Principles of Anti-Cancer Drug Therapy Flashcards
1
Q
What is Chemotherapy?
A
- problem is thart we gives them to the whole animal and their action is not specific to cancer cells
- While they can be good at targeting rapidly dividing cancer cells, they can be toxic to other cells in the body
- Try and find a balance between toxicity and efficacy
2
Q
Veterinary vs. Human Chemotherapy
A
- smaller doses with less intense dosage schedules
- Don’t expect to see the same degree of adverse effects as some people experience
- We don’t always have the same management facilities for any complications and extensive treatment
- Discuss all options available and think about what the owner wants
3
Q
Indications for Chemotherapy
A
- treatment for widespread disease in the body on tumors that we KNOW are chemosensitive (and will respond)
- ex: lymphoma (very common in practice)
- Leukaemias affecting bone marrow which will affect all over the body
4
Q
Indications for Chemo
(highly metastatic tumours)
A
- adjuvant: applied after initial treatment for cancer, especially to suppress secondary tumour formation
- ex: osteosarcoma of long bone or splenic hemangiosarcoma
- can treat the primary tumor adequately with surgery, but often they have spread elsewhere
- May not see secondary tumors on the imaging, but we know with these types of tumors there will likely be micrometastatic disease present
- To prolong the patients life, we would follow up with adjuvent therapy to delay the growth of those secondary tumors
- another ex: high grade mast cell tumor
5
Q
Other Indications for Chemotherapy and Contra-indications
A
- mop up for anything left behind?- but may have to consider a recut or radiation therapy in that situation
- Neo-adjuvant: sink the tumor prior to surgery. may make surgery an option by shrinking
- Some chemo-sensitive tumors may not be amenable (controlled) to resection or radiation due to location or size - chemo may be best option in these cases
- First line use of chemo –> TVT
- don’t see too often in UK, but it is there and chemo is highly effective!
6
Q
Routes of Administration
(5)
A
- intra-cavitary - using mesothelioma as an example, a cancer that affects the cells linging the body cavities (thoracic, abdominal) making it quite diffuse and often a lot of refusion associated with it, can treat with intra-cavitary treatment (in picture) - pots buried just under the skin and then the tube goes into the body cavity
- can access the subcutaneous pot with a special needle, can then drain the effusion (make patient feel better)
- can palliate the clinical signs associated with that effusion
- can apply chemotherapy through the pot into the cavity - diffusely spreads where it needs to
- Intra-lesional: not very common, stick treatment directly into the lesion
7
Q
Conventional Chemotherapy/ Cytotoxic Drugs
(actively Dividing Cells)
A
- we know that cancer cells like to grow and proliferate –> can generally target these
- some drugs target specific stages of the life cycle and some are non-specific
- G(knot) - outside of the cell cycle –> tends to be the more resistant part of the cycle
- high mitotic index: high number
8
Q
A
Y axis: cell number
X axis: time
- Tumors tend to grow rapidly in the early stages
- then once they get big, they don’t grow as well as they become a bit too large for their blood supply
- best time for chemo is the rapid growth phase when there are lots of cells dividing
- but unfortunately, the tumors tend to be disovered relatively late
- goal is to treat as early as possible
9
Q
Timing of Treatment
A
- want to get started as soon as we can!
10
Q
Dosing of Cytotoxic Drugs:
MTD and cell kill hypothesis
A
- tend to dose the cytotoxic chemotherapy drugs at the maximum tolerated dose
- realted to the cell kill hypothesis
- certain dose of a drug will kill a percentage of cells rather than a number of cells
- cant kill usually with single dose of treatment
11
Q
Dosing of Cytotoxic drugs at MTD
A
- tend to dose the drugs at maximum tolerated dose
- then aim for greatest fractional cell kill/treatment
12
Q
Dosing of Cytotoxic Drugs
(SA vs. BW)
A
- Often dosed on a surface area basis
- relates to things like the blood flow of the organs of excretion
- with chemotherapy drugs, they are written on mg/m^2 basis (DONT MISREAD THIS ON LABEL!)
