Cancer Treatment: Chemotherapy Flashcards
how is chemo in vet med different to human med
much lower doses and fewer side effects
what are the aims of chemotherapy
To prolong survival
To maintain good quality life
To minimize side effects
how is a patient selected for chemotherapy (4)
1. Confirm the diagnosis of neoplasia and stage the clinical extent
-Blood +/- marrow to assess marrow function in hemopoietic tumours
2. Treat/stabilize paraneoplastic syndromes
3. Decide that systemic treatment is appropriate and necessary (wide spread or highly metastatic tumour)
4. Exclude concurrent disease which may prevent chemotherapy (stop NSAIDs for arthritis is planning to use prednisolone)
which tumorus is chemotherapy most effective on
drugs work best on rapidly dividing cells
Hematopoietic (LSA/leukaemia)
Mast cell tumours (high grade)
Solid carcinomas/sarcomas
what is conventional chemotherapy
non-specific toxic effect of high doses of cytotoxic drugs acting on any dividing cells
max tolerated dose
what are targeted therapies
Drugs which specifically target pathways or molecules only altered in cancer cells
Should have reduced side-effects if only cancer cells affected
how does conventional chemotherapy work
Works on rapidly dividing cells in a non-specific way
Doesn’t differentiate between tumour and normal cells
how do you minimize side effects when using conventional chemotherapy
allow normal cells to recover between doses
how do chemotherapy drugs work on the cell cycle
why should you use a combination of drugs when treating lymphoma (3)
- different drugs should have a different mode of action
- affect different phases of the cell cycle
- and have different methods of resistance
what do you need to make sure of when combining drugs
- drug toxicities don’t overlap
- drugs do not interfere with eachother
what are the general side effects of chemotherapy drugs
bone marrow suppression
alopecia
GI upsets
delayed effects (infertility, new tumour induction)
perivascular reaction/irritation
what are side effects of cyclophosphamide
hemorrhagic cystitis
what are side effects of doxorubicin
cardiomyopathy
arrhythmias
what are side effects of lomustine
liver damage
what are side effects of vincristine, vinblastine
peripheral neuropathies
what are side effects of cisplatin
nephrotoxicity
which drugs can cause hypersensitivity
doxorubicin
L-asparaginase
how do you chose a protocol to treat lymphoma (5)
- B cell/T cell
- high grade/low grade
- induce clinical remission with high doses
- continue with maintenance (lower doses)
- intensify protocol if response not complete or change to different drugs
how do you assess if chemotherpy is effective
1. is animal in remission (is there evidence drugs are working)
yes = continue
no = add a boost (ex. L-asparaginase or change protocol)
2. is animal well with no unacceptable side effects after last dose?
yes = continue
no = consider dose reduction, more GI protectants/anti nausea or change drugs/protocols or stop treatment
what is low dose COP protocol
vincristine (Oncovin)
Cyclophosphamide
Prednisolone
what is the induction phase of low dose COP
high doses of drugs for first 6-8 weeks to induce remission
vincristine: 0.5mg/m^2 IV q7 days
cyclophosphamide 50mg/m^2 po q48h
prednisolone 40mg/m^2 po 24h for 7 days, then 20mg/m^2 po q48h
if the animal is in clinical remission with the low dose COP protocol what should you do
go to maintenance doses
if the animal is in partial remission or stable disease (SD) with the low dose COP protocol what should you do
keep on weekly or change protocol
what is the maintenance phase of COP
alternate week therapy (week of drugs, week of no drugs, week of drugs etc)
then 1 week in 3, 1 week in 4 etc for up to 2 years if the animal survives that long
change cyclophosphamide to chlorambucil after 6 months to reduce risk of hemorrhagic cystitis developing
what drug does hemorrhagic cystitis occur with
cyclophosphamide
how does cyclophosphamide cause hemorrhagic cystitis
due to metabolite acrolein
in contact with bladder wall
usually sterile cystitis –> hematuria, dysuria but may get secondary bacterial component so culture to be sure
how is hemorrhagic cystitis prevented
give cyclophosphamide in morning
encourage drinking and urination (prednisolone is helpful)
monitor urine for traces of blood by dipstick (cheap) or urinalysis (precise)
administer a diuretic (furosemide) at time of administration if infrequent use of cyclophosphamide (CHOP)
use a uroprotectant concurrently – MESNA (IV or oral)
how is hemorrhagic cystitis treated (3)
- stop cyclophosphamide
