Anticancer Tx Principles Flashcards
How does veterinary chemo differ to humans?
- same drugs, smaller doses- less intense schedule- palliation rather than cure- lack of intensive facilities for complications- QoL most important
WHen is chemotherapy advocate?
- 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
Is chemostherapy advoacted with osteosarcoma?
Yes highly metastatic - micromets will be present even if not visable on radiography- ^ survival time
less common Indications for chemotherpy?
- 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)
What possible routs of chemo are available?
- Oral - IV- rare SC- intra-cavitary (eg. mesothelioma) - intra-lesionary (health and safety indications, not common)
How do cytotoxic drugs work? 2 types?
- 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
which cells are resistnat to chemo?
Cells in G0 resting phase
Which phase of tumour growth is chmo most effective?
First log phase (before enters the plataux phase)
When should chemo as adjunctive therapy after surgery be initiated?
after wound has healed
What kinetics does tumour cell killing follow? How does this affect clinical use?
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
Why is a single chemotherapy agent not used?
cancer cells can respond to selection pressure
How can combination chemotherapy drugs be chosen?
- known efficacy as single agent- differnet modes of action that do NOT interfere!- act at different stages of cell cycle- no overlapping toxicity
Give 3 therapy protocols for treating lymphoma
- 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
Outline stages of chemotherapy
- 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
How are chemo drugs dosed? hen may this cause problems?
- 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
WHat is metronomic therapy?
- NSAIDs + chemotherpy - aim to prevent angiogenesis and promote anti-cancer immune - RTKIs interefere with cell signalling and angiogenesis
How is metronomic therapy different to usual chemo?
- given continous/semi-continuous basis- response slower and less dramatic- but if it -> stable disease that doesnt grow then ok
What factors affect the success of chemo?
> 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
Give one mechanism of drug resistnace in tumour cells
- MDR1 upregulation (pumps chemo esp. doxorubicin and vinca out of cells) - glucocorticoids cause MDR1 upregulation (only use as part of a combined protocol)
Adverse effects of chemotherapy?
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
What is doxorubicin commonly used for? What side effects may it have?
> 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
What is cyclophosphamide used for? Side effects?
> 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
Side effects of vincrsitine? What can be used instead?
- ileus (->constipation: give metoclopramide/ranitidine)- peripheral neuropathy (rare) - skin sloughs if extravasated > vinblastin lower ileus risk
What is lomustine used for? Side effects? What must be checked before giving the drug?
- 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)
Which platinum drugs are commonly used? Side effects?
> 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
Which dogs are particularly susceptable to vincristine and doxorubicin? Why?
Herding breeds (collies, shelties, australian sheppard, LH whippets) - mutation in MDR1 gene - poor drug excretioin- PCR test on blood to check for mutation
eg. of a drug that may not work as predicted if liver function impaired? why?
Cyclophasphamide activated by liver so has unpredictable action with impaired liver function
Mechanism of action of alkylating agents? Names of drugs in this group and common uses?
- 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)
Mechanism of action of mitotic spindle inhibitors? Names of drugs and common uses?
- cell cycle specific, bind to tubulin and interfere with mitotic spindle formation > vincristine (lumphoma, TVT, sarcomas (VAC))> vinblastine (high grade MCT)
Mechanism of action of antimetabolites? Names of drugs and common uses?
- 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)
Mechanism of action of platinum compounds? Names of drugs and common uses?
- non cell-cycle specific, cross link DNA strands > carboplatin (cisplatin)- OSA, carcinomas
Mechanism of action of anti-tumour ABx? Names of drugs and common uses?
- 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
Which misc drugs can be use in cancer tx that are not cytotoxic?
> 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