- Use tables provided to look up animals weight in kg and then match up the equivalent body surface area that would correspond to (different charts for dogs and cats)
- smaller animals tend to have a larger SA relative to their body weight –> can tend to get overdosed on a mg/m^2 regime
- therefore sometimes depending on drug there may be a different regime listed for those smaller weights
13
Q
Combination Chemotherapy
(Cytotoxic Drugs)
A
- tend to be more effective than a single agent
- Using a single agent can lead to selection of cells that are resistant to that drug
- combination allows you to target the tumor in a number of different ways
14
Q
A
- can get 80-90% response rate with combination chemotherapy in dogs with lymphoma and good quality of life during treatment
- COP protocol –> 3 drugs with different mechanisms of action
- overall, different drugs, different mechanisms of action
- trying to avoid selecting for resistance
15
Q
Phases of Chemotherapy
(4)
A
- Induction: relatively intense sequence of drugs
- maintenance: only in some protocols, may shift onto a less intense and less aggressive protocol after induction (mainly if they have the induction protocol and then are in remission for a long time)
- Re-Induction: If they come out of remission at some point, the disease flares up again and if they have not been on chemotherapy treatment otr are on a maintenance regime–> may go back to the induction protocol to intensify
- Rescue: If you are already in your induction phase and initially it is working well and the dog relapses while it is in the induction phase, may need to switch to entirely different drugs or a different protocol
16
Q
Alternatives to Conventional Cytotoxic Drugs
(Dosing Strategy for Metronomic Therapy)
A
- RTKI’s: Receptor tyrosine kinase inhibitors
- these drugs are different in the strategies that we are using
- not a case of using them at max tolerated dose
- Metronomic: basically giving on a semi-continuous basis (daily, every other day, or every third day) - give small doses frequently rather than the maximum tolerated cytotoxic dose (larger doses and then gap b/w doses to allow tissues to become healthier before next max dose)
- RTKI’s: more targeted cancer drugs, will target cancer target cells specifically. can also inhibit growth signalling pathways (proliferation)
- these are performed in continous/semi- continuous dosing schedules as they arent killing the cells directly like cytotoxic drugs
- responses tend to be slower and less dramatic, can take time to see effects!
- Remember: sometimes stable disease is ok! Tumor may not shrink or go away, but if we are preventing growth and at least somewhat stabilizing it then that could also be a satisfactory situation
- Can even use cytotoxic therapy and then have a metronomic therapy as a maintenance regime - ways to combine things with different strategies
17
Q
Factors Affecting the Success of Chemotherapy
(3)
A
- some types of cancer are just intrinsically resistant to chemotherapy - malignant melanoma (like in people), may carcinomas
- If tumor doesnt have great blood supply, the drugs may not penetrate the tumor well
- OR if it is in the CNS, a lot of drugs cannot penetrate the BBB
- genetically unstable –> can acquire mutations that will allow them to become resistant to therapy you are using
- continual drug exposure puts a selection pressure on these cells –> selecting for resistant phenotypes
18
Q
Factors Affecting the Success of Chemotherapy
(Resistance)
A
- many mechs by which they can develop resistance - might be that they metabolize the drug quicker or develop alternative pathways
- multidrug resistance pump
- cancer cells can upregulate their MDR1 gene which that gene encodes a P- glycoprotein efflux pump
- this pump can be responsible for pumping cancer drugs OUT of the cell
- ex: in lymphoma, you can get upregulation of this process and then you can get resistance to drugs such as Doxorubicin and Vincristine
- also cross resistance against different classes of drugs as well
- don’t want to pre-treat lymphoma with prednisolone for a long period of time bc that can potentially induce resistance and your chemo drugs may not work
- may work fine to use alongside the chemotherapy drugs, just try to avoid pre-treating with glucocorticoids
19
Q
Alkylating Agents
A
- tend to bind and cross-link DNA strands
- when strands try and separate they wil break
- can act at any point in cell cycle
- listed some common ones
- Lomustine can penetrate the BBB
20
Q
Mitotic Spindle Inhibitors
A
- tend to act in the late G2 moving into M phase of cell cycle
- arrested in metaphase and cannot progress through the cell cycle to divide
- MCT: mast cell tumor
- Vinblastine: also used for lymphoma
- Vinorelbine: can be used for lung carcinomas
21
Q
Anti- Metabolites
A
- these drugs act in the S-phase
- either inhibit enzymes in DNA/RNA syn or they can result in non-functional molecules after synthesis
- Cytosine arabinoside (Cytarabine) is probably one of the biggest ones we use for lymphome –> penetrates the CNS so it is good for CNS lymphoma or renal lymphoma that often spreads to the CNS
22
Q
Platinum Compounds
A
- cause strand breakage and interfere cell division and interfere with the DNA replication and transcription
- tend not to use Cisplatin as much as it is nephrotoxic - tend to to use for osteosarcomas in adjuvant setting and sometimes for carcinomas
23
Q
Anti-tumour AB’s
A
- topoisomerase II - involved in unraveling the DNA so that it is able to replicate
- Doxorubicin - one of the more common in this class, can get free radical formation which damages the DNA directly. one of the most common agents we use in this category
- a rather broad spectrum agent
24
Q
Micellaneous Agents in Cancer Treatment
(non-cytotoxic)
A
- sometimes use these as part of our protocol (but they are non-cytotoxic!)
