Oncology - medical therapies Flashcards
What is chemotherapy?
Chemotherapy is genotoxic (i.e. damaging to DNA) treatment of disease by the use of chemical substances, especially the treatment of cancer by cytotoxic and other drugs
Chemotherapy is the mainstay treatment for which diseases?
Disseminated neoplastic diseases
Chemotherapy can be used in combination with …?
Surgery
Radiotherapy
What are the 3 requirements of chemotherapy?
Standardised approaches
Multiple agents (usually)
Multiple cycles
How is primary chemotherapy used?
As the sole anti-cancer treatment in highly sensitive tumour types
How is adjuvant chemotherapy used?
Treatment is given after surgery to “mop up” microscopic residual disease
- Best to be given before severity increases to increase effectiveness
- Given for tumours when there’s a high chance of metastatic disease
What is neoadjuvant chemotherapy?
Treatment is given before surgery to shrink tumour and increase chance of successful resection
What is concurrent chemotherapy?
Treatment is given simultaneous to radiation to increase sensitivity of cancer cells to RT
Chemotherapy is mainly active against which cells?
Highly proliferating tissues
- Does not specifically target cancer cells
- Cannot tell the difference between a rapidly dividing cancer cell and a rapidly dividing normal cell
Cells in which part of the cell cycle are chemo resistant?
Cells that are not actively dividing (those in G0)
What is the main issue with cells in G0?
They act as a reservoir to repopulate the tumour
Which 4 parts of the cell are targeted by chemotherapy?
DNA synthesis
RNA synthesis
Protein synthesis
Cell cycle progression
What are indolent tumour?
Slow growing
How are indolent tumours affected by chemotherapy?
Typically resistant and are best treated with other methods (surgery if possible). Adjunctive chemotherapy can still be a part of treatment but not typically the sole therapy.
At which point of tumour growth is chemotherapy most likely to be affective?
Small number of rapidly dividing cells
- high growth factor and mitotic index
- few cells in G0
Describe Nowell’s hypothesis on tumour cell heterogeneity
Cancer is the result of genetic instability
- If a cell develops a genetic mutation this is transferred to further clones
- New clones may develop further genetic mutations that can lead to cancer
- Tumours are heterogenous. As they progress there are often ‘subclones’ that have additional mutations
- If there are sufficient cells a resistant clone is very likely
- Stem cells may also pay a role
List 6 factors that affect chemotherapy success
- Growth fraction and mass doubling time
- Tumour cell heterogeneity (evolution of resistance)
- Inherent tumour sensitivity
- Drug dosage
- Tumour blood supply/oxygenation
- Interval between treatments
How can drug resistance be minimised?
- Treat as early as possible
- Use standard protocols
- Use correct doses
- Administer agents properly
What causes drug resistance in lymphoma and mast cell tumours?
Pre-treating patients with steroids
What factors should be considered when choosing chemotherapy agents?
- What is the indication for chemotherapy
- What is the evidence of benefit of chemotherapy for that indication
- Chemotherapy is often palliative (longer or shorter term)
- Balance between QoL and treatment effect
- Signalment (may link to pharmacogenomic issues)
- ADME
- Co-morbidities
- Dosing and schedule
ADME stands for?
Administration
Distribution
Metabolism
Excretion
How can administration affect response and side effects of chemotherapy?
Dose, ability to get into blood stream if oral
How can distribution affect response and side effects of chemotherapy?
Ability of molecule to get to target site
- Size of drug, vasculature, necrosis, environment
- Blood barriers e.g. blood brain barrier
Cellular uptake / efflux pumps e.g ABCB1
How can metabolism affect response and side effects of chemotherapy?
Drug activation / deactivation e.g. CYP450, glutathione s-transferase
How can excretion affect response and side effects of chemotherapy?
Clearance – hepatobiliary system, kidney, (lung)
For kidney excreted GFR correlates with adverse effects of some drugs
When is single agent chemotherapy indicated?
- Used for exquisitely sensitive tumours e.g. Transmissible venereal tumour (TVT)
- When second effective agent unknown
- Tends to select rapidly for drug resistance
- Not capable of adequate antineoplastic activity
What is sequential polychemotherpay?
Several drugs given at different times
What is combined polychemotherapy?
Several drugs given at the same
Agents given as a part of polychemotherapy should have what characteristics?
- Have proven efficacy against the tumour
- Have different modes of action
- Affect different stages of the cell cycle
- Have non-overlapping dose limiting toxicities
- Not interfere with each others actions
Is toxicity more common in combined or sequential polychemotherapy?
Combined
Chemotherapy can be administered via which routes?
Oral
Intravenous - Bolus (rapidly) or Infusion (slowly)
IM/SC
Intracavitary
What factors of a pateint may pose chemotherapy dosing problems
- Obese patients
- Collies and others with known drug sensitivity
- Animals with hepatic functional compromise
- Animals with reduced renal function
When using high dose chemotherapy what needs to be communicated to owners?
- If we start too low treatment is ineffective
- If we start too high it will be toxic
- Hence need to give a dose that is safe for most patients, management any issues and adjust dose if severe AEs (typically 10% reduction is sufficient)
At what dose should chemotherapy be started on?
Maximum tolerated dose
- Most dogs tolerate chemotherapy well with minimal side effects
- Don’t start low assuming they will get sick.
- Only lower as needed based on actual adverse effects
How is the interval between chemotherapy drug doses designed?
To allow recovery of normal tissues
- Rapidly dividing tissue such as bone marrow and GI tract have tremendous capacity to repair rapidly
- These tissues tend to repair more rapidly than most tumours
What happens if chemotherapy treatments are too close together or too far apart?
