Anticancer Tx Principles

Question 1

How does veterinary chemo differ to humans?

Answer 1

• same drugs, smaller doses- less intense schedule- palliation rather than cure- lack of intensive facilities for complications- QoL most important

Question 2

WHen is chemotherapy advocate?

Answer 2

• disseminated disease- chemo-sensitive tumours > lymphoma> leukaemia, myeloma> disseminated MCT> disseminate histiocytic sarcoma - adjuvant tx after surgery if likely to metastasise > OSA> HSA> high grade STS> high grade MCT

Question 3

Is chemostherapy advoacted with osteosarcoma?

Answer 3

Yes highly metastatic - micromets will be present even if not visable on radiography- ^ survival time

Question 4

less common Indications for chemotherpy?

Answer 4

• incomplete resection dirty margine (radiotherapy?) - neo-adjuvant chemo (shrunk prior to surgery) - not amenable to surgical resection - TVT: vincristine (transmissable venereal tumour, not in UK)

Question 5

What possible routs of chemo are available?

Answer 5

• Oral - IV- rare SC- intra-cavitary (eg. mesothelioma) - intra-lesionary (health and safety indications, not common)

Question 6

How do cytotoxic drugs work? 2 types?

Answer 6

• Some act as specific stages of cell cycle- Some cell cycle non-specific (affect all stages)> all interfere with cell growth or division so work well on high mitotic index tumours

Question 7

which cells are resistnat to chemo?

Answer 7

Cells in G0 resting phase

Question 8

Which phase of tumour growth is chmo most effective?

Answer 8

First log phase (before enters the plataux phase)

Question 9

When should chemo as adjunctive therapy after surgery be initiated?

Answer 9

after wound has healed

Question 10

What kinetics does tumour cell killing follow? How does this affect clinical use?

Answer 10

First order (will always kill % of cells, no matter how many cells present initially)-pulse dosing at intervals - allow normal cells to regrow but tumour not to

Question 11

Why is a single chemotherapy agent not used?

Answer 11

cancer cells can respond to selection pressure

Question 12

How can combination chemotherapy drugs be chosen?

Answer 12

• known efficacy as single agent- differnet modes of action that do NOT interfere!- act at different stages of cell cycle- no overlapping toxicity

Question 13

Give 3 therapy protocols for treating lymphoma

Answer 13

1. COP - based- cyclophosphamide, vincristine, prednisolone2. doxorubicin-containing protocols (CHOP) - eg. wisconsin-madison protocol 3. Modified LOPP protocol for T-cell lymphoma- lomustine, vincristine, procarbazine, pred

Question 14

Outline stages of chemotherapy

Answer 14

1. initial treatment protocol fairly intense aim to induce remission2. maintainence (some protocols) less intense, maintain remission3. re-induction when tumour elapses - return to initial protocol 4. rescue - when tumour becomes resistant try different mechanisms of action

Question 15

How are chemo drugs dosed? hen may this cause problems?

Answer 15

• Maximum tolerated dose (MTD) - mg/m^2 basis (surface area of patient relates to toxicity and blood flow to excretion organs) - BSAVA conversion charts for dogs and cats > small dogs <10kg dosed on mg/kg to avoid overdose

Question 16

WHat is metronomic therapy?

Answer 16

• NSAIDs + chemotherpy - aim to prevent angiogenesis and promote anti-cancer immune - RTKIs interefere with cell signalling and angiogenesis

Question 17

How is metronomic therapy different to usual chemo?

Answer 17

• given continous/semi-continuous basis- response slower and less dramatic- but if it -> stable disease that doesnt grow then ok

Question 18

What factors affect the success of chemo?

Answer 18

> tumour cell type - instrinsic resistance eg. many carcinomas and melanomas> drug distribution - blood supply and barriers to diffusion (CNS etc.) > resistance- tumours are genetically unstable

Question 19

Give one mechanism of drug resistnace in tumour cells

Answer 19

• MDR1 upregulation (pumps chemo esp. doxorubicin and vinca out of cells) - glucocorticoids cause MDR1 upregulation (only use as part of a combined protocol)

Question 20

Adverse effects of chemotherapy?

Answer 20

Rapidly dividing cells affected more > bone marrow (myelosuppression -> neutopenia, thrombocytopenia)- lowest neutropenia “nadir” ~ 1 week after chemo- lowest thrombocytopenia “nadir” ~10d after chemo- test CBC frequently before dosing - if sick/febrile and neutropenic give IVB ABx and fluids > gut - 3-5d after chemo- risk of bacterial translocation esp. if neutropenic -> sepsis - QoL - bland diet- metronidazole immunomodulatory > chemoreceptor trigger zone - vomiting- give maropitant or ondansetron- metacloprimide - H2 blockers/proton pump inhibitors - apetite stimulants > whisker loss or facial hairloss or curly coated hair loss- normally not much hairloss> drug extravasation- necrosis - vincristine hot compress and hyaluronidase to break down ECM - doxorubicin ice and dexrazoxane

Question 21

What is doxorubicin commonly used for? What side effects may it have?

