Medical therapies

What is chemotherapy?

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

What are the different ways chemotherapy can be used?

• Primary chemotherapy - sole anti-cancer tx, common with lymphoma

• Adjuvant Chemotherapy - after surgery to remove any mets (/microscopic residual dz)

• Neoadjuvant chemotherapy - given before surgery to shrink tumour and increase chance of successful resection (mast cell tumour, mammary carcinoma)

How does chemotherapy work?

Active against rapidly proliferating tissues

(Does not specifically target cancer cells —> Cannot tell the difference between a cancer cell and a normal cell)

What cells are relatively chemo resistant?

Cells that are not actively dividing (those in G0)

At what time point is chemotherapy most likely to be effective?

Before a mass can be identified - the more cells the more likely there is going to be a resistant one

What are the factors that affect chemotherapy success?

• Tumour cell heterogeneity (evolution of resistance) – linked to tumour size

• Inherent tumour sensitivity

  • Origin tissue (e.g. eye quite resistant)

  • Growth fraction

• Drug dosage

• Tumour blood supply/oxygenation

• Interval between treatments

• Other drugs (steroids when treating a lymphoma)

How does tumour heterogenicity effect chemotherapy success?

• Sub-clones have multiple mutations

• If there are sufficient cells a resistant clone is very likely therefore chemo less effect

• Stem cells may also pay a role

• Mass physical structure also relevant

How can drug resistance of cancer cells be minimised?

• Treat as early as possible

• Follow properly evaluated protocols

• Use correct doses

• Avoid pre-treatment with drugs that induce resistance (selects for resistant cell population)

• At relapse, act ASAP

What considerations need to be made about drug pharmacology?

• Administration - ability of oral drugs to get in blood stream

• Distribution - ability get to target

  • size drug

  • vasculature

  • necrosis

  • blood barriers (blood brain barrier)

• Metabolism - drug activation/deactivation

  • glutathionine

• Excretion - abnomral GFR?

  (issues with animals with hepatic and renal problems)

How do you dose obese patients?

Estimating lean weight?

What are some problems that can affect dosing?

• obesity

• drug sensitivities

• Animals with hepatic functional compromise

• Animals with reduced renal function

What drug sensitivity is common in collies?

MDR1 (ABCB1) mutations

When is single agent chemotherapy used?

• Sensitive tumours - Transmissible venereal tumour (TVT)

• OR when second effective agent unknown

• Tends to select rapidly for drug resistance

  • Selection pressure high leading to rapid dominance of resistant cells

How does the risk of toxicity differ between sequential and combined polychemotherapy?

combined > sequential

What are the 2 types of polychemotherapy approach?

• Sequential —> Several drugs given at different times

• Combined —> Several drugs given at the same time

With polychemotherapy, what should each agent do and what should be avoided?

Should:

• 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

Avoid:

• Arbitrarily excluding one of the drug from the protocol

• Arbitrarily reducing a drug dose

  • Toxicity to one drug is not always indicative of toxicity to another

What routes of administration are used for chemotherapy?

• Oral

• Intravenous

  • Bolus (rapidly)

  • Infusion (slowly)

• IM/SC

• Intracavitary

(always wear appropriate PPE when doing this and consider environmental risk)

avoid topical + intratumoral

How is dosing worked out for patients?

High dose chemotherapy has a narrow therapeutic window

• Start at the maximum tolerated dose (will be the dose listed in protocol) - reduce/adjust if there are adverse effects

• Dosing based on body surface area

  • Correlate with liver/kidney blood supply (metabolism) better than weight

• For smaller patients (<10kg) some drugs are administered on mg/kg

  • Carboplatin, doxorubicin, epirubicin

What is the interval between treatments for?

Dose density

• Allow recovery of normal tissues

• Bone marrow + GIT capacity to repair rapidly

• These tissues tend to repair more rapidly than most tumours (treatments too close together leads to toxicity of normal tissue)

What is the first line chemotherapy protocol for lymphoma in dogs and cats?

