Chemotherapy

 

 

Alkylating Agents

These drugs have a broad range of clinical activity.

Cytoxicity is due to damage/interference with DNA replication and transcription.

  • Covalent bonding of an alkyl group to important cellular macromolecules.
  • Damage to DNA template and induction of apoptosis (programmed cell death).

The alkyl group binds to the electrophilic sites on DNA, crosslinks the strands and impedes DNA replication.

They can be:

  • Monofunctional (interacting with one strand of DNA)
  • Bifunctional (interacting with two strands of DNA).

Alkylating agents play an important role in lymphoma, Hodgkin lymphoma, breast and ovarian cancer, multiple myeloma, other malignancies and blood and marrow transplant (BMT).

Most alklylating agents are cell-cycle non-specific:

  • Most active in G0 phase
  • Cross-link DNA strands
  • Unlink coiled DNA
  • Inhibit DNA synthesis
  • Major toxicities:
    • Hematopoiectic
    • GI tract
    • Reproductive

 

Examples:

MUSTARD DERIVATIVES

Cyclophosphamide/ Ifosfamide

Melphalan

Mechlorethamine (nitrogen mustard).

Chlorambucil

AZIRIDINES

Thiotepa

Mitomycin

HYDROZINES

Procarbazine

ALKYL SULFONATES

Busulfan

TRIAZENES

Dacarbazine (DTIC)

Temozolomide

NITROSOUREAS

BCNU (bischlorethylnitrosoureas)

CCNU (cyclohexylchloroethylnitrsourea)

Semustine and nimustine.
HEAVY METALS

Carboplatin

Cisplatin

(see Platinum compounds)

TOPISOMERASE I INHIBITORS

Topotecan

Irinotecan

( see Camptothecins )

 

Nitrogen Mustards

Clinical application stems from observation during World War I that sulphur mustard gas suppressed hematopoietic and lymphoid systems.

Mechlorethamine (nitrogen mustard, Mustargen)

  • Occasionally used in combination with vincristine, procarbazine and prednisone in the treatment of Hodgkin lymphoma.  Very rarely used in pediatrics.
  • Given intravenously or topically for cutaneous lymphoma (mycosis fungoides).
  • May cause topical irritation and injection site pain.

Cyclophosphamide

  • Pro-drug (activated in the liver)
  • used extensively in the treatment of pediatric tumours, lymphoma, solid tumours, blood and marrow transplant (BMT) and breast cancer.
  • Can be given in tablet form (usually for autoimmune diseases) or intravenously.

Ifosfamide

  • Isomer of cyclophosphamide
  • Used to treat sarcomas and pediatric tumours.
  • The increased chloroethyl side-chain content of ifosfamide is responsible for it’s neuro and renal toxicity.
  • Given intravenously.

High dose cyclophosphamide and ifosfamide are administered with Mesna (a stabiliser of urotoxic compounds) to reduce and prevent hemorrhagic cystitis.

The safety and efficacy of melphalan and chlorambucil are not well established in pediatric patients.

 

Amirdines and Epoxides

Thiotepa and mitomycin C are amirdines

Thiotepa is

  • Used in the treatment of pediatric osteogenic sarcoma, Hodgkin lymphoma and non-Hodgkin lymphoma as well as bladder, breast and ovarian cancers.
  • Can be given : oral, intravenous, intramuscular, subcutaneous, intracavity or intrathecal.

Mitomycin C is

  • An antibiotic derived from Streptomyces lavendulae
  • Given intravenously (treatment of breast and GI tumors) or intravesically for bladder cancers.

Dianhydrogalactitol is an epoxide.

  • Used in combination chemotherapy for breast, cervical and brain cancers.

 

Alkyl Sulfonates

Busulfan is an alklyl sulfonate

  • Most commonly used to suppress myeloid cell lines in preparation for BMT.
  • It is given orally or intravenously, usually at a dosage of 1mg/kg every 6 hours for 4 days.

 

Nitrosoureas

  • Lipid soluble drugs which attain high CNS concentrations.
  • Have a severe and delayed hematotoxicity
  • usually given at a maximum frequency of every six weeks.

BCNU

  • also known as carmustine
  • used in the treatment of primary and secondary CNS malignancies as well as multiple myeloma, malignant melanoma, Hodgkin lymphoma and other lymphomas.
  • Given intravenously or as a directly applied at the time of resection of brain tumours.

CCNU

  • also called lomustine
  • given orally and is primarily used in the treatment of brain tumours.

Semustine (methylcychlohexylchloroehtylnitrosourea)

  • Investigational agent that has been
  • Used in the treatment of gastrointestinal cancers.

