Chemotherapy 1 Flashcards
Principles of Chemotherapy in animals
- does it kill cancer?
- PK, doses
- effectiveness over time?
Reality check !!
- Rarely cures cancer > 90% kill – not 100%
- Tumor the size of a dime (~10 g):
> 1x1010 cells prior to chemotherapy
> Kill 90% with chemotherapy
> 1x109 cells remain
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- Pharmacokinetics are not well known
> Difficult to predict tumor levels of drugs
> Drug interactions often unknown
- Narrow therapeutic margins
- Cancer cells develop resistance
Commonly treated veterinary cancers
- Lymphoma (lymphosarcoma)
- Osteosarcoma
- Anal sac adenocarcinoma
- Hemangiosacroma
- Plasma Cell Tumors
- Mammary carcinoma
- Mast cell tumors
- Transmissible venereal tumor
Practical Aspects of Chemotherapy
-administration of drug-
- Handler safety considerations
- Most agents are both toxic and mutagenic
- Alkylating agents are associated with highest risks
- Handler precautions: preparation, administration and disposal of wastes
- See Material Data Safety Sheets (MSDS)
Practical Aspects of Chemotherapy
-administration of drug-
- routes of administration
- Most agents delivered by intravenous route
> Also by oral route; occasionally IM/SC - Intracavitary route for with some agents
- Intralesional chemotherapy
- Liposomal encapsulation of some agents may reduce toxicity
Practical Aspects of Chemotherapy
-administration of drug-
- Dosing goals, considerations
- with newer drugs
- based on what?
- interval? considerations
- Goal of initial dosage with an agent has traditionally been MTD
> Highest dose tolerated by animal ie. maximum tolerated dose
> Highest dose without unacceptable toxicity
> Reduction in tumor size used as the measured efficacy response
<><><><> - More recent development of targeted therapies eg. monoclonal antibodies, immunotherapy and the biologically effective dose
> Dose resulting in measurable response at the proposed target or a biomarker
<><><><> - Dosing usually based on Body surface area (m2)
> Small dogs (<10 kg) may be dosed on weight ie mg/kg to reduce overdosing on BSA
<><><><> - Dosing interval based on normal tissue recovery
> Rapidly dividing cells; bone marrow and GI tract
<><><><> - Metronomic chemotherapy
> aka low-dose continuous chemotherapy
> Antiangiogenic effects; TSP-1 and VEGF
> Prevents tumor cell rebound at dosing breaks
Therapeutic Support of Patients with Cancer
- types of drugs we can use
n Antiemetics
n Appetite Stimulants
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n Medical marijuana and cannabidiols, and recreational marijuna
Antiemetics as Therapeutic Support of Patients with Cancer
- Vomiting and nausea can be concerning
- Mild-moderate cases; metoclopramide
- More common with cisplatin (dogs), and doxorubicin (cats and dogs)
> 5-HT antagonists: ondansetron (Zofran®) or dolasetron (Anzemet®)
> Maropitant (Cerenia®); NK1 antagonist
> Mirtazapine (Remeron®)
Appetite Stimulants for Therapeutic Support of Patients with Cancer
- Anorexia is a common adverse effect with cats particularly with vincristine and doxorubicin
> Cyproheptadine (Periactin®)
> Mirtazapine (Remeron®)
> Diazepam (Valium®)
Extravasation of chemotherapeutics
- which are the worst?
- what to do?
- Doxorubicin and vincristine most severe
- Try to remove as much as possible with the syringe still attached
- Infiltrate area with sodium chloride and dexamethasone
- Hot pack (Vinca alkaloids) or Cold (Doxorubicin) pack 3-4x a day for 1-2 days
- Surgical debridement may be required
- Hyaluronidase injected into affected area
> Injections repeated weekly until signs of resolution - Dexrazoxane (Zinecard®)
> Iron chelator used to combat doxorubicin toxicity
> Should be given within 2-3 hrs of extravasation
Chemotherapeutic Classes
- Alkylating Agents
> Cyclophosphamide
> Chlorambucil
> Melphalan
<><> - Antitumor Antibiotics
> Doxorubicin
> Mitoxantrone
> Dactinomycin
Cyclophosphamide
- what is this?
- mechanism
- use?
Chemotherapeutic drug, alkylating agent
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- A nitrogen mustard; cross links ie. alkylates DNA guanine bases rendering tumor DNA incapable of replication; also cause DNA strand breaks
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- Prodrug; hepatic metabolites responsible for effects
> Hydroxyphosphamide
> Aldophosphamide
=> Phosphoramide mustard; produces most of alkylating effects
=> Acrolein
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- Used primarily for lymphoma in dogs and cats
Cyclophosphamide
- Toxicity considerations
- Predictable and potentially dangerous dose-related myelosuppression
> Watch neutrophil counts
<><> - Hemorrhagic cystitis with long-term therapy
> Due to acrolein accumulation in bladder
§ Avoid/minimize by maintaining hydration
status and frequent urination
§ Do not give drug at night
§ Prednisone can reduce toxicity
<><> - Alopecia in breeds with continuous hair growth breeds eg. Poodles
- Vomiting via CRTZ stimulation, and diarrhea possible
Chlorambucil
- what is it?
- comparison to cyclophosphamide
- use
Chemotherapeutic, alkylating agent
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- Another nitrogen mustard derivative
- Myelosuppression less than cyclophosphamide and later in onset
- Substitute for cyclophosphamide when cystitis present
- Used primarily to treat low-grade lymphoma or chronic lymphocytic leukemia; has been used in mast cell tumors
Doxorubicin
- what is it?
- mechianism
- uses?
- eliminatino
Chemotherapeutic drug, Antitumor Antibiotics
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- Primary action is to damage the DNA helix following interacalation
- Also, impairs DNA, RNA and protein (enzyme) synthesis
> Topoisomerase II-dependent activity
- Also, free radical production and lipid peroxidation
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- Used alone or in combination extensively to treat lymphoma, and also used in osteosarcoma and a variety of carcinomas and other sarcomas
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- Eliminated primarily in feces and bile
Doxorubicin
- toxicity considerations
Dose-limiting effect is myelosuppression and cardiotoxicity
- Free radical production and iron chelation yielding mitochondrial damage in myocytes
- Arrhythmia (acute toxicity) or congestive heart failure (cumulative effects of doxorubicin)
- Liposomal encapsulated formulas; less cardiotoxic
- Dexrazoxane (iron chelator) can be given to reduce cardiac effects
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Possible anaphylactoid reactions d/t histamine release
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Cats relatively resistant to cardiotoxicity
- Renal toxicity possible in cats
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Extreme phlebitis with extravasation possible
