L48: Anti Cancer drugs

What is chemotherapy

• Treatment of cancer with drugs

• Many of the drugs are cytotoxic

• Interfere with cell growth/division

• action is not specific to cancer cells- destroy rapidly dividing cells

what is the difference between veterinary and human chemotherapy

• same drugs but smaller doses

• less intense schedules

• QOL over curative intent

• prolonging life over curative intent

define induction chemotherapy

induce a remission

define consolidation chemotherapy

sustain a remission

define adjuvant chemotherapy

administered in the microscopic setting

define neo-adjuvant chemotherapy

Administered in the macroscopic setting

define maintenance therapy

maintain remission

controversial benefitde

define reinduction chemotherapy

re introduce the induction protocol

define rescue chemotherapy

administered if patient out of remission and presumed resistance against induction chemotherapy

what are the indications for chemotherapy

• treatment of disseminated disease

  • lymphoma

  • multiple myeloma

  • leukemia

  • mast cell tumour

  • histiocytic disease

• adjuvant following surgical resection

  • incase of incomplete excision, metastasis, high malignancy

• neo-adjuvant to reduce tumour size prior to surgery or RT

• transmissible venereal tumour

What are the routes of administration of chemotherapy

• oral

• IV

• intracavitary

• intralesional

• subcutaneous

What is the MOA of chemotherapy

• Interfere with cell growth and division

• some cell cycle specific, others not

• most drugs work best on actively dividing cells

• tumours with high mitotic index are more likely to be sensitive

• Cells in G0 (resting) are relatively resistant

How do you time chemotherapy

• time as early as possible

  • unlikely effective in macroscopic and end stage disease

  • as early as possible post surgery (10-14 days)

define maximum tolerated dose

a fixed dose kills off a fixed % of cells rather than number of cells

• cannot kill tumour with on dose

what do you aim for when chemotherapy dosing

• multiple doses

• pulse dose at intervals

  • Normal tissue recovery

  • prevent tumour regrowth

How do you dose chemotherapy

• dosing for body surface area (mg/m2)

• conversion charts available

• dogs <10kg are often overdosed

  • dose for mg/kg

  • doxorubicin, carboplatin

What is combination chemotherapy

• combination protocols often more effective

• drugs that are

  • effective as single agents

  • different MOA and dont interfere

  • avoid overlapping toxicities

What are some examples of combination therapy

• CHOP-based protocols (cyclophosphamide, doxorubicin/epirubicin, vincristine, prednisolone)

• COP-based protocols

• LOP/LOPP based protocols (lomustine, vincristine, +/-procarbazine, prednisolone)

define metronomic chemotherapy

administration of regular low, daily dose of cytotoxic agents

targets blood vessels

whats an example drug of metronomic chemotherapy

cyclophosphamide

What does metronomic chemotherapy act on

• tumour microenvironment

  • anti-angigenic

  • induction of tumour dormancy

What is tumour dormancy

where tumour doesnt grow or change

what is targeted therapy

not to do with interrupting cell cycle

but growth factors on cell surface- this avoids cell proliferation, metastasis and angiogenesis

what are some examples of targeted drugs

• toceranib phosphate

• masitinib

What determines the success of chemotherapy

• Tumour cell type (e. g. Lymphoma vs. Melanoma)

• Drug distribution

  • Blood supply

  • Blood-brain barrier

• Development of resistance

  • Tumours are genetically unstable

  • Drug exposure →selects resistant cells

  • MDR1 gene up regulation

What are some classes of chemotherapy drugs

• Alkylating agents: cyclophosphamide, lomustine, chlorambucil, melphalan.