- culture urine +/- give antibiotics for secondary infection
- substitute chlorambucil/melphalan for cyclophosphamide in protocol
how do you monitor during the low dose COP
moderate frequency of monitoring because generally low risk of side effects (possible GI effects from vincristine)
- hematology (for neutropenia)
- urine (for hemorrhage)
how often should you monitor hematology in low dose COP protocols
baseline before treatment
monthly if all normal at start or more frequently if concerned about neutropenia
check if unexplained pyrexia, illness at any time
how often should you monitor urine in low doses COP
weekly dipstick
monthly urinalysis
what is the COP high dose
3 weekly pulses of drugs rather than daily/EOD tablets
useful for cats where 50mg tablet size can be difficult to dose accurately or for animals/owners that want fewer visits
what is the induction phase of high dose COP
vincristine (oncovin) 0.75mg/m^2 IV q7 days for 28 days, then q21 days
cyclophosphamide 250 mg/m^2 IV (po) q21 days
prednisolone 1mg/kg po q24h for 28 days, then q48h
what is the maintenance phase of high dose COP
after ~6 months, reduce cycle to every 4 weeks
after ~12 months, reduce cycle to every 5 weeks
after ~18 months, reduce cycle to every 6 weeks
substitute chlorambucil or melphalan if hemorrhagic cystitis develops
what is the CHOP protocol
Cyclophosphamide
Hydroxydaunorubicin = doxorubicin (adriamycin)
vincristine (oncovin)
Prednisolone
what is the induction phase of CHOP protocol
induction phase over 10 weeks is essentially 2 cycles of 4 drugs, given as weekly pulses
what should you do if the animal is in complete remission after 2 cycles in the CHOP protocol
go to maintenance phase
what is the maintenance phase of CHOP
- repeate 10 week cycle with 2 weeks between drug administration
- total of 25 weeks (6 months) although some 12 week modified protocols available
can substitute chlorambucil for cyclophosphamide if hemorrhagic cystitis occurs
what drug does cardiotoxicity occur with in the CHOP protocol
doxorubicin
what is the acute effects with singe use of doxorubicin
acute arrhythmias
variable ECG findings
what is the chronic cumulative effect of doxorubicin
myocytolysis, myofibre swelling, degeneration, vacuolation, late fibrosis
dilated cardiomyopathy
congestive heart failure
increased risk in breeds with cardiomyopathy
how do you prevent cardiotoxicity (5)
- assess cardiac function prior to 1st dose and continue to monitor after 4-6 doses
- baseline echocardiography measurements of fractional shortening, ejection fraction
- measure serum ctroponin I
- do not exceed cumulative dose 180mg/m^2
- consider less cardiotoxic equivalent drugs: epirubicin, mitoxantrone
what does hypersensitivity reaction look like
vomiting
restlessness
pruritis
wheals
edema
dyspnea
mouth breathing (Cat)
how do you prevent hypersensitivity reactions
use antihistamine premedication
ensure correct route of admin
administer slowly for doxorubicin
how do you treat hypersensitivity
stop drug admin
IV fluids
antihistamines
dexamethasone
adrenaline
how is CHOP protocol monitored
high risk of side effects therefore freq monitoring is essential to use the drugs safely
what should you monitor CHOP procotol (3)
- hematology (neutropenia): baseline before treatment, weekly
- urine (hemorrhagic cystitis): baseline, after each cyclophosphamide admin/prior to next
- echocardiography (heart contractility): baseline, at 4th doxorubicin treatment
how is neutropenia managed in CHOP
what are the GI effects seen in CHOP protocols (4)
- anorexia
- vomiting
- diarrhea
- colitis
how are the GI effects managed (4)
- anti-emetics
- gut protectants/antacids
- anti-diarrheal agents
- fluids
- stop tablets/chemotherapy temporarily until animal has recovered
what acute tumour lysis syndrome and what does it cause
large tumour burden rapid cell kill in 1st week
-rapid release of ions, i-cellular products
hyperkalemia, hyperphosphatemia, hypocalcemia
metabolic acidosis, uric acid production
acute renal failure
what are the signs of acute tumour lysis syndrome
acute depression, bradycardia, vomiting, diarrhea, shock
how is acute tumour lysis syndrome treated
treat with fluids and supportive care
how is alopecia managed
generally not a problem
coat thinning, whisker loss
slow to regrow after clipping
what is multidrug resistance encoded by
MDR1 gene
ATP binding cassette transporter pumps out drugs from cell
induces cross resistance to other drugs
what are the affected drugs of multidrug resistance
vinca alkaloids
anthracylcines (dox, mitox)
actinomycin D
what are the unaffected drugs of multidrug resistance