- Prednisolone: can help dampen down inflammation associated with mast cell tumors. can get some adverse effects associated with dosing these drugs
- remember “-ase” indicates an enzyme
- L-asparagine is an aa that NORMAL cells can synthesize on their own (will L-asparagine synthestase) but the neoplastic lymphoma cells can’t
- remove this supply from their environment and then they can’t synthesize their proteins
- because the enzyme is a foreign protein, there is a possibility of there being an anaphylactic reaction to it -tend to premedicate with an antihistamine if we are going to use it (only really with the 2nd or 3rd administration of the drug)
- Pro: is that it is not myelosuppressive! normal body cells do not depend on this external supply of L-asparagine
- can therefore use in a neutropenic patient for example bc you are not going to risk any myelosuppression (decreased bone marrow activity)
- Note: L-asparaginase is very expensive! - but if oyu have any leftover you can freeze it and use it a second time
25
Q
MIcellaneous Agents: NSAIDs
A
- dont use at the same time as prednisolone
- think there may be other anti-cancer activities through COX-2 inhibition
- effect on stromal cells in micro-environment
- TCC: Transitional Cell Carcinoma of the bladder
- remember: we use these as part of metronomic therapy as well!
26
Q
“Metronomic”/Continuous Low Dose Chemo
A
- immunomodulatory- tends to deplete the regulatory T-cells - tends to push the immune system in favor of anti-tumor immunity
- bc it acts on the tumor microenv’t, it can be quite useful in acting against tumors conferring resistance to conventional cytotoxic drugs
- since this works on the microenvironment of tumor cells, even low mitotic index tumors are susceptible as it does not depend on more actively dividing cells
- some studies looking at this in STS (soft tissue sarcomas - like what PME rat had) and seemed to delay time to recurrence
- HSA (hemangiosarcoma) - where they used it in the place conventional Doxorubicin chemotherapy and it had positive results (on small number of dogs)
- also on TCC in the bladder
27
Q
Receptor Tyrosine Kinase Inhibitors
A
- these are a relatively new class of drugs that have been licensed
- licensed for the treatment of mast cell tumors
- MAst Cell tumors tend to have KIT receptors on their cell surface which send signals for cell proliferation and survival
- in a normal situation those receptors have to bind a ligand or cell factor to switch on and to signal to the nucleus
- around 30-40% of mast cell tumors (generally the high grade ones) can have a mutation in the KIT gene - these receptors then think they are pretty much on all the time whether there is a ligand bound or not to signal the nucleus for division and proliferation all the time
- these drugs essentially switch off the abberant signalling - quite a specific action, but they do act on other receptors as well!
28
Q
Adverse Effects of Chemotherapy
A
- need to be able to recognize, avoid and minimize these effects as much as possible
- we are always aware of Quality of Life! - always need to check in and get feedback from the owner
- these patients generally need extra and prompt care so communicate with your clients!
29
Q
Adverse Effect of Chemo - Toxicity of Drugs
A
- often with these drugs we have a relatively narrow therapeutic index
- if oyu are testing bloods on a patient prior to chemo, make sure you are looking at biochemistry profile closely
- may need to change drug choice if liver or kidney function is not optimal (metabolism or excretion issues will change drug toxicities)
30
Q
Adverse Effect of Chemo - Damage to Tissues
A
- Normal tissues with rapidly dividing cells are more susceptible to damage by cytotoxic drugs
- bone marrow that produces our RBCs and WBCs
- enterocytes in the crypts of the gut lining that move up to the tips of the villi
31
Q
Myelosuppression
A
- In terms of the BM, if we get effects on the rapidly dividing cells, we can see effects in the circulation after dosing with chemotherapy
- May see a drop in neutrophils (which is out first line of defense in infection) about a week after dosing (danger period essentially)
- may see effects on platelets, but less clinically significant, but about 10 days after treatment
32
Q
Myelosuppression and Monitoring CBC
A
- when we have a patient getting chemotherapy, we check CBC freq
- check neutrophil nadir after first dose of any new drug!
- If patient is due for chemotherapy dose and the neutrophil count is low, we may need to think about delaying and retesting
- If the neutrophil count is REALLY low then that patient is at significant risk of developing infection –> give AB prophylactically even if they seem fine and alert
- if sick and really low–> emergency (give IV AB’s and IV fluids)
- may adjust therapy so we don’t perpetuate issue!
33
Q
GI Adverse Effects
A
- remember effect on enterocytes!
- there is bacteria living on gut wall, so if the enterocytes are affected and they are neutropenic then you really run a risk of sepsis in that patient - MUST communicate this with the owner
- chemotherapeutic drugs can act on the Chemoreceptor Trigger Zone and cause the vomiting reflex to occur
34
Q
Vomiting
A
- Can use a combination of therapies (anti-emetics)
35
Q
Diarrhoea
A
- metronidazole can have immunomoderatory effects ( for example with Doxorubricin induced colitis this can be quite effective)
- would need to give IV fluid therapy if severe (but unusual!)
