > neutropenia)
■NEURO: peripheral neuropathy, neuropathic pain, dizziness, and headache
■Ocular: diplopia and blurred vision
■PULM: dyspnea
■Other: asthenia, fatigue, fever, insomnia, and arthralgia
Comments
■The reconstitution volume/concentration is different for the intravenous and subcutaneous routes. Use caution when calculating the volume to be administered.
■The incidence of peripheral neuropathy is lower when bortezomib is administered by the subcutaneous route of administration compared to the intravenous route. Starting bortezomib subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy.
BOSUTINIB (BOSULIF)
Mechanism of Action
■Tyrosine kinase inhibitor (TKI) that inhibits the Bcr–Abl kinase that promotes chronic myelogenous leukemia (CML); also an inhibitor of Src-family kinases including Src, Lyn, and Hck.
FDA-Approved Indications
■Chronic, accelerated, or blast-phase Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy.
FDA-Approved Dosage
■500 mg orally once daily with food
Dose Modification Criteria
■Hepatic (mild, moderate, and severe): yes
■Renal (CrCL 25 to 90 mL per minute): no
■Renal (CrCL <25 mL per minute): not studied
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
Adverse Reactions
■DERM: pruritus and rash
■GI: abdominal pain, anorexia, diarrhea, and N/V (low)
■HEMAT: anemia, neutropenia, and thrombocytopenia
■HEPAT: elevated LFTs
■NEURO: dizziness and headache
■PULM: cough, nasopharnygitis, and respiratory tract infection
■Other: arthralgia, asthenia, back pain, fatigue, fluid retention, and pyrexia
Comments
■Avoid the concomitant use of strong or moderate CYP3A and/or P-glycoprotein (P-gp) inhibitors and inducers.
■Bosutinib may increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin.
■Proton pump inhibitors (PPIs) may decrease bosutinib drug levels. Consider short-acting antacids or H2-blockers in place of PPIs, and separate antacid or H2-blocker dosing from bosutinib by more than 2 hours.
■Bosutinib did not inhibit the T315I and V299L mutant cells in mice.
■Monitor hepatic enzymes at least monthly for the first 3 months and as needed.
■Pregnancy category D: Bosutinib may cause fetal harm when administered to a pregnant woman.
BRENTUXIMAB VEDOTIN (ADCETRIS)
Mechanism of Action
■Antibody–drug conjugate (ADC) consisting of a chimeric IgG1 directed against CD30 and monomethyl auristatin E (MMAE), a microtubule disrupting agent that is covalently attached to the antibody via a linker. The ADC binds to CD30-expressing cells, is internalized and, subsequently, MMAE is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis.
FDA-Approved Indications
■Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates.
■Systemic anaplastic large cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.
FDA-Approved Dosage
■1.8 mg/kg as an intravenous infusion over 30 minutes every 3 weeks.
■Do not administer as an intravenous push or bolus.
■Continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity.
■The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.
Dose Modification Criteria
■Hepatic: unknown
■Renal: unknown
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
Adverse Effects
■DERM: alopecia, night sweats, pruritus, and rash
■GI: abdominal pain, constipation, diarrhea, N/V (low), and oropharyngeal pain
■HEMAT: anemia, neutropenia, lymphadenopathy, and thrombocytopenia
■INFUS: anaphylaxis, breathing problems, chills, fever, and rash
■NEURO: dizziness, headache, and motor and sensory peripheral neuropathy
■PULM: cough, dyspnea, and upper respiratory tract infection
■Other: arthralgia, back pain, chills, fatigue, insomnia, myalgia, pain in extremity, pyrexia, and tumor lysis syndrome
Comments
■JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities.
■Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity.
■Brentuximab vedotin-induced peripheral neuropathy is predominantly sensory, and is cumulative.
■A higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies.
■MMAE is primarily metabolized by CYP3A. Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely monitored for adverse reactions. Coadministration of brentuximab vedotin with strong CYP3A4 inducers should be avoided.
■Pregnancy category D: Brentuximab vedotin may cause fetal harm when administered to a pregnant woman.
