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Onco Flashcards

1
Q

Six hallmarks of cancer?

A 
Self sufficiency in growth signals
Evade apoptosis
Sustain angiogenesis
Insensitivity to active growth signals
Tissue invasion and mets
Limitless replicative potential
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2
Q

Alkylating agents?

A

Cross link DNA
Strand breaks
Cross resistance between different alkylating agents and other classes of drugs

Cyclophosphamide, chlorambucil, melphalan, lomustine, procarbazine

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3
Q

Anti tumour antibiotics?

A

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

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4
Q

Mitotic inhibitors?

A

Inhibit assembly (vinca alkaloids) or disassembly (paxlitaxel) of mitotic spindle

Vincristine vinblastine vinorelbine

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5
Q

Platinums?

A

Cross link DNA, similar mechanism alkylating agents, no cross resistance other classes of drugs

Cisplatin carboplatin

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6
Q

Antimetabolites?

A

Analogues of normal metabolites incorporated into DNA, interfere with enzyme activity/transcription/translation. Sig tox low efficacy @ vet dose.

Gemcitabiine (infusion rate/time imp).

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7
Q

TKI?

A

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)

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8
Q

Tumour cell resistance?

A

Due to high mutation rate after drug exposure

Combination might overcome resistance - but more tox normal cells?

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9
Q

Myelosuppression potential of chemo drugs?

A

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

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10
Q

Metronomic chemo?

A

Mainly antiangiogenic (target tumour endothelial cells) and immunomodulatory (inhibit Treg)

Cyclo, lomustine, chlorambucil

COX inhibitors increased antiangiogenic and immunomod effect

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11
Q

Chemoprotection?

A

Mesna - less cyclo/ifosfamide bladder tox by binding metabolites in urine

Dexrazoxane - protect cf doxo cardiotox and help with extravasation

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12
Q

Overall response rate and clinical benefit?

A 
ORR = CR + PR 
CB = CR + PR + SD
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13
Q

What cells as resistant to l-asparaginase?

A

Those with asparagine synthase

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14
Q

Multiple drug resistance?

A

P glycoprotein pump mediated

Level and prevalence increases with chemo

Anthracycline, mitotic inhibitors etc

Alkylating agents NOT P glycoprotein substrates

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15
Q

Post chemo neutrophil count reactions?

A

> 3 no change
1 - 3 delay chemo
< 1 - febrile, ABs and hosp, afebrile, monitor/reduce dose 25 %, prophylactic AB

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16
Q

Late radiation effects?

A

> 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

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17
Q

Use of toceranib in MCT?

A

Unrescectable grade 2/3 MCT

60 % overall response 2x as likely if KIT mutation and more if no LN involvement

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18
Q

Toceranib dose?

A

2.4 - 2.9 EOD

Reduced adversed effects at this dose

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19
Q

Masitinib?

A

KIT, PDGFR, cytoplasmic kinase Lyn

MCT w/ KIT mutation

Higher response primary cf relapsed dz

Imatinib response in cats with MCT and KIT mutation

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20
Q

When to use mg/kg chemo dosing?

A

Small patients doxo and carbo

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21
Q

What drugs cause nadirs not at 7 days?

A

Carbo 14d dog, variable cat (14 - 25)

Lomustine cats unpredictable, 7 - 28d

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22
Q

Vinc + laspar?

A

More BM supp

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23
Q

MDR1 drugs?

A

ABCD1-1 delta gene mutation

Vinca alkaloid, doxorubicin, mitoxantrone, taxanes, dactinomycen

GSD collies

Does reduction for affected individual, problem if homozygous

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24
Q

When not to give myelosupp drug?

A

Plt < 75

Neut < 2

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25
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
26
Drugs associated with cumulative thrombocytopenia?
Lomustine, melphalan, chlorambucil
27
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
28
Liposomal doxorubicin?
Palmar-plantar erythrodysesthesia Reduced by pyridoxine (B6) admin Less cardio toxicosis
29
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
30
Maropitant and doxo?
Sig decrease both V+ and D+
31
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
32
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
33
Chemo neurotox?
5-FU contraindicated cats ABCB1-1delta mutation Chlorambucil myoclonus/seizures
34
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 ```
35
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
36
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
37
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
38
Helicobacter in cats?
Poss mucosa associated lymphoid tissue lymphoma Dogs?
39
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
40
Signalment for lymphoma?
Cat - Siamese, esp non-FeLV mediastinal in young <3y
41
Feline large granular lymphoma?
FIV/FeLV neg | CD3+/CD8+ T cell or NK cell - SI intraepithelial origin
42
Hodgkin's?
Cats, single or regional LN head/neck, Tcell rich B cell lymphoma Reed Sternberg like cells NO FeLV/FIV
43
Lymphoma presentation?
Cats more likely to be unwell at presentation
44
Ophthalmic abnormalities lymphoma?
1/3-1/2 dog + cat Retinal haemorrhage, uveitis, ocular infiltration
45
What are markers of proliferation?
Ki67 Proliferating cell nuclear antigen (PCNA) Argyrophilic nucleolar organiser regions (AgNOR)
46
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
47
Lymphoma response/remission/MST dog?
CHOP: 90 %, 8m, 12m 20 - 25 % alive 2y Doxo/pred: 70 % response 5m 7m
48
Pred and chemo response?
Pretx pred decrease survival time, response rate, shorter remission if real chemo added
49
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
50
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
51
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
52
BBB chemo?
Cytarabine crosses Nitrosureas L-aspar DOESN'T but will deplete asparagine in CSF
53
Cutaneous lymphoma?
Lomustine, 80 % response, median duration 3m Less responsive to chemo cf multi centric
54
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
55
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
56
Feline ALL?
Often FeLV pos and young
57
How many ALL only dx on BM?
10 % - no circulating cells
58
Differentiate ALL from lymphoma?
LNs not huge CD34 + Rapid progression Poor chemo response
59
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
60
How to manage chronic myeloproliferative disorders?
Hydroxyurea to effect Exclude secondary causes of BM hyperplasia
61
Hydroyurea SE?
Onychomadesis (sloughing of claw/toenail)
62
Acute and chronic myelogenous leukaemia?
Acute myeloblast | Chronic neutrophils and late precursors
63
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
64
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
65
What is hyperviscosity syndrome?
Magnitude type shape size conc M component Lesss common cats Renal dz in 30 - 50 % dogs
66
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
67
Most common melphalan tox?
Thrombocytopenia
68
Wat defines MM response?
Good = decrease M component 50 %
69
How to treat hypervics?
Plasmaphresis | Platelet rich plasma if plt decreased
70
Negative px MM?
Hypercalcaemia Bence jones Extensive bony lysis Worse px cat
71
Extramedullary plasmacytoma?
Solitary osseous progress MM Oral or cutaneous in dogs benign Noncutaneous aggressive, mets common BM/gammopatht not Colorectal progress more slowly
72
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 ```
73
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
74
Alkylating agents?
Non cycle specific Cross link DNA Nitrosurea (lomustine) also carbamylate tyrosine residues. BBB penetration. Nitrogen mustards (cyclophosphamide, melphalan, chlorambucil) no BBB
75
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
76
Vinca alkaloids?
M phase Prevent polymerisation of microtubules and therefore mitosis Bile excretion Vincristine - peripheral neurotox with long term use
77
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
78
L-aspar?
G1 Hydrolyses asparagine to aspartic acid and ammonia No L-asparagine synthase in neoplastic cells
79
Platinum?
Crosslink DNA

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