Alkylating agents

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


Mechanism of action

Alkylating agents are among the oldest of anticancer agents used clinically. These cytotoxic agents exert their antiproliferative effects by covalently binding alkyl groups to cellular molecules.

Alkylation of DNA occurs through the formation of reactive intermediates that attack nucleophilic sites. The majority of clinically useful alkylating agents cause DNA cross-linking, which results in inhibition of DNA synthesis and cell death.

Some alkylating agents cause DNA strand breaks rather than cross-linking.

Resistance

Resistance to alkylating agents is multifactorial and may differ between classes of alkylating agents, e.g., resistance to nitrosoureas is probably mediated by increased expression of the enzyme O6-alkyl transferase.

In addition to enhanced DNA repair, resistant cells may exhibit an increased ability to detoxify alkylating agents. Such mechanisms include increased

  • Glutathione
  • Metallothionein
  • Glutathione-S-transferase

Nitrogen mustards

Chlorambucil

  • Clinical indications: Chronic lymphocytic leukemia (CLL) and lymphomas.
  • Dosing: CLL in adults: 0.1 mg/kg po daily for 3 – 6 months or until a remission is achieved. Maintenance is 2– 4 mg po daily.

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Interstitial pneumonitis or pulmonary fibrosis (rare)
  • Tumor lysis syndrome
  • Infertility
  • Secondary malignancies
  • Rash (uncommon)
  • Toxic epidermal necrolysis (rare)

Cyclophosphamide

Cyclophosphamide is a prodrug that requires hepatic activation in order to exert its cytotoxicity. in addition to cytotoxic effects, cyclophosphamide has significant immunosuppressant effects.

  • Clinical indications: Acute and chronic leukemia, lymphoma, breast cancer, multiple myeloma, other solid tumors, autoimmune diseases, hematopoietic stem cell transplantation
  • Dosing: 200 –1000 mg/m2 IV per cycle; oral regimens are also used

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (dose-related)
  • Hemorrhagic cystitis
  • Alopecia
  • Pneumonitis or pulmonary fibrosis (rare)
  • Tumor lysis syndrome
  • Immunosuppression
  • Syndrome of inappropriate antidiuretic hormone (SIADH)
  • Infertility
  • Secondary malignancies
  • Cardiotoxicity (more likely in high-dose setting)
  • Veno-occlusive disease of the liver (more likely in high-dose setting)
  • Rash (uncommon)
  • Toxic epidermal necrolysis or Stevens– Johnson syndrome (rare)

Additional comments

  • Cyclophosphamide undergoes extensive hepatic p450 metabolism; caution is warranted when using inhibitors or inducers of these enzymes concurrently with cyclophosphamide.
  • Patients should maintain adequate hydration to prevent hemorrhagic cystitis; mesna may be considered in the high-dose setting.

Ifosfamide

Ifosfamide is a synthetic analog of cyclophosphamide. it also requires hepatic activation to exert its cytotoxic effects.

  • Clinical indications: Soft tissue sarcomas, osteogenic sarcomas, lung cancer, testicular cancer, lymphomas
  • Dosing: Testicular cancer 1.2–2 g/m2 per day IV for 5 days

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Hemorrhagic cystitis
  • Neurotoxicity, encephalopathy
  • Alopecia
  • Renal insufficiency
  • Infertility
  • Secondary malignancies
  • Cardiotoxicity

Additional comments

  • Ifosfamide undergoes extensive hepatic p450 metabolism; caution is warranted when using inhibitors or inducers of these enzymes concurrently with ifosfamide.
  • Patients should maintain adequate hydration to prevent hemorrhagic cystitis; mesna must always be given with ifosfamide.
  • Neurotoxicity is thought to be caused by the metabolite chloroacetaldehyde; it is more common in patients with impaired renal function.

Mechlorethamine

Mechlorethamine is also known as nitrogen mustard.

  • Clinical indications: Hodgkin’s disease and lymphomas
  • Dosing: 6 mg/m2 IV on days 1 and 8 (Mopp regimen)

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (severe)
  • Infertility
  • Secondary malignancies
  • Ototoxicity
  • Alopecia
  • Tumor lysis syndrome
  • Thrombophlebitis
  • Skin ulceration (vesicant)

Melphalan

  • Clinical indications: Multiple myeloma, hematopoietic stem cell transplantation
  • Dosing: oral: 0.15 mg/kg per day for 7 days every 4 weeks or 0.25 mg/kg per day for 4 days every cycle or 6 mg daily; high-dose 140 –200 mg/m2 IV once

Dose should be reduced for impaired renal function.