BUSULFAN (MYLERAN); BUSULFAN INJECTION (BUSULFEX)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Oral busulfan: palliative treatment of CML
■Parenteral busulfan: conditioning regimen (in combination with cyclophosphamide) prior to allogeneic hematopoietic progenitor cell transplantation for CML
FDA-Approved Dosage
■Oral busulfan: induction, 4 to 8 mg orally daily; maintenance, 1 to 3 mg orally daily
•Patients should receive phenytoin or an alternative antiseizure regimen prior to starting busulfan and continuing through the busulfan regimen.
•For nonobese patients, use ideal body weight (IBW) or actual body weight, whichever is lower.
•For obese or severely obese patients, use adjusted IBW. Adjusted IBW (AIBW) should be calculated as follows: AIBW = IBW + 0.25 × (actual weight – IBW).
•0.8 mg/kg IV over 2 hours every 6 hours × 16 doses (total course dose: 12.8 mg/kg) with cyclophosphamide.
Dose Modification Criteria
■Myelosuppression: yes
Adverse Reactions
■DERM: hyperpigmentation
■GI: N/V oral (<4 mg/kg/day): low, intravenous: moderate
■HEMAT: severe myelosuppression
■HEPAT: veno-occlusive disease
■NEURO: seizures
■PULM: pulmonary fibrosis
Comments
■Therapeutic drug monitoring to determine area under the curve (AUC) with the first administered dose is frequently done with high-dose parenteral busulfan.
■Alternative high-dose once daily parenteral dose regimens and multiple dose oral regimens have been utilized for conditioning regimens in the allogeneic blood and marrow transplant setting. Consult current literature for dosing regimens.
■Phenytoin reduces busulfan plasma AUC by 15%. Use of other anticonvulsants may result in higher busulfan plasma AUCs, and potentially increased toxicity. Consult current literature in regard to the antiseizure regimen utilized within a regimen.
CABAZITAXEL (JEVTANA)
Mechanism of Action
■Microtubule inhibitor that binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to stabilization of microtubules, which results in inhibition of mitotic and interphase cellular functions.
FDA-Approved Indication
■In combination with prednisone for the treatment of hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen
FDA-Approved Dosage
■25 mg/m2 as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone 10 mg administered daily throughout cabazitaxel treatment
Dose Modification Criteria
■Hepatic: avoid use
■Hematologic toxicity: yes
■Nonhematologic toxicity: yes
■Renal (CrCL 30 to 120 mL per minute): no
■Renal (CrCL <30 mL per minute): use caution
■End-stage renal disease: use caution
Adverse Effects
■DERM: alopecia
■GI: abdominal pain, anorexia, constipation, diarrhea, dysgeusia, dyspepsia, and N/V (low)
■HEMAT: anemia, leukopenia, neutropenia, and thrombocytopenia
■INFUS: hypersensitivity reactions
■NEURO: peripheral neuropathy
■PULM: cough and dyspnea
■Other: arthralgia, asthenia, back pain, fatigue, and pyrexia
Comments
■Cabazitaxel should not be used in patients with neutrophil counts of ≤1,500/mm3
■Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age >65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Monitoring of CBCs is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed.
■Elderly patients (≥65 years of age) may be more likely to experience certain adverse reactions. The incidence of neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection, and dehydration occurred at rates ≥5% higher in patients who were aged ≥65 years compared to younger patients.
■Since cabazitaxel is extensively metabolized in the liver, it should not be given to patients with hepatic impairment (total bilirubin ≥ upper limit of normal [ULN], or AST and/or ALT≥ 1.5XULN).
■Cabazitaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to other drugs formulated with polysorbate 80.
■Cabazitaxel requires two dilutions prior to administration, one with the supplied diluent (contains 5.7 mL of 13% w/w ethanol in water), followed by dilution in either 0.9% sodium chloride or 5% dextrose solution.
■Do not use PVC infusion containers and polyurethane infusion sets for preparation and administration. Use an in-line filter of 0.22 µm nominal pore size during administration.