alkylating agents (melphalan, lomustine)
carboplatin
what occurs if there is relapse therapy for lymphoma
start induction phase again
use a novel drug (single agent)
use novel potent drug combinations
what novel drugs could you use in relapse therapy for lymphoma
L-asparaginase
doxorubicin
lomustine
rabacfosadine (B cell)
what novel potent drug combinations can be used in CHOP protocols if there is relapse in lymphoma (3)
- DMAC: dexamethasone, melphalan, actinomycin D, cytosine arabinoside
- ALP: L-asparaginase, lomustine, prednisolone
- MOPP or LOPP: mechlorethamine or lomustine, vincristine, procarbazine, prednisolone
what is the outcome for lymphoma with no treatment
1-2 months
what is the outcome for lymphoma with steroids only
2-3 months
what is the outcome for lymphoma with COP protocol
6-9 months
what is the outcome for lymphoma with CHOP protocol
10-12 months
how is acute lymphoblastic leukaemia ALL treated and what is the prognosis
similar to high grade LSA
lymphoma protocols if sufficient neutrophils
poor prognosis
how is chronic lymphocytic leukaemia treated
similar to low grade LSA (mature lymphocytes, slowly dividing)
no treatment needed in some cases
OR
chlorambucil 2-4mg/m^2 daily, then q48h
prednisolone 40mg/m^2 daily then 20mg/m^2 q48h
how is acute myeloid leukaemia treated (AML)
poorly established protocols
poor outcome
cytosine
doxorubicin
prednisolone
6-thioguanine
how is chronic granulocytic leukaemia (CLG/CML) treated
very rare and difficult to distinguish from inflammation/infection
hydroxyurea
busulphan
how is multiple myeloma treated with chemo
melphalan 2mg/m^2 daily then q48h
prednisolone 40mg/m^2 daily for 7d then 20mg/m^2 q48h
what do you need to do before treating multiple myeloma
stabilize patient and make sure to address paraneoplastic complications
hypercalcemia (IV fluids)
hyperviscosity (plasmaphoresis)
secondary infection (antibiotics)
what is the prognosis of multiple myeloma
can be good if no hyperviscosity
how are solid tumours treated with chemotherapy
not usually chemosensitive
use surgery (or radiotherapy) to remove the tissue bulk and stimulate division of any residual tumour cells
use adjuvant chemo for residual primary tumour (microscopic)
use adjuvant chemo to delay growth of subclinical metastasis
what does the tumour growth curve look like
describe how chemotherapy of solid tumours is administerd to stop growth
how are hemangiosarcomas treated
Splenic mass with rapid metastasis to lungs (and organs of abdominal cavity)
Chemotherapy with single agent doxorubicin q3 weeks for 4-6 doses to delay metastasis
what is the median survival time of hemangiosarcomas
Varies according to site but generally short —> extended with chemotherapy (doxorubicin)
Surgery alone = 1-3 months
+ chemotherapy = 5-7 moths
what chemo is used to treat hemangiosarcomas
VAC protocol:
Vincristine, Adriamycin, Cylcophosphamide
Metronomic cyclophosphamide + NSAID therapy
how is hemangiosarcoma treated using metronomic chemotherapy
Antiangiogenic and immunomodulatory
Cytotoxic drugs given at LOW doses on a more continuous DAILY administration protocol rather than as high doses in pulses
Prevents repair and repopulation of endothelial cells in breaks needed with MTD therapy —> anti-angiogenic (prevents blood vessels that supply the tumour from regrowing)
what are the benefits of metronomic chemotherapy
May also reduce T regs —> immunomodulatory
May target dormant cells and cancer stem cells —> prevents tumour repopulation
low doses mean fewer side effects (well tolerated)
what drugs are metronomic chemotherapies usually combined with
anti angiogenic drugs
ex. COX inhibitors –> NSAIDs piroxicam, celecoxib
what are metronomic chemotherapy drugs
cyclophosphamide
chlorambucil
lomustine
temozolamide
how are osteosarcomas treated
amputation for primary tumour (possibly limb salvage or radiotherapy for pain relief)
chemotherapy with single agent carboplatin for 4-6 doses to delay metastasis
what are the median survival times of bone tumours
No treatment = 1 month
Amputation alone = 3-4 months
+ cisplatin = 10-13 months
+ carboplatin = 10 months
+ doxorubicin = 12 months
+ cisplatin + dox (alt) = 10 months
+ cisplatin + dox (combo) = 11-18 months
what are examples of tyrosine kinase inhibitors TKIs
Imatinib (Gleevec)
Masitinib (masivet)
Toceranib (palladia)
what TKIs are licensed for unresectable gross mast cell tumours in dogs
Masitinib (masivet)
Toceranib (palladia)
what are side effects of TKIs
GI signs
PLN
Weight loss
Neutropenia
Liver damage
Monitor hematology/biochemistry and urine (protein loss)