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (with high doses)
  • Vasculitis
  • Alopecia
  • Pruritis
  • Rash
  • SIADH
  • Mucositis (with high doses)
  • Hemorrhagic cystitis
  • Interstitial pneumonitis or pulmonary fibrosis
  • Hypersensitivity
  • Infertility
  • Secondary malignancies

Aziridine analogs

Thiotepa

  • Clinical indications: bladder cancer, breast cancer, ovarian cancer, lymphomas, sarcomas, intrathecal use for leukemia, lymphoma, and carcinoma, hematopoietic stem cell transplantation
  • Dosing: 0.3 – 0.4 mg/kg IV once every 1– 4 weeks

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (with high doses)
  • Dizziness, fever, headache
  • Confusion, somnolence (with high doses)
  • Rash, pruritis
  • Hyperpigmentation (with high doses)
  • Mucositis (with high doses)
  • Transaminitis, hyperbilirubinemia (with high doses)
  • Hemorrhagic cystitis
  • Infertility
  • Secondary malignancies

Alkane sulfonates

Busulfan

  • Clinical indications: oral therapy for CMl (not commonly used today); oral and IV formulations used in hematopoietic stem cell transplantation
  • Dosing: CMl chronic phase: 4 –8 mg po daily (or 1.8– 4 mg/m2 po daily); maintenance therapy: 1–3 mg/day po; stem cell transplantation: 1 mg/kg po q6h x 16 doses or 0.8 mg/kg IV q6h x 16 doses or 130 mg/m2 IV daily x 4 days

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (with high doses)
  • Seizures (with high doses)
  • Hyperbilirubinemia
  • Veno-occlusive disease of the liver (sinusoidal obstruction syndrome)
  • Mucositis (with high doses)
  • Tumor lysis syndrome
  • Cataracts
  • Rash
  • Alopecia
  • Infertility
  • Secondary malignancies
  • Erythema multiforme (rare)
  • Fever
  • Headache
  • Nail discoloration
  • Skin hyperpigmentation
  • Pulmonary fibrosis

Additional comments

  • Phenytoin (or another antiepileptic medication) should be given to prevent seizures in patients receiving high-dose therapy.
  • Therapeutic drug monitoring is commonly per formed in the high-dose setting; maintaining drug concentrations within a given range has been shown to reduce the complication of veno-occlusive disease of the liver (sinusoidal obstruction syndrome).
  • Busulfan is a substrate of cytochrome p450 3A4; caution should be used when inducers or inhibitors of this enzyme are used concurrently.

Nitrosoureas

Nitrosoureas are highly lipophilic and therefore cross the blood-brain barrier.

Carmustine

  • Clinical indications: brain tumors (IV and implantable wafers), multiple myeloma, Hodgkin’s disease, non-Hodgkin’s lymphoma, hematopoietic stem cell transplantation
  • Dosing: 150 –200 mg/m2 IV every 6 weeks

Adverse events

  • Bone marrow suppression (delayed, cumulative)
  • Nausea and vomiting (severe, dose-related)
  • Alopecia
  • Infertility
  • Secondary malignancies
  • Elevated hepatic enzymes
  • Encephalopathy
  • Flushing
  • Hypotension (with high doses)
  • Headache
  • Pneumonitis or pulmonary fibrosis (cumulative, dose-related)
  • Rash
  • Renal failure
  • Seizures (primarily with implanted wafers or high doses)
  • Skin hyperpigmentation
  • Mucositis
  • Injection site reactions
  • Hypothyroidism
  • Veno-occlusive disease of the liver (sinusoidal obstruction syndrome)

Additional comments

  • Cycles of carmustine (BCNU) should only be given every 6 – 8 weeks to allow for bone marrow recover y.
  • Diluent contains absolute alcohol, which is responsible for flushing and hypotension in the high-dose setting.