Too close = cumulative toxicity or normal tissue - so damage to normal and tumour tissue
Too far = number of cells in normal and tumour tissue doesn’t decrease overall
CHOP chemotherapy uses which combined agents?
Vincristine
Doxorubicin
Cyclophosphamide
Prednisolone
CEOP chemotherapy uses which combined agents?
Vincristine
Epirubicin
Cyclophosphamide
Prednisolone
Compare first line chemotherapy protocols for lymphoma in dogs and cats
Dogs = CHOP or CEOP
Cats = High dose COP or chlorambucil/pred (low grade)
How should patients be assessed before chemotherapy?
- Discuss tolerance of any previous treatment
- Assess patient
- Assess tumour status
- Biochemistry
- Haematology prior to each treatment
- Urinalysis start or treatment, prior to cyclophosphamide
How should you plan for chemotherapy treatment?
- Discuss risks and benefits for patients with owner
- Ensure the owners context is appropriate for their pet to give chemotherapy: not pregnant or planning to be, no very young children
- Practice set up and staffing is sufficient to administer the drugs safely
- Appropriate PPE is available
- Written owner info
Describe the effects of immediate chemotherapy toxicity?
<24hrs
- Anaphylaxis/hypersensitivity
- Cardiac arrythmias
- Emesis
How is anaphylaxis/hypersensitivity due to immediate chemotherapy toxicity managed?
IVFT, dex iv, H1 blocker, adrenaline
How are cardiac arrythmias due to immediate chemotherapy toxicity managed?
Doxorubicin
Which cancer cases are at risk of acute tumour lysis syndrome (due to chemotherapy toxicity)
Large tumour burdens
Rapid destruction of cancer cells e.g. lymphoma
First 24 – 48 hours
Describe the clinical pathology and management of acute tumour lysis syndrome (due to chemotherapy toxicity)
Electrolyte abnormalities
Acute kidney injury
Careful monitoring of at risk patient
Early IVFT
Management of AKI
List the main general side effects of chemotherapy
- Bone marrow: lowest white count typically 7 – 10 days
- Alopecia: uncommon in dogs /cats except a few breeds
- GI: does not usually lasts longer than the first 4 days
- Rapidly dividing cells most affected
- Most side effects are transient and self resolving
- <10 % have side effects -> hospitalisation
- 1 – 2 % chance of death (usually sepsis)
Describe chemotherapy toxicity 1-5 days post treatment
- Direct damage to enterocytes
- Anorexia, nausea, vomiting, diarrhoea
- Disrupted mucosal barrier with neutropenia increases risk of sepsis (…bacterial translocation)
Describe pre-emptive / home management of GI toxicity (1-5 days post chemotherapy treatment)
Maropitant – dispense for home use to prevent vomiting
Not so effective for nausea
Pre-treatment fasting reduces diarrhoea
Consider dispensing smectite in case of diarrhoea (VBS clay)
Probiotics ineffective
GI toxicity is most severe in which cases?
Signs prolonged longer than 24 – 48 hours
Patient unwell / off food
Describe chemotherapy toxicity 7-10 days post treatment
- Dip in neutrophil counts for 48 – 96 hours typically
- Too low = risk of sepsis
Describe management of pyrexic neutropenic patients post chemotherapy
- Medical emergency as may be septic
- Translocation of bacteria from patient’s own GI flora
- Hospitalisation - until systemically well
- Stop all cytotoxic drugs- dose reduce next time
- Barrier nurse and aseptic techniques
- Supportive therapy
Name 6 drug associated complications of chemotherapy
- Cumulative cardiotoxicity (DCM)
- Sterile haemorrhagic cystitis
- Hepatotoxicity
- Nephrotoxicity
- Peripheral neuropathy
- Fatal non-cadiogenic pulmonary oedema
Define extravasation
The leakage of blood, lymph, or other fluid, such as an anticancer drug, from a blood vessel or tube into the tissue around it
Which chemotherapy drugs are perivascular irritants?
Vincristine and vinblastine
Which chemotherapy drugs are catastrophic perivascular irritants?
Doxorubicin, epirubicin, Actinomycin D
How can extravasation be avoided?
- ALWAYS use a cleanly placed first stick catheter
- Monitor for any swelling, discomfort, changes in resistance to injection or rate of infusion
- Never leave an animal unsupervised on an infusion
- Do not use a syringe driver or pump
- Flush catheters appropriately before catheter removal
What should you do if you suspect extravasation?
If you suspect an extravasation, do not flush!
Raise vein and draw back
How should you treat extravasation due to Doxorubicin/Epirubicin/Actinomycin D?
Apply COLD packs
Dexrazoxane
Topical DMSO
Consider (immediate) surgical debridement
How should you treat extravasation due to Vincristine/Vinblastine?
Apply WARM compresses
Topical DMSO
What is metronomic chemotherapy?
Continuous low dose chemotherapy
Usually used palliatively or after completion of MTD chemo
Describe how metronomic chemotherapy works?
Main target is angiogenesis
Stimulation of immune response
Direct action on tumour cells
What is the action of tyrosine kinase inhibitors?
Inhibit the activation of specific signalling pathways involved in specific types of cancer
When are tyrosine kinase inhibitors indicated?
More effective in presence of KIT mutation
Licensed for incomplete excision
Generally used for metastatic disease
What are the most common adverse affects of tyrosine kinase inhibitors?
Diarrhoea, vomiting and anorexia
Bone marrow suppression