• Lymphoma (dogs): CHOP (vincristine, doxorubicin, cyclophosphamide and prednisolone) or CEOP (epirubicin vs doxorubicin) or COP (high dose)

• Lymphoma (cats): high dose COP (high grade) or chlorambucil/pred (low grade)

What is the first line chemotherapy protocol for mast cell tumours?

Mast cell tumours: vinblastine/prednisolone. Use a TKI if have c-kit mutation. If owner cant afford mutation testing is better to use vinb/pred

What is the first line chemotherapy protocol for osteosarcomas?

carboplatin q3w for 4-6 doses (after amputation)

What needs to make up Pre-chemotherapy assessment?

• Discuss tolerance of any previous treatment

• Assess patient

• Assess tumour status

• Biochemistry (preprotocol, every few mths)

• Haematology prior to each treatment

  • neutrophils (most important for patient to fend off infec)

  • platelets

• Urinalysis start or treatment, prior to cyclophosphamide

What are the different responses you can have to the therapy?

• Complete remission CR - all lesions gone, no new lesions (assoc. with improved outcome)

• Partial remission PR - ≥ 30% reduction in size, no new lesions

• Stable disease SD - between PR and PD

• Progressive disease PD - ≥20% increase or new lesions

  (can only monitor this for primary and neoadjuvant chemo)

How common are side effects from chemotherapy?

• 30 – 50 % of patients have some side effects during treatment course

• Most side effects are transient and self resolving

• <10 % have side effects that lead to hospitalisation

• 1 – 2 % chance of death (usually sepsis)

What immediate toxicities can you get (<24hrs)?

What treatment would you use for these?

• Anaphylaxis/hypersensitivity - tx w. steroids, antihistamines

  • esp caused by L-asparaginase (especially repeat doses), anthracyclines, cisplatin, cytosine

  • IVFT, dex iv, H1 blocker, adrenaline

• Cardiac arrhythmia

  • esp caused by Doxorubicin (epirubicin)

• Emesis - tx w. maropitant, Metaclopromide (short t_1/2), ondansetron

  • esp caused by Platinum compounds, actinomycin-D

What is acute tumour lysis syndrome?

• Rapid destruction of cancer cells in patients with large tumour burdens

  • lymphoma

  • 24-48 hrs

• Electrolyte abnormalities

  • Hyperkalaemia

  • Hyperphosphatemia

  • Hypocalcemia

• Acute kidney injury

How would you deal with a patient with high tumour burdens?

• Careful monitoring of at risk patient - keep in the hospital for 24-48 hours

• Early IVFT if you see signs

• Management of AKI

What longer term side effects can you see?

• Bone marrow - Low WBC count (7-10 days)

• Alopecia - uncommon, specific breeds

• Gastrointestinal – does not usually lasts longer than the first 4 days

(Rapidly dividing cells most affected)

What signs will you see with GI toxicity?

• direct damage to enterocytes

• Anorexia, nausea, vomiting, diarrhoea

• Disrupted mucosal barrier with neutropenia increases risk of sepsis (…bacterial translocation)

1-5 d post-tx

What chemo drugs can cause GI toxicity?

doxo cytarabine /epi, vincristine, cyclophosphamide (in cats), infusion, platinum compounds

How can you manage GI toxicity initially?

• Maropitant – dispense for home use to prevent vomiting

• Pre-treatment fasting reduces diarrhoea

• Consider dispensing smectite in case of diarrhoea (VBS clay)

What do you do if signs of GI toxicity last longer than 24 – 48 hours (more severe)?

• IVFT

• Anti-emetics – metoclopramide (great for nausea), ondansetron

• Diarrhoea – maropitant, smectite, benefit of abs unclear

incr risk sepsis if neutropenia

Why may toxicity occur 7-10d post chemotherapy?

• Damage to emerging haematopoetic cells

  • Dip in neutrophil counts for 48 – 96 hours typically

  • Timing varies a little by drugs and patient (most 7 days)

• Some reduction in neutrophil counts is associated with improved outcome.

