M

Vinca alkaloids, taxanes

figure 2.3. Cell-cycle-specific chemotherapeutic drugs and specific cell-cycle phase.

proliferating, that is, in cycles other than resting GO phase (Figure 2.3). Moreover, these drugs are usually most active in a specific phase of the cell cycle. Cell-cycle-specific drugs include the antimetabolites, antitubulin agents, and drugs targeting topoisomerase. Tables 2.3 and 2.4 describe common toxicities for each drug that is discussed in more detail in the subsequent sections.

Classic Alkylating Agents

Alkylating agents were the first class of agents to be clinically tested for cancer therapeutics. The alkylating agents form covalent bonds with nucleophilic cellular molecules, such as oxygen-, nitrogen-, phosphorus-, or sulfur-containing sites, through their alkyl groups. As a class, alkylating agents lack tumor selectivity but are generally active at very low doses. The bifunctional alkylating agents (two alkylating groups) not only alkylate but also crosslink DNA, leading to DNA template damage, subsequent cessation of DNA synthesis, and initiation of apoptosis upon recognition by cell-cycle checkpoint proteins such as p53. Alkylating agents thus are cytotoxic, teratogenic, and carcinogenic. Most secondary malignancies resulting from their use are acute leukemias.

Dose-dependent myelosuppression is the usual toxicity common to alkylating agents. Dose-dependent nausea and vomiting are frequently encountered. Gonadal atrophy and alopecia are also common sequelae of alkylating agent treatment. Because of the steep dose-response curve, alkylating agents are standardly included in myeloablative high-dose chemotherapy regimens in various hematologic malignancies. In such cases, pulmonary toxicity, veno-occlusive disease of the liver (nitrosoureas, busulfan, thiotepa, cyclophosphamide, mitomycin C), and neurotoxicity (lipophilic agents such as ifosfamide, nitrosourea, thiotepa, busulfan, nitrosourea) may arise and are life threatening.

The classic alkylating agents typically contain a chloroethyl group. They are classified as nitrogen mustards, aziridines, nitrosoureas, and alkyl alkane sulfonates. Non-classic monofunctional alkylating agents, on the other hand, feature a common N-methyl group, do not produce DNA crosslinks, and are essentially prodrugs requiring metabolic transformation into active intermediates. Included in this latter group are procarbazine, dacarbazine, hexamethylme-lamine, and temozolomide.

Nitrogen Mustards

Mechlorethamine Nitrogen mustards have been the most commonly used alkylating agents. The prototype is the vesicant mechlorethamine. It has an extremely short half-life of 15 to 20 minutes, as it undergoes rapid hydrolysis in the plasma to reactive metabolites. Its chief uses currently are in the treatment of lymphoma and mycosis fungoides (topical). Derivatives of mechlorethamine that have gained broader clinical use are the oxazaphosphorines cyclophosphamide and ifosfamide, chlorambucil, and melphalan.

Cyclophosphamide Both cyclophosphamide and ifosfamide require metabolic transformation by the cytochrome P-450 mixed-function oxidases in hepatic microsomes into their reactive intermedi-ates.15 They are also capable of induction of the microsomal enzymes responsible for their metabolism. In the case of cyclophosphamide, the intermediates 4-hydroxycyclophos-phamide and aldosphosphamide that escape oxidation by aldehyde dehydrogenase are converted by tumor cells into acrolein and phosphoramide mustard,16 the active alkylating agent that is responsible for the biologic effects of cyclophos-phamide; this reaction is similar for ifosfamide. Because these metabolites are renally cleared, accumulation of acrolein in urine is responsible for hemorrhagic cystitis unique to these two agents,17 especially ifosfamide. Transitional cell carcinoma of the bladder developing as a late sequela has been described.18 Bladder toxicity may be reduced by hydration, frequent bladder emptying, and the use of thiol-containing agents such as N-acetyl cysteine (NAC) and mercaptoethane sulfonate (MESNA). These protectants are rich in sulfhydryl groups that bind and inactivate the charged toxic metabolites.

Cyclophosphamide can be administered orally or intravenously. Nausea and vomiting are usually delayed, occurring hours after drug administration. Relative sparing of the platelet count at doses less than 30mg/kg is very characteristic. Moreover, it exhibits a stem cell-sparing effect even at high doses, in contrast to busulfan and melphalan, because of the high levels of aldehyde dehydrogenase in the early bone marrow progenitor cells. Cyclophosphamide is the most immunosuppressive anticancer agent available. Cardiac toxicity is dose limiting in high-dose administration,19 although no cumulative toxicity of low to moderate doses is evident. A toxic tubular effect has also been described wherein water retention, and an SIADH-like (syndrome of inappropriate antidiuretic hormone) picture can occur with the use of 50 mg/kg or higher doses.20,21 Cyclophosphamide is used in various settings, such as in breast cancer, bone marrow transplant, and non-Hodgkin's lymphoma (NHL), to name a few.