■Cabazitaxel requires premedication with an antihistamine, corticosteroid, and H2 antagonist, and patients should be observed closely for hypersensitivity reactions.
■Diarrhea and electrolyte abnormalities may be severe, and require intensive measures.
■Since cabazitaxel is primarily metabolized through CYP3A, concomitant administration of strong CYP3A inhibitors and inducers should be avoided. Patients should refrain from taking St. John’s Wort.
■Pregnancy category D: Cabazitaxel may cause fetal harm when administered to a pregnant woman.
CABOZANTINIB (COMETRIQ)
Mechanism of Action
■Inhibits tyrosine activity of RET; MET; VEGFR-1, -2, and -3; KIT; TRKB; FLT-3; AXL; and TIE-2
FDA-Approved Indications
■Progressive, metastatic medullary thyroid cancer
FDA-Approved Dosage
■140 mg orally once daily.
■Do not eat for at least 2 hours before and at least 1 hour after taking cabozantinib.
Dose Modification Criteria
■Hepatic (moderate, severe): use not recommended
■Renal (mild, moderate): no
■Renal (severe): unknown
■Hematologic: yes
■Nonhematologic toxicity: yes
Adverse Effects
■CV: hypertension
■DERM: palmar-plantar erythrodysesthesia and wound complications
■ELECTRO: hypocalcemia and hypophosphatemia
■GI: abdominal pain, constipation, decreased appetite, diarrhea, nausea, oral pain, and stomatitis
■GU: proteinuria
■HEMAT: lymphopenia, neutropenia, and thrombocytopenia
■HEPAT: hyperbilirubinemia and transaminitis
■Other: decreased weight, dysgeusia, fatigue, hair color changes, hemorrhage, and thrombosis
Comments
■Gastrointestinal perforations and fistula formation have been reported. Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage have been reported. Monitor patients for signs and symptoms of bleeding, and do not administer cabozantinib to patients with a recent history of hemorrhage or hemoptysis.
■Cabozantinib treatment results in an increased incidence of thrombotic events.
■Withhold cabozantinib for wound dehiscence or complications requiring medical intervention. Stop treatment with cabozantinib at least 28 days prior to scheduled surgery.
■Monitor blood pressure and discontinue for hypertensive crisis.
■Treatment with cabozantinib can cause osteonecrosis of the jaw. Oral examination should be performed prior to initiation of cabozantinib and periodically during therapy. Patients should maintain good oral hygiene practices. For invasive dental procedures, therapy should be withheld for at least 28 days prior to scheduled surgery, if possible.
■Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.
■For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily dose of cabozantinib by 40 mg.
■For patients who require treatment with a strong CYP3A4 inducer, increase the daily cabozantinib dose by 40 mg as tolerated. The daily dose of cabozantinib should not exceed 180 mg. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort) known to induce CYP450 activity.
■Pregnancy category D: Cabozantinib may cause fetal harm when administered to a pregnant woman. Effective contraception during treatment with cabozantinib and up to 4 months after completion of therapy is recommended.
CAPECITABINE (XELODA)
Mechanism of Action
■Antimetabolite that is enzymatically converted to fluorouracil in tumors
FDA-Approved Indications
■Colorectal cancer
•Adjuvant therapy: Indicated as a single agent for adjuvant treatment in patients with Dukes C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred.
•Metastatic disease: First-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
■Breast cancer
•Combination therapy: Capecitabine combined with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure with prior anthracycline-containing chemotherapy.
•Breast cancer monotherapy: Third-line therapy for metastatic breast cancer (after paclitaxel and an anthracycline-containing chemotherapy regimen) or second-line (after paclitaxel) if anthracycline is not indicated.
FDA-Approved Dosage
■Give 1,250 mg/m2 orally twice daily (total daily dose: 2,500 mg/m2) at the end of a meal for 2 weeks, followed by a 1-week rest period, given as 3-week cycles. See product labeling for a dosing chart.