• Too low leads to a risk of sepsis

  • <0.75 x 109/L if assymptomatic

  • Or up to 1.5 x109/L if pyrexi

Why are patients presenting 7-10d post chemotherapy with pyrexic neutropenia a medical emergency?

• 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

  • Bactericidal antibiotics (aerob/anaerob continue for 3-7d after recovery). Ideally IV (cefuroxime 20mg/kg IV q8hr)

How does you approach differ depending on the amount of neutrophils?

• Neutrophil count <1x109/L

  • Antibiotics (amox/clav 20mg/kg bid 7d or TMOS)

  • Drug discontinuation (if on tablets)

  • Check temperature

  • Subsequent dose reduction

• Neutrophil count 1-1.5x109/L

  • If next dose due will need to be delayed

  • No abs unless good reason

• Neutrophil count 1.5-2.5x109/L

  • Dose may require postponement/modification depending on schedule.

What other drug associated complications can occur?

• Cumulative cardiotoxicity (DCM)

  • Doxorubicin (+/- epirubicin?!- thought to be less cardiotoxic) (dogs)

• Sterile haemorrhagic cystitis

  • Cyclophosphamide (dogs)

• Hepatotoxicity

  • Lomustine (dogs)

• Nephrotoxicity

  • cisplatin, doxorubicin (cats), lomustine (dogs)

• Fatal non-cadiogenic pulmonary oedema

  • cisplatin (cats)

• Fatal CNS signs

  • 5-FU (cats)

  • dihydropyrimidine dehydrogenase activity

What can be done to prevent sterile haemorrhagic cystitis?

• Furosemide

• Increase drinking

• Frequent outdoor access

What can reduce the risk of hepatotoxicity?

SAM-E

What is being shown here?

• Extravasation

• ALWAYS use a cleanly placed first stick catheter, never leave unsupervised and flush before removal

• Monitor for any swelling, discomfort, changes in resistance to injection or rate of infusion

• Do not use a syringe driver or pump (pressure can go quite high before alerted)

• Flush catheters appropriately before catheter removal

What chemotherapy drugs are perivascular irritants?

• Vincristine and vinblastine are perivascular irritants

• Doxorubicin, epirubicin, Actinomycin D are catastrophic perivascular irritants

How can extravasation be treated?

• If you suspect an extravasation, do not flush!

  • Raise vein and draw back

• Doxorubicin/ Epirubicin /Actinomycin D

  • Apply COLD packs

  • Dexrazoxane

  • Topical DMSO

  • Consider (immediate) surgical debridement

• Vincristine/Vinblastine

  • Apply WARM compresses

  • Topical DMSO

  • Hyaluronidase (not recommended)

What are the features of metronomic chemotherapy?

• Daily low dose chemotherapy

  • Main target is angiogenesis

  • Direct action on tumour cells and stim immune response

• Prevent local recurrence STS

• Slow metastatic disease HSA

What is commonly used for metronomic chemotherapy?

low dose cyclophosphamide with piroxicam (or other NSAIDs)

monitor haem + urine dipstick

What is MOA of Receptor Tyrosine Kinase?

• Inhibit the activation of specific signalling pathways involved in specific types of cancer

  • have an effect on angiogenesis (eg via VEGF)

• Two oral drugs targeting the RTK KIT (toceranib and masitinib) licensed for treatment of mast cell tumours in dogs

  • More effective in presence of KIT mutation

  • used for metastatic disease

What side effects can be seen with receptor tyrosine kinase inhibitors?

• Diarrhoea and anorexia

  • 35 – 45 %, but only severe in 10%

  • Many owners report soft stools

  • Usually managed by treatment pauses

• Bone marrow suppression

  • Around 10 % not typically severe

side effects may be delayed 4-6w

What are some more rare adverse effects of receptor tyrosine kinase inhibitors?

• Masitinib - Protein losing nephropathy and haemolytic anaemia (both rare)

• Toceranib – Epistaxis (nose bleeds), elevated blood pressure, muscle pain / weakness