Ifosfamide

Similar to cyclophosphamide, ifosfamide is well absorbed after oral administration. However, the oral metabolite chlo-racetaldehyde is highly neurotoxic and hence the oral form is not commercially available.22,23 It has a lower affinity for its activating enzymes, and thus its transformation to alkylating

TABLE 2.3. Selected pharmacokinetic and toxicity features.

Chemotherapeutic agent

Metabolism/ excretion

Toxicity

Administration

Dose reduction in renal or liver dysfunction

Classic Chlorambucil alkylating agents Cyclophos phamide

Ifosfamide

Mechlorethamine Melphalan

Mitomycin C

Nonclassic alkylating agents

Thiotepa

Carmustine (BCNU)

Lomustine (CCNU)

Streptozocin Busulfan

Procarbazine

Dacarbazine Altretamine

Temozolomide

Liver Liver

Liver

Plasma hydrolysis

Plasma hydrolysis, renal

Liver

Liver

Liver

Liver

Liver, renal

Liver

Liver

Liver, renal Liver, renal

Plasma decomposition, renal

Myelosuppression, hyperuricemia, mild N&V, pulmonary fibrosis, seizures, gonadal toxicity, secondary malignancies Myelosuppression, hemorrhagic cystitis, N&V, alopecia, headache, nasal congestion with rapid infusion, SIADH, cardiomyopathy, immunosuppression, gonadal toxicity, pulmonary fibrosis (high-dose), secondary malignancy Myelosuppression, hemorrhagic cystitis, N&V, alopecia, metabolic acidosis, neurotoxicity (somnolence, hallucinations, ataxia, neuropathy), arrhythmias, CHF, SIADH, Fanconi syndrome, gonadal toxicity, azotemia, secondary malignancy Myelosuppression, severe N&V, dermatitis, thrombophlebitis, hyperuricemia, gonadal toxicity, secondary malignancy Myelosuppression, mild N&V, vasculitis, mucositis, diarrhea, SIADH hypersensitivity reactions, gonadal toxicity, secondary malignancy Myelosuppression, N&V, mucositis, HUS, DIC, microangiopathic hemolytic anemia, interstitial pneumonitis, thrombophlebitis, hepatic VOD, cardiomyopathy, bladder fibrosis (intravesical therapy) Myelosuppression, mild N&V, hyperuricemia, dermatitis, secondary malignancy, hemorrhagic cystitis (intravesical therapy)

Myelosuppression, severe N&V, thrombophlebitis, seizures (wafers), hepatotoxicity, nephrotoxicity, pulmonary fibrosis, infusion-related hypotension and arrhythmias at high doses, gonadal toxicity, secondary malignancy Myelosuppression, severe N&V, gonadal toxicity, neurotoxicity (confusion, ataxia, dysarthria, lethargy), hepatotoxicity, nephrotoxicity, pulmonary fibrosis, secondary malignancy Nephrotoxicity, N&V, elevated transaminases and/or mild cholestasis, hypoglycemia, secondary malignancy

Myelosuppression, gonadal toxicity, secondary malignancy, mild N&V, skin hyperpigmentation (oral), hyperuricemia, cholestasis, hepatic VOD, seizures, bronchopulmonary dysplasia with pulmonary fibrosis, adrenal insufficiency

Myelosuppression; N&V, hemolysis (G6PD deficiency), MAOI crises, flu-like syndrome, disulfiram reactions with alcohol; neurotoxicity (paresthesias, neuropathies, ataxia, confusion, seizures), gonadal toxicity, secondary malignancy Myelosuppression, N&V, flu-like syndrome, photosensitivity N&V, myelosuppression, neurotoxicity (neuropathy, ataxia hallucinations), flu-like syndrome Myelosuppression, N&V, anorexia, headache, neurotoxicity (insomnia, somnolence, ataxia, hemiparesis, seizures), elevation of transaminases or cholestasis, peripheral edema

Oral

Infusion or oral

Infusion or slow IV push

Slow injection IV bolus, infusion or oral Slow IV push or infusion, intravesical

IV bolus or infusion, intrathecal, intravesical IV infusion, wafer implant (glioblastoma)