Dose Modification Criteria
■Renal (mild impairment; CrCl 51 to 80 mL per minute): no
■Renal (moderate impairment; CrCl 30 to 50 mL per minute): yes
■Hepatic (mild-to-moderate impairment due to liver metastases): no
■Toxicity (grade 2 toxicity or higher): yes
■See product labeling for dose modification guidelines.
Adverse Reactions
■DERM: hand and foot syndrome (palmar-plantar erythrodysesthesia) and dermatitis
■GI: N/V (low), diarrhea, mucositis, abdominal pain, anorexia, and hyperbilirubinemia
■HEMAT: myelosuppression
■NEURO: fatigue/weakness, paresthesia, and peripheral sensory neuropathy
Comments
■Altered coagulation parameters and/or bleeding have been reported in patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulation therapy. Anticoagulant response (INR and prothrombin time [PT]) should be monitored frequently to adjust anticoagulant dose accordingly.
CARBOPLATIN (PARAPLATIN)
Mechanism of Action
■Alkylating-like agent producing interstrand DNA cross-links
FDA-Approved Indications
■Advanced ovarian cancer
•First-line therapy (in combination with other agents)
•Second-line therapy (including patients who have previously received cisplatin)
FDA-Approved Dosage
■With cyclophosphamide: 300 mg/m2 IV × one dose on day 1 of the cycle; repeat cycles every 4 weeks × six cycles.
■Single agent: 360 mg/m2 IV × one dose every 4 weeks.
■Formula dosing may be used as an alternative to body surface area (BSA)-based dosing.
■Calvert formula for carboplatin dosing:
Total dose in milligrams = (target AUC) × [glomerular filtration rate (GFR) + 25].
■The target AUC of 4 to 6 mg/mL/minute using single-agent carboplatin appears to provide the most appropriate dose range in previously treated patients.
■The Calvert formula was based on studies where GFR was measured by 51Cr-EDTA clearance. Alternatively, many clinicians commonly use estimated CrCl equations to determine GFR.
Dose Modification Criteria
■Renal: yes
■Myelosuppression: yes
Adverse Reactions
■GI: N/V (moderate)
■ELECTRO: Mg, Na, Ca, and K alterations
■GU: Inc. Cr and BUN
■HEMAT: myelosuppression (thrombocytopenia > leukopenia and anemia)
■HEPAT: increased LFTs
■NEURO: neuropathy
■Other: anaphylactic reactions, pain, and asthenia
Comments
■Do not confuse with cisplatin for dosing or during preparation.
■Use caution when estimating CrCl for use in formula (e.g., Calvert equation) dosing. The current IDMS method to measure serum creatinine appears to underestimate serum creatinine values compared to older methods when the serum creatinine values are relatively low (e.g., 0.7 mg/dL). Overestimating the GFR may result when using a serum creatinine measured by the IDMS method. The FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. The maximum dose recommended by the FDA is based on a GFR estimate that is capped at 125 mL to minute for patients with normal renal function.
CARFILZOMIB (KYPROLIS)
Mechanism of Action
■Tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome
FDA-Approved Indications
■Multiple myeloma in patients who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy
FDA-Approved Dosage
■Recommended cycle 1 dose is 20 mg/m2/day. If tolerated, increase cycle 2 dose and subsequent cycle doses to 27 mg/m2/day.
■Carfilzomib is administered intravenously over 2 to10 minutes, on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28). Each 28-day period is considered one treatment cycle.
Dose Modification Criteria
■Hepatic (for baseline impairment): not studied
■Renal (for baseline impairment): no
■Nonhematologic toxicity: yes
Adverse Reactions
■Cr: acute renal failure and increased serum creatinine
■CV: cardiac toxicity, CHF, and pulmonary arterial hypertension
■GI: diarrhea and nausea (low)
■HEMAT: anemia, neutropenia, and thrombocytopenia
■HEPAT: increased bilirubin and increased LFTs
■INFUS: angina, arthralgia, chest tightness, chills, facial edema, facial flushing, fever, hypotension, myalgia, shortness of breath, syncope, vomiting, and weakness
■NEURO: headache and peripheral neuropathy
■PULM: cough, dyspnea, and upper respiratory tract infection
■Other: back pain, edema, fatigue, pyrexia, and tumor lysis syndrome
Comments
■Dosing is capped at a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.