36
Q
Anorexia
A
- think about WHY they may have stopped eating
37
Q
A
- uncommon to see complete hair loss in pets for chemotherapy
- in animals, there is periods of a resting phase (telogen phase) and active hair growth (anagen phase)
- typically don’t go completely bald
- may see complete alopecia in poodles or Bichon Frises
- terriers get more marked effects
- cats: loss of guard hair or loss of whiskers bc their whiskers tend to grow continuously
38
Q
Drug Extravasation
A
- some of these drugs can cause adverse effects if they are injected outside of the vein
- really must be careful!
- right pic: Doxorubicin application complication, really nasty
- just a lot of extra care with catheter
- If it happens, best to seek advise!
- hyaluronidase helps the Vincristine disperse
- Doxorubicin is much more toxic - want to keep it very local. Use ice to cause vasoconstriction and dexrazoxane which is a free radical scavenger (very $$$ -referral centers will carry it)
39
Q
Doxorubicin
A
- toxicities to think about with individual drugs
- can cause tachyarrythmias when given too quickly during administration
- can cause long term effects on the heart –> damage to heart muscle itself, Dilated Cardiomyopathy with cummulative dosing
- risk around 180 mg/m^2 or about 6 doses
- need to give slowly! over 20-30min
- even more cautious with pre-exisiting heart disease
- can cause mast cell degranualtion and swelling (not common)
- nasty if it goes perivascularly!
- cats - do use it, but must monitor renal function before each dose
40
Q
Cyclophosphamide
A
- Often used in lymphoma
- one of the metabolites (acrolein) can irritate the bladder lining –> can get hemorrhagic cystitis
- monitor patient for discolored urine, etc.
- often give it in the morning so that they have time to go urinate
- Furosemide will promote extra drinking and urination to try and minimize contact with the bladder
- Oxybutinin: anti-spasmotic
- GAGs (glycosaminoglycans) to coat the bladder
41
Q
Vincristine
A
- Ileus is the medical term for this lack of movement somewhere in the intestines that leads to a buildup and potential blockage of food material
- need to think about drugs that will help with gut motility - prokinetics, etc.
42
Q
Lomustine
A
- sometimes toxic to the liver
- monitor ALT - which an enzyme that indicates liver damage
- measure before each dose
- also tend to put them on a liver protectant to reduce the risk (ex: Denamarin)
43
Q
Platinum Drugs
A
- tend not to use it a lot anymore bc you needed to give hours and hours of diuresis
- tend ot give maropitant for nausea
44
Q
RTKI’s
A
- nice bc you can give orally and even though they aren’t cytotoxic, they can have adverse effect
- can get some myelosuppression and that causes issues when given in combination with cytotoxic drugs
45
Q
Cats- Contraindicated Drugs
A
- Cisplatin SPLATS cats - NEVER GIVE THEM THIS!!!
46
Q
Herding Breeds - MDR1 Mutation
A
- this can mean that they have defective drugs excretion into the kidneys or bile
- these drugs act as substrates for that pump
- can do PCR to see if they are carriers or homozygous for gene defect
47
Q
A
48
Q
DO THIS CAL
(what lymph nodes should you palpate during this exam?)
A
The peripheral lymph nodes which should be palpated during your clinical examination are:
- Mandibular / Submandibular
- Prescapular
- Axillary
- Popliteal
- Inguinal / Superficial Inguinal
49
Q
What are the LN’s you should be able to palpate on examination in a dog?
A
50
Q
What LN’s are not normally palpable in a dog and may indicate disease if they are?
A
51
Q
From the following list of differential diagnoses, which ones would you consider as possible causes of generalised lymphadenopathy?
A
infection, immune mediated disease, neoplasia (primary) and neoplasia (secondary).
70
Q
cystocentesis urine culture
and
cyclophosphamide induced hemorrhagic cystitis
A
- If the urine culture is negative – this suggests sterile haemorrhagic cystitis, secondary to cyclophosphamide treatment (one of the metabolites can irritate the bladder lining).
- Analgesia may be required e.g. tramadol or gabapentin.
- Consider glycosaminoglycans to help coat the bladder lining and oxybutinin to relieve detrusor spasm.
- Cyclophosphamide should not be used again in cases with sterile haemorrhagic cystitis.
- Another alkylating agent (e.g. chlorambucil) should be introduced in place of cyclophosphamide.
- The cystitis usually resolves with time.
74
Q
A
- Normal Radiograph of a Cat
75
Q
On a cat
What is shown by this radiograph?
A
76
Q
What is shown by the US images of this cat?
A
