Onco Flashcards
Six hallmarks of cancer?
Self sufficiency in growth signals Evade apoptosis Sustain angiogenesis Insensitivity to active growth signals Tissue invasion and mets Limitless replicative potential
Alkylating agents?
Cross link DNA
Strand breaks
Cross resistance between different alkylating agents and other classes of drugs
Cyclophosphamide, chlorambucil, melphalan, lomustine, procarbazine
Anti tumour antibiotics?
Anthracyclines
DNA intercalation, interfere with topoisomerases
Cross resistance with others in class and some other classes esp mitotic inhibitors
Substrates MDR
Doxorubicin, mitoxantrone, dactinomcin, bleomycin
Mitotic inhibitors?
Inhibit assembly (vinca alkaloids) or disassembly (paxlitaxel) of mitotic spindle
Vincristine vinblastine vinorelbine
Platinums?
Cross link DNA, similar mechanism alkylating agents, no cross resistance other classes of drugs
Cisplatin carboplatin
Antimetabolites?
Analogues of normal metabolites incorporated into DNA, interfere with enzyme activity/transcription/translation. Sig tox low efficacy @ vet dose.
Gemcitabiine (infusion rate/time imp).
TKI?
Toceranib/masitinib
Toceranib needs lower dose than label
c-kit and tumour angiogenesis with VEGF. Immunomodulatory.
Toceranib:
Reversible competitive ATP binding to prevent phosphorylation/downstream signalling of receptor tyrosine kinases. VEFGR2/3, PDGFRalpha/beta, KIT , CSF1R, FLT3, RET = targets
Benefit also 75 % solid tumours
Synergistic with vinblastine and RT
Immunomodulatory (Treg decreased), increased IFNgamma
Probably no benefit in microscopic dz without tumour driver like mutant KIT (MCTs)
Tumour cell resistance?
Due to high mutation rate after drug exposure
Combination might overcome resistance - but more tox normal cells?
Myelosuppression potential of chemo drugs?
High - doxo, lomustine, cyclophosphamide, carbo, vinblastine, mitox
Medium - vinc, chlorambucil, melphalan, methotrexate, cisplatin, hydroxyurea, 5-fluorourracil
Low - steroid, L-aspar, lower dose zinc, bleomycin, streptozocin
Metronomic chemo?
Mainly antiangiogenic (target tumour endothelial cells) and immunomodulatory (inhibit Treg)
Cyclo, lomustine, chlorambucil
COX inhibitors increased antiangiogenic and immunomod effect
Chemoprotection?
Mesna - less cyclo/ifosfamide bladder tox by binding metabolites in urine
Dexrazoxane - protect cf doxo cardiotox and help with extravasation
Overall response rate and clinical benefit?
ORR = CR + PR CB = CR + PR + SD
What cells as resistant to l-asparaginase?
Those with asparagine synthase
Multiple drug resistance?
P glycoprotein pump mediated
Level and prevalence increases with chemo
Anthracycline, mitotic inhibitors etc
Alkylating agents NOT P glycoprotein substrates
Post chemo neutrophil count reactions?
> 3 no change
1 - 3 delay chemo
< 1 - febrile, ABs and hosp, afebrile, monitor/reduce dose 25 %, prophylactic AB
Late radiation effects?
> 6m
Heart, lung, kidney, nerves brain, bone, muscle
Slowly proliferating/non-renewing tissues
Progressive/irreparable
Vascular damage, fibrosis, necrosis, chronic inflam and loss of normal tissue stem cells
Use of toceranib in MCT?
Unrescectable grade 2/3 MCT
60 % overall response 2x as likely if KIT mutation and more if no LN involvement
Toceranib dose?
2.4 - 2.9 EOD
Reduced adversed effects at this dose
Masitinib?
KIT, PDGFR, cytoplasmic kinase Lyn
MCT w/ KIT mutation
Higher response primary cf relapsed dz
Imatinib response in cats with MCT and KIT mutation
When to use mg/kg chemo dosing?
Small patients doxo and carbo
What drugs cause nadirs not at 7 days?
Carbo 14d dog, variable cat (14 - 25)
Lomustine cats unpredictable, 7 - 28d
Vinc + laspar?
More BM supp
MDR1 drugs?
ABCD1-1 delta gene mutation
Vinca alkaloid, doxorubicin, mitoxantrone, taxanes, dactinomycen
GSD collies
Does reduction for affected individual, problem if homozygous
When not to give myelosupp drug?
Plt < 75
Neut < 2
Grades of white cell supp?
1 - neut > 1.5, pot > 100, pcv > 30/25
2 - 1-1.5, 50 - 99, 20-30/20-25
3 - 0.5-1, 25-49, 15-20/15-20
4 - < 0.5, < 25, <15/<15
Drugs associated with cumulative thrombocytopenia?
Lomustine, melphalan, chlorambucil
Perivascular extravasation drug issues?