Oral

IV bolus or infusion

Oral or IV infusion

Oral

IV infusion Oral

Oral

Clcr < lOmL/min: 25% reduction

Clcr 10-50mL/min: 25%

reduction Clcr < lOmL/min: 50% reduction Clcr < lOmL/min: 25% reduction

Clcr 10-50mL/min: 25%

reduction Clcr < lOmL/min: 50% reduction

Clcr 10-50mL/min: 25%

reduction Clcr < lOmL/min: 50% reduction

Consider dose reduction if bilirubin >3mg/dl

Platinum Cisplatin compounds

Carboplatin Renal

Oxaliplatin Renal

Antitumor antibiotics

Doxorubicin

Daunorubicin

Idarubicin

Liver

Liver, renal

Liver, renal

Epirubicin

Liver, renal

Mitoxantrone Liver

Dactinomycin Liver

Bleomycin

Kidney, renal

Antimetabolites Methotrexate Renal

N&V, nephrotoxicity, electrolyte abnormalities, peripheral neuropathy, ototoxicity, myelosuppression, thromboembolic events, myocardial ischemia, ocular toxicity, thrombophlebitis, gonadal toxicity, mild elevation of transaminases or cholestasis, hypersensitivity reaction Myelosuppression, N&V, nephrotoxicity, neuropathy, electrolyte abnormalities, mild elevation of transaminases or cholestasis, delayed hypersensitivity reaction sensory > motor neuropathy, N&V, diarrhea, elevated liver transaminases, myelosuppression, nephrotoxicity, edema, hypersensitivity reaction

Myelosuppression, mild N&V, mucositis, alopecia, cardiotoxicity, elevation of transaminases, radiation recall, hyperpigmentation, thrombophlebitis, urine discoloration

Myelosuppression, mild N&V, mucositis, alopecia, cardiotoxicity, elevation of transaminases, radiation recall, hyperpigmentation, urine discoloration

Myelosuppression, mild N&V, mucositis, alopecia, elevation of transaminases or cholestasis, GI hemorrhage, cardiotoxicity, radiation recall, hyperpigmentation, urine discoloration, thrombophlebitis

Myelosuppression, mild N&V, mucositis, cardiotoxicity, radiation recall, alopecia, hyperpigmentation, urine discoloration, thrombophlebitis, gonadal toxicity

Myelosuppression, mucositis, N&V, arrhythmias, cardiotoxicity) cumulative doses >140-160 mg/m2 cause CHF in -10% of patients), elevated transaminases, urine discoloration, alopecia, secondary malignancy

Myelosuppression, severe N&V, mucositis, cardiotoxicity, radiation recall, fatigue, hyperpigmentation, elevated transaminases, thrombophlebitis, hypocalcemia, hepatic VOD

Skin reactions (erythema, peeling, etc.), pneumonitis, pulmonary fibrosis, anaphylactoid reactions, Raynaud's phenomenon, arterial thrombosis, myocardial ischemia

Myelosuppression, mucositis, renal failure, uric acid nephropathy, elevation in transaminases or cholestasis, hepatic fibrosis, pneumonitis, serositis, neurotoxicity (high-dose or intrathecal), gonadal toxicity, vasculitis, thromboembolic disease

IV infusion

IV infusion

IV infusion, intraarterial, intravesical

IV push or infusion

Oral, slow IV push or infusion

IV infusion

IV infusion, intraperitoneal

Slow IV push

Slow IV bolus, IM, SC or intracavitary injection

Oral, IV, IM, intrathecal

Clcr 10-50mL/min: 25%

reduction Clcr < lOmL/min: 50% reduction

Calvert's formula

Consider in renal dysfunction

reduction Bilirubin 3.1-5mg/dL: 75%

reduction Bilirubin 2.1^3 mg/dL or AST

60-180IU: 25% reduction Bilirubin 3.1-5 mg/dL or AST

>180IU: 50% reduction Bilirubin >5mg/dL: omit use Serum creatinine >2 mg/dL: 25% reduction

Bilirubin 1.5-5 mg/dL or AST

60-180IU: reduce dose 50%. Bilirubin >5 mg/dL or AST >180

IU: do not administer Serum creatinine >5 mg/dl: consider dose reduction Bilirubin 1.2^3 mg/dL or AST 2-4 times the upper limit of normal: 50% reduction Bilirubin >3 mg/dL or AST >4 times the upper limit of normal: 75% reduction Bilirubin 1.5^3 mg/dL: 50%

reduction Bilirubin >3 mg/dl: 75% reduction

Clcr 10-50mL/min: 25%

reduction Clcr <10mL/min: 50% reduction

Clcr 61-80mL/min: 25%

reduction Clcr 51-60mL/min: 30%

reduction Clcr 10-50mL/min: 50-70%

reduction Clcr <10 mL/min: avoid use Bilirubin 3.1-5 mg/dL or AST >180 units: administer 75% of dose

Bilirubin >5mg/dL: do not use

(continued)

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