  • oral

• Vinka alkaloids: vincristine, vinblastine, vinorelbin

  • lymphoma

• Antimetabolites: cytarabine, gemcitabine, methotrexate, 5-FU

  • interefere with metabolism

• Platinum agents: carboplatin

  • osteosarcoma

• Anti-tumourantibiotics: doxorubicin, epirubicin, mitoxantrone

  • lymphoma

• L-asparaginase (enzyme)

What are some examples of commonly used chemotherapy drugs and what do they treat

• Cyclophosphamide(lymphoma, softtissuesarcoma)

• Lomustine(lymphoma, mast cell tumour, histiocyticsarcoma)

• Chlorambucil(lymphoma, chroniclymphocyticleukaemia)

• Melphalan(multiplemyeloma)

• Vincristine(lymphoma, transmissible venereal tumour)

• Vinblastine(mast cell tumour)

• Doxorubicin(lymphoma, carcinomas, sarcomas)

• Epirubicin(lymphoma, carcinomas, sarcomas)

• Mitoxantrone(lymphoma, carcinomas)

What is the role of prednisolone

• Apoptosis of lymphoid cells

  • lymphoma

  • leukaemia

• apoptosis of mast cells

  • mast cell tumour

• Adverse events Pu/PD, panting, muscle wastage

What are some NSAIDS that can be used as chemotherapy

• COX inhibition

  • plays role in cancer progression

  • inflammation and angiogenesis

• Anti-angiogenic

• promote apoptosis

• anti-inflammatory

• analgesic

• indications

  • transitional cell carcinoma, other carcinomas and sarcomas

What are some adverse effects of chemotherapy

• mild and self limiting

• prevention medicine

• increase with organ dysfunction (hepatic or renal)

  • metabolism of drug

  • activation through liver

    • cyclophosphamide

What areas/ cells are more susceptible to toxicity

• bone marrow

  • myelosuppression

• gastrointestinal

What is seen in myelosuppression

• neutropenia

• nadir down around 7 days post chemotherapy

• platelets can also drop

  • mild to moderate thrombocytopenia

What are some adverse effects of myelosuppression and how can it be avoided

• Monitor CBC prior to each treatment

  • Neutrophil nadir may be recommended (e. g. Doxorubicin, carboplatin)

• Delay + retest if neutropenic in 3-7 days dependent on severity

• Antibiotics if:

  • Neutrophil count <0.75 x109/l -DO NOT hospitalise

  • Neutropenia + febrile -HOSPITALIZE for IV

• Consider dose reduction

What are the adverse effects of GI toxicity

• Effects of gut epithelium

• risk of bacterial translocation

• acting via CRTZ

• consider preventative medicine- antiemetics

• antibiotics if

  • haemorrhagic diarrhoea

  • Persistent diarrhoea (other causes excluded)

How can you prevent/treat the adverse effects from GI toxicity

Antiemetics

• Maropitant

• Ondansetron

• Metoclopramide

Gut protectants

• Omeprazole

• Ranitidine

Anti-diarrhoeal medication

• Bland diet

• Pro-kolin

• Metronidazole

What drugs are more susceptible to hair loss

• alopecia is a breed disposition in

  • old english sheepdog

  • maltese

  • WHW terrier

  • etc

• loss of whiskers

How do you prevent drug extravasation

• clean placed catheter

• firmly taped in

• flush with saline

How do you treat drug extravasation

• Try aspiration of drug

• incristine

  • hot compresses

  • hyalauronidas

• doxorubicin: ice, dexrazoxane

What are some cardiotoxicity adverse effects

• dysrhythmmia

• cardiomyopathy

• monitor

  • cardiac murmur

  • predisposed breed: Great Dane, Cocker spaniel, doberman

• Cats-nephrotoxicity

how do you prevent sterile haemorrhagic cystitis

• monitor

• access to water

• furosemide

what does sterile haemorrhagic cystitis cause

• haematuria and stranguria but cultures negative

how do you treat sterile haemorrhagic cystitis

• stop medication

• analgesia

• instillation of DMSO, glycoaminoglycans

What are some other adverse effects

what chemotherapy drugs do you not give to cats

• cisplatin (pulmonary oedema)

• 5-fluorouracil (neurotoxicity)

What is the MDR1 mutation

• Breed predisposition

  • shepherds

• Defective drug excretion and uptake across blood brain barrier

• Vincristine, doxorubicin

  • MDR1 metabolised

• PCR test