Irritants -platinums, dacarbazine, mitoxantrone, taxanes
Vesicants - vinca alkaloids, anthracyclines, dactinomycin, meechlorethamine
Vina alkaloid - warm compress, DMSO, hyaluronidase
Doxo/epirubicin/dactinomycin - cold compress, dexrazocane (iron chelator), DMSO
Liposomal doxorubicin?
Palmar-plantar erythrodysesthesia
Reduced by pyridoxine (B6) admin
Less cardio toxicosis
Mechanism of GI side effects chemo drugs?
CRTZ (quick)
Enterocyte in crypts (1-5d)
TKI direct GI irritation
Vinc - ileus (enteric neurotox) - can replace with vinblastine
Maropitant and doxo?
Sig decrease both V+ and D+
Doxo cardiotoxicosis?
Acute - transient vent arrhythmia d/t histamine/catecholamine release
Cumulative - oxidative sarcoplasmic reticulum injury, decreased contractility +/- arrhythmia, CHF
> 180 - 240mg/m2
Use less cardiotox or give dexrazoxane after max dose
Lomustine hepatotoxicicosis?
ALT inc 86 %
Cumulative, often irreversible
Acute liver failure can occur after single tx
Delay/discontinue if ALT increases > 3x RI
Less common in cats
Other drugs increasing ALT:
Streptozoocin
TKI
Other:
Vinc biliary excretion, avoid/drop dose with cholestasis
Chemo neurotox?
5-FU contraindicated cats
ABCB1-1delta mutation
Chlorambucil myoclonus/seizures
Nephrotoxic chemo drugs?
Cisplatin (don't use in cats pulm oedema) Ifosfamide (dog and cat) Streptozoocin (dog) Doxo (cats) Lomustine (dog) NSAIDs (don't combo with cisplatin) Bisphosphonate TKI PLN (10 % - reversible) Carbo cats, ideally GFR individualisation
Sterile haemorrhagic cystitis?
Cyclophosphamide/ifosfamide
Acrolein
Mesna/furosemide reduce risk
Cats lower risk but care FIC
Ifosfamide needs saline diuresis any d/t nephrotox, meson mandatory
Monitor for microscopic haematuria
NSAID/oxybutinin
Chemo drug hypersensitivity?
L-aspar IgE type 1 - higher risk with higher dose numbers - NEVER IV
Doxorubicin anaphylactoid, histamine from mast cells, non-IgE med, more pronounced faster admin
Cutaneous hypersensitivity inert vehicle mediated - paclitaxel cat/dog, etoposide dog due to cremophor - micellar paclitaxel/subq administration improves
Pulmonary tox?
Fibrosis bleomycin cumulative
Pulm oedema cat cisplatin
Lomustine pulm hypertensio fibrosis cum dose cat
Rabacfosadine pulm fibrosis
Streptozoocin DM 42 %
Pancreatitis, lameness, muscle cramp TKI
Helicobacter in cats?
Poss mucosa associated lymphoid tissue lymphoma
Dogs?
Most common lymphoma dogs/cats?
Dog:
85 % multicentric
70 % B cell
Cat:
Small cell GI - T cell
Intermediate/large cell GI - B cell
Mediastinal Tcell - FeLV (also sometimes multicentric B or T FeLV)
Nasal/peripheral node/laryngeal and tracheal uncommon
Rest rare
Nasal and renal B cell
Signalment for lymphoma?
Cat - Siamese, esp non-FeLV mediastinal in young <3y
Feline large granular lymphoma?
FIV/FeLV neg
CD3+/CD8+ T cell or NK cell - SI intraepithelial origin
Hodgkin’s?
Cats, single or regional LN head/neck, Tcell rich B cell lymphoma
Reed Sternberg like cells
NO FeLV/FIV
Lymphoma presentation?
Cats more likely to be unwell at presentation
Ophthalmic abnormalities lymphoma?
1/3-1/2 dog + cat
Retinal haemorrhage, uveitis, ocular infiltration
What are markers of proliferation?
Ki67
Proliferating cell nuclear antigen (PCNA)
Argyrophilic nucleolar organiser regions (AgNOR)
PARR?
T cell receptor gene
Immunoglobulin receptor gene
70 - 90 % sens dog, less cat
False neg - null cell, incorrect PCR primer
False pos - ehrlichia, lyme around 5 %
Flow cytometry might be superior
Lymphoma response/remission/MST dog?
CHOP: 90 %, 8m, 12m
20 - 25 % alive 2y
Doxo/pred: 70 % response 5m 7m
Pred and chemo response?
Pretx pred decrease survival time, response rate, shorter remission if real chemo added
Lymphoma response/remission/MST cat?
COP/CHOP might be no different and doxo not effective as single agent
Less remission response and survival cf dogs for intermediate and high grade
50 - 80 %, 4-6m, 6-8m
If complete response 30 - 40 %live 2y
What to do when lymphoma relapses?
If > 2m since stop chemo, reinduction
High response, less response time
Reinducation failure - rescue 40 - 90 % response, 1.5-2.5m duration
Indolent lymphoma?