Nimustine (N'-[(4-Amino-2-Methyl-5-Pyrimidinyl)Methyl]-N-(2-Chloroethyl)-N-Nitrosourea)

  • given intraarterially and intrathecally in the treatment of CNS tumours.

 

Hydrazine and Triazine Derivatives

Procarbazine, dacarbazine and temozolomide are

  • Hydrazine and triazine derivatives, analogous to nitrosoureas.
  • Inhibit cellular gluconeogenesis as well alklyating DNA.

Procarbazine

  • Used in combination with other agents in treatment of Hodgkins -
  • MOPP (Mechlorethamine, Vincristine (Oncovin), Prednisone, Procarbazine)
  • Used in treatment of malignant gliomas - PCV (Procarbazine, CCNU and Vincristine).
  • Given orally.

Dacarbazine

  • Cell-cycle non-specific
  • Given intravenously for the treatment of Hodgkin lymphoma and malignant melanoma.

Temozolomide

  • Pro-drug given orally in the treatment of astrocytomas, glioblastomas, and melanomas.

 

Side Effects

Alkylating agent toxicities include:

  • Hematopoietic (low counts)
  • Gastrointestinal (nausea and vomiting)
  • Gonadal
  • Pulmonary
  • Immunological
  • Dermatological effects (Cyclophosphamide and ifosfamide most likely to be associated with alopecia)

Fertility

  • Alkylating agents are associated with direct damage to the gonads and a significant risk of infertility.
  • Males are more likely to be affected than females.
  • There is a reduction in ovarian reserve and increased risk of premature menopause.

Second Malignancy

  • Most commonly acute AML is seen as a side effect, but also increased risk of solid tumors.
  • Usually preceded by a myelodysplasia.
  • Cytogenetic abnormalities in long arm of 5,7 or both.
  • Latent period is 3.5 to 5.5 years.
  • Risk is 1 - 2% at 20 years.

Summary Table of Early Alkylating Agent Toxicities:

Drug Toxicity Special Considerations

Cyclophosphamide

Ifosfamide

Hemorrhagic cystitis can occur due to the irritating effects of urinary metabolites on bladder mucosa.

 

Antidiuretic effects can lead to fluid retention.

 

At high doses cardiac toxicity can be fatal - tends to occur in the setting of BMT.
  • Maintain adequate hydration, urine output
  • Frequently check urine for blood and specific gravity
  • Administer ifosfamide and high dose cyclophosphamide with Mesna

Thiotepa

Major toxicity is neutropenia

 

Skin rash

 

Mucositis and esophagitis at high doses (BMT)

  • Use 0.22 micron filter for infusions
  • Thiotepa is excreted via the skin: use gloves for direct patient contact during and for 24 hours post administration
  • Patient should bathe/shower every 6-8 hours and avoid use of creams/lotions during and for 24 hours post
  • Change diapers every 2 hours and do nut use occlusive dressings for 24 hours post
Busulfan

Prolonged myelosuppression

 

Mild nausea

 

Seizures with high dose

 

Major toxicity with high doses is hepatic veno-occlusive disease.
  • Prophylactic anticonvulsant therapy
  • Blood sampling for PK studies required to determine correct patient dose
Carmustine (BCNU)

Major dose-limiting toxicity is bone marrow suppression. Delayed hematologic toxicity (nadir 4 weeks 4-6 weeks)

  • Vesicant: avoid extravasation or local contact with skin
  • Monitor pulmonary function (see late effects below).

Procarbazine

When taken with ethanol a disulfuram like reaction may occur.

 

Has monoamine oxidase properties and can cause CNS depression and acute hypertension if taken with tyramine-rich foods.
  • Provide patient with written list of foods and medications to avoid: alcohol, MAO inhibitors, phenothiazines, phenytoin, thricyclic antidepressants, barbiturates, aged cheese, wine, bananas, yogurt, chocotate.
  • Should be taken 1 hour before meals or 2 hours after

Temozolomide

Nausea

 

Major dose-limiting toxicity is myelosuppression.

 
  • Should not be taken with food
  • Best taken at bedtime to decrease incidence of nausea and vomiting
  • Best to take capsules whole, but may be opened and mixed with small amount apple juice or sauce

 

Summary Table of Late Alkylating Agent Toxicities:

Mustargen

 

 
  • Second malignancy
  • Infertility

Cyclophosphamide

Ifosfamide
  • Second malignancy
  • Infertility

Thiotepa

  • Second malignancy
  • Infertility
Busulfan
  • Major toxicity with high doses is hepatic veno-occlusive disease.
  • “Bronzing” of the skin
  • Second malignancy
  • Infertility
BCNU
  • Long-term therapy can cause pulmonary fibrosis
  • Second malignancy
  • Infertility

Procarbazine

  • Second malignancy
  • Infertility

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