■Hydrate patients prior to and following administration of carfilzomib to prevent tumor lysis syndrome and renal toxicity. Prior to each dose in cycle 1, give 250 to 500 mL of IV normal saline or other appropriate IV fluid. Give an additional 250 mL to 500 mL of IV fluids as needed following carfilzomib administration. Continue IV hydration as needed in subsequent cycles.
■Premedicate with dexamethasone 4 mg orally or intravenously prior to all cycle 1 doses, during the first cycle of dose escalation, and if infusion reaction symptoms develop or reappear. Infusion reactions can develop up to 24 hours after administration of carfilzomib.
■Monitor platelet counts frequently during treatment.
■New onset or worsening of preexisting CHF with decreased left ventricular function or myocardial ischemia has occurred following administration of carfilzomib. Monitor for cardiac complications. Patients with NYHA class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials; these patients may be at greater risk for cardiac complications.
■Monitor for heart failure and ischemia.
■Monitor for pulmonary hypertension. Monitor for and manage dyspnea immediately.
■Cases of hepatic failure have been reported. Monitor liver enzymes and bilirubin frequently during treatment.
■Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.
■Pregnancy category D: Carfilzomib can cause fetal harm when administered to a pregnant woman.
CARMUSTINE (BICNU)
Mechanism of Action
■Alkylating agent
FDA-Approved Indications
■Indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: brain tumors, multiple myeloma, Hodgkin lymphoma, and NHL.
FDA-Approved Dosage
■Single agent in previously untreated patients: 150 to 200 mg/m2 IV × one dose every 6 weeks or 75 to 100 mg/m2 IV daily × two doses every 6 weeks
Dose Modification Criteria
Adverse Reactions
■GI: N/V >250 mg/m2 (high), ≤250 mg/m2 (moderate)
■GU: nephrotoxicity with large cumulative doses
■HEMAT: myelosuppression (can be delayed)
■HEPAT: increased LFTs
■Ocular: retinal hemorrhages
■PULM: pulmonary fibrosis (acute and delayed)
Comments
■Risk of pulmonary toxicity increases with cumulative total doses >1,400 mg/m2 and in patients with a history of lung disease, radiation therapy, or concomitant bleomycin.
CETUXIMAB (ERBITUX)
Mechanism of Action
■Recombinant chimeric monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, thus blocking phosphorylation and activation of receptor-associated kinases.
FDA-Approved Indications
■Head and neck cancer
•Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy
•Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU
•Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy as single-agent therapy
■Metastatic colorectal carcinoma (K-Ras mutation-negative [wild-type], EGFR-expressing metastatic disease)
•Monotherapy: single-agent therapy in patients who have failed irinotecan- and oxaliplatin-based regimens or in patients who are intolerant of irinotecan-based chemotherapy
•Combination therapy: in combination therapy with FOLFIRI (irinotecan, 5-FU, leucovorin) for first-line treatment OR in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
FDA-Approved Dosage
■Squamous cell carcinoma of the head and neck: 400 mg/m2 intravenous infusion over 120 minutes administered 1 week prior to the first course of radiation therapy or on the day of initiation of platinum-based therapy with 5-FU followed by subsequent weekly doses of 250 mg/m2 intravenous infusion over 60 minutes for the duration of radiation therapy (6 to 7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU. Complete cetuximab administration 1 hour prior to radiation therapy or platinum-based therapy with 5-FU.
■Squamous cell carcinoma of the head and neck (monotherapy): The recommended initial dose is 400 mg/m2 intravenous infusion over 120 minutes followed by subsequent weekly doses of 250 mg/m2 intravenous infusion over 60 minutes until disease progression or unacceptable toxicity.
■Metastatic colorectal carcinoma (monotherapy or in combination with irinotecan or FOLFIRI [irinotecan, 5-FU, leucovorin]): 400 mg/m2 intravenous infusion over 120 minutes as an initial loading dose (first infusion) followed by a weekly maintenance dose of 250 mg/m2
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