T cell GI (MST 3y)
Dog marginal zone/mantel cell/T zone lymphoma
Single agent chlorambucil/cyclophosphamide and pred
Splenectomy/solitary node resection
BBB chemo?
Cytarabine crosses
Nitrosureas
L-aspar DOESN’T but will deplete asparagine in CSF
Cutaneous lymphoma?
Lomustine, 80 % response, median duration 3m
Less responsive to chemo cf multi centric
Prognostic factors canine lymphoma?
B > T (T zone exception) Stage V Substage b High/intermediate grade. high response but shorter MST Low B cell MHCII expression Female? P glycoprotein expression in tumour Mediastinal - poor response and survival Diffuse cutaneous and alimentary, hepatosplenic, leukaemia
POS - grade III/IV neutropenia
Prognostic factors feline lymphoma?
Pos: Indolent Response to tx Negative retroviral (FeLV probably not FIV) Early clin stage Doxo addition? Nasal and small cell GI
Neg:
large granular
Feline ALL?
Often FeLV pos and young
How many ALL only dx on BM?
10 % - no circulating cells
Differentiate ALL from lymphoma?
LNs not huge
CD34 +
Rapid progression
Poor chemo response
CLL features?
T cell CD8+
Many granular
Older might be symptomatic
NO assoc FeLV cat
Responsive chemo - use if clin sig problems
Chlorambucil pred MST 1.5y
Becomes resistant/progresses to ALL
How to manage chronic myeloproliferative disorders?
Hydroxyurea to effect
Exclude secondary causes of BM hyperplasia
Hydroyurea SE?
Onychomadesis (sloughing of claw/toenail)
Acute and chronic myelogenous leukaemia?
Acute myeloblast
Chronic neutrophils and late precursors
Myeloma related disorders?
MM
IgM (Waldesnstrom’s)
Macroglobulinaemia
Solitary plasmacytoma (extraosseous and extramedullary)
Immunoglobulin secreting lymphomas/leukaemia
Hypercalcaemia 15 - 20 % MM dogs, rare in cats
Melphalan/pred
Cat - pred cyclophosphamide vincristine
Cyclophosphamide faster acting
Chlorambucil IgM
Multiple myeloma?
Light chain - Bence Jones
Heavy chain - heavy chain dz
Cat mostly extra medullary more common than dogs but BM still affected in most
NOT retroviral assoc
IgM = high molecular weight
IgA most common dog, then IgG. Cat IgG
What is hyperviscosity syndrome?
Magnitude type shape size conc M component
Lesss common cats
Renal dz in 30 - 50 % dogs
MM coagulopathy mechanism?
M components inhibit platelet agg, stop release platelet factor 3, adsorption minor clotting proteins, generate abnormal fibrin polymerisation, produce heparin like factor, functional calcium decrease
Most common melphalan tox?
Thrombocytopenia
Wat defines MM response?
Good = decrease M component 50 %
How to treat hypervics?
Plasmaphresis
Platelet rich plasma if plt decreased
Negative px MM?
Hypercalcaemia
Bence jones
Extensive bony lysis
Worse px cat
Extramedullary plasmacytoma?
Solitary osseous progress MM
Oral or cutaneous in dogs benign
Noncutaneous aggressive, mets common BM/gammopatht not
Colorectal progress more slowly
Prognostic indicators MCT?
Neg: High grade Node involvement Subungual, oral, mucous membrane Mitotic index, AgNOR, PCN, Ki67 pos Recurrence Systemically unwell Shar pei Activating ckit gene mutation Aberrent (cytoplasmic) KIT localisation
What chemo drugs work on specific cell cycle?
G1: L-aspar
S - methotrexate, hydroxyurea
G2 - cytarabine, bleomycin
M - vinca alkaloids
non cell cycle specific - anthracyclines (but most effective S), alkylating agents
Alkylating agents?
Non cycle specific
Cross link DNA
Nitrosurea (lomustine) also carbamylate tyrosine residues. BBB penetration.
Nitrogen mustards (cyclophosphamide, melphalan, chlorambucil) no BBB
Antimetabolites?
Folic acid analogues:(methotrexate) - inhibit enzymes for purine and pyramidine syth
S phase
Pyrimidine analogues:
cytarabine - s phase, penetrate CNS
5-fluorouracil - penetrate CNS , not cell cycle specific
Vinca alkaloids?
M phase
Prevent polymerisation of microtubules and therefore mitosis
Bile excretion
Vincristine - peripheral neurotox with long term use
Antineoplastic antibiotics?
Anthracycline - doxo - intercalate between DNA base pairs. biliary excretion
Dactinomycin - bile, same as doxo
Bleomycin - pulm fibrosis as no aminopeptidase for breakdown in lungs, G2
L-aspar?
G1
Hydrolyses asparagine to aspartic acid and ammonia
No L-asparagine synthase in neoplastic cells
Platinum?
Crosslink DNA