Answer 21

> used for lymphoma and sarcoma > may cause cardiotoxicity - DCM and dysrhthmias > care if cardio disease concurrently> risk at cumulative high doses, given slowly to prevent > mast cell degranulation > GI colitis> cats nephrotoxic > necrosis if extravasated > hair loss sometimes

Question 22

What is cyclophosphamide used for? Side effects?

Answer 22

> Lymphoma> can cause haemorrhagic cystits (metabolite is irritant) - monitor dipsticks and behaviour around urination - free access to water and toileting- furosemide or prednisolone to encourage drinking and urination> avoid long term > tx: analgesia, oxybutinin (antispasmodic), DMSO into bladder

Question 23

Side effects of vincrsitine? What can be used instead?

Answer 23

• ileus (->constipation: give metoclopramide/ranitidine)- peripheral neuropathy (rare) - skin sloughs if extravasated > vinblastin lower ileus risk

Question 24

What is lomustine used for? Side effects? What must be checked before giving the drug?

Answer 24

• mast cell tumours and lymphoma - hepatotoxic (monitor ALT for hepatocyte dmage before dosing) - SAMe to protect the liver - potentially nephrotoxic (monitor renal function SG and glucouria on dipstick)

Question 25

Which platinum drugs are commonly used? Side effects?

Answer 25

> Carboplatin - cisplatin nephrotoxic so not used so much > cause nausea so give antiemetics> cisplatin causes fatal pulmonary oedema in CATS (cisplatin splats cats!) > 5-flurouracil causes neurotoxicity in cats

Question 26

Which dogs are particularly susceptable to vincristine and doxorubicin? Why?

Answer 26

Herding breeds (collies, shelties, australian sheppard, LH whippets) - mutation in MDR1 gene - poor drug excretioin- PCR test on blood to check for mutation

Question 27

eg. of a drug that may not work as predicted if liver function impaired? why?

Answer 27

Cyclophasphamide activated by liver so has unpredictable action with impaired liver function

Question 28

Mechanism of action of alkylating agents? Names of drugs in this group and common uses?

Answer 28

• not cell cycle specific, interfere iwth DNA replication and transcription> cyclophosphamide (lymphoma, sarcoma) > chlorambucil (CLL, lymphoma, IBD)> lomustine (MCT, cutaneous and T-cell lymphoma, brain)> melphalan (myeloma)

Question 29

Mechanism of action of mitotic spindle inhibitors? Names of drugs and common uses?

Answer 29

• cell cycle specific, bind to tubulin and interfere with mitotic spindle formation > vincristine (lumphoma, TVT, sarcomas (VAC))> vinblastine (high grade MCT)

Question 30

Mechanism of action of antimetabolites? Names of drugs and common uses?

Answer 30

• cell cycle specific, mimic normal substrates in DNA/RNA synth> cytosine arabinoside (lymphoma, GME) > methotraxate (lymphoma) >5-fluorouracil (some carcinomas)> gemcytabine> azathioprine (immunosupression) > hydroxycarbamide (polycythaemia vera)

Question 31

Mechanism of action of platinum compounds? Names of drugs and common uses?

Answer 31

• non cell-cycle specific, cross link DNA strands > carboplatin (cisplatin)- OSA, carcinomas

Question 32

Mechanism of action of anti-tumour ABx? Names of drugs and common uses?

Answer 32

• non cell cycle specific, multiple actions (inhibit topoisomerase, break/link DNA strands ~ alkynating agents, doxorubicin -> free radical formation)> doxorubicin (lymphomam sarcoma, some carcinomas) > epirubicin> mitoxantrone> actinomycin-D

Question 33

Which misc drugs can be use in cancer tx that are not cytotoxic?

Answer 33

> prenisolone- apoptosis of lymphoid and mast cells - lymphoma, MCT - side effects PUPD, PP, panting, mm weakness, slow healing, immunosuprression> L-asparaginase- breaks down L-asparagine (neoplastic cells dependent on this so inhibits protein synthesis) - normal cells can synthesise themselves- lymphoma and leukaemias- possible allergic reaction so give antihistamine on 2* administration > NSAIDs- anti-angiogenic- COX-2 inhibtiion - promote apoptosis- anti inlfam and analgesic-change local tumour environment- part of metronomic protocols (along with alkynating agents) > RTKIs - masitinib and toceranib for MCT - inhibit downstream signalling from cell surface growth Rs that ^ proliferation