Lomustine

  • Clinical indications: brain tumors, Hodgkin’s disease, non-Hodgkin’s lymphoma, melanoma, renal carcinoma, lung cancer, colon cancer
  • Dosing: 100 –130 mg/m2 po once every 6 weeks on an empty stomach as a single agent; consider dosage reduction with renal impairment

Adverse events

  • Bone marrow suppression (delayed, cumulative)
  • Nausea and vomiting (severe, dose-related)
  • Alopecia
  • Infertility
  • Secondary malignancies
  • Neurotoxicity
  • Mucositis
  • Diarrhea
  • Renal failure, interstitial nephritis
  • Hepatotoxicity
  • Pulmonary fibrosis (cumulative)
  • Elevated hepatic enzymes

Additional comments

  • Cycles of lomustine (CCNU) should only be given every 6 – 8 weeks to allow for bone marrow recover y.
  • Lomustine is a substrate of cytochrome p450 2D6 and an inhibitor of 2D6 and 3A4; use caution when concurrently administering with substrates, inhibitors, or inducers of these enzymes.

Streptozocin

  • Clinical indications: Carcinoid, colorectal cancer, pancreatic cancer
  • Dosing: 500 mg/m2 per day IV as a short or continuous infusion for 5 days every 4 – 6 weeks or 1000 mg/m2 IV once weekly up to 1500 mg/m2
  • Dosage reduction is recommended with renal impairment.
  • Adverse events
  • Bone marrow suppression (delayed, cumulative)
  • Nausea and vomiting (severe, dose-related)
  • Nephrotoxicity (dose-related, cumulative)
  • Injection site reactions (irritant)
  • Hypoglycemia or hyperglycemia
  • Lethargy, confusion, depression
  • Infertility
  • Secondary malignancies
  • Diarrhea
  • Elevated hepatic enzymes
  • Hyperbilirubinemia

Hydration may reduce the incidence and severity of nephrotoxicity.

Nonclassical alkylating agents

Dacarbazine

  • Clinical indications: Metastatic malignant melanoma, osteogeneic sarcoma, soft-tissue sarcoma, Hodgkin’s disease

Dosing

  • Melanoma: 100 –250 mg/m2 IV once daily for 5 days every 3 – 4 weeks or 850 –1000 mg/m2 IV once on day 1 repeated every 3 – 4 weeks
  • Hodgkin’s disease: 375 mg/m2 IV days 1 and 15 every 28 days (ABVD regimen)

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (dose-related, severe)
  • Facial flushing
  • Headache
  • Rash
  • Alopecia
  • Hepatotoxicity
  • Myalgia
  • Fever
  • Hypotension (with high doses)
  • Photosensitivity
  • Vein irritation
  • Infertility
  • Secondary malignancies

Additional comments

  • Dacarbazine (DTiC) requires activation by the liver to its active form, monomethyl triazenoimidazole carboxamide (MTIC)

Procarbazine

  • Clinical indications: Hodgkin’s disease, non-Hodgkin’s lymphoma, brain tumors, melanoma, lung cancer, multiple myeloma
  • Dosing: 100 mg/m2 per day orally on days 1–14 every 28 days (Mopp regimen); consider dose adjustment with renal or hepatic dysfunction

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (severe)
  • Mental depression
  • Hallucinations
  • Dizziness, ataxia
  • Headache
  • Confusion
  • Seizures
  • Weakness
  • Paresthesias
  • Neuropathy
  • Tremors
  • Pleural effusion
  • Cough
  • Alopecia
  • Hyperpigmentation
  • Mucositis
  • Nystagmus
  • Infertility
  • Secondary malignancies
  • Disulfiram-like reactions
  • Hypertensive crisis
  • Orthostatic hypotension
  • Pneumonitis

Additional comments

  • Procarbazine has monoamine oxidase inhibitor (MAOI) activity. Foods high in tyramine must be avoided.

Temozolomide

Temozolomide is an oral prodrug that undergoes rapid nonenzymatic conversion to form the same active metabolite as dacarbazine (MTIC); activation by the liver is not required.

  • Clinical indications: brain tumors, malignant melanoma
  • Dosing: 150 –200 mg/m2 per day orally for 5 days every 28 days (reduce dose if giving concurrently with radiation). Consider dose reduction with severe renal or hepatic impairment; food reduces the rate and extent of absorption.

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Peripheral edema
  • Headache
  • Fatigue
  • Dizziness
  • Neurotoxicity
  • Visual disturbances
  • Rash
  • Allergic reactions
  • Infertility
  • Secondary malignancies

Additional comments

  • Administer Pneumocystis carinii pneumonia (PCP) prophylaxis if patient is receiving temozolomide in combination with radiation therapy.
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