Principles of Clinical Oncology Flashcards
(223 cards)
1
Q
What increases susceptibility to cancer?
A
Mutations in certain genes
2
Q
What two ways can gene mutations occur?
A
Inherited
Acquired - random events, environmental insults
3
Q
Give examples of four breeds of dog that are more susceptible to cancer
A
Boxers - lymhoma, MCT, others
Flat coat retrievers - soft tissue sarcomas
Irish wolfhound - osteosarcoma
GSD - haemangiosarcoma
4
Q
Give examples of hormonal factors that can affect the aetiology of cancer
A
Oestrogen/progesterone in females - mammary tumours
Androgens in males - prostate carcinoma, perianal adenoma
5
Q
What are the three environmental factors that affect the aetiology of cancer?
A
Exposure to carcinogens/mutagens
Exposure to mitogens
Exposure to biological agents
6
Q
How does exposure to carcinogens/mutagens result in cancer?
A
Induce mutations in DNA - chemical agents (organic/inorganic). radionuclide, radiation
7
Q
How does exposure to mitogens result in cancer?
A
Stimulates cell proliferation
Increased risk of random mutation
8
Q
Why does UV radiation result in squamous cell carcinoma?
A
No pigment to soak up radiation
Causes mutations
9
Q
What are some examples of biological agents that can result in cancer?
A
Retroviruses - FeLV
Poxviruses - BPV, equine sarcoids
Others - Helicobacter pylori, gastric carcinoma
10
Q
What are proto-oncogenes?
A
Genes that normally: promote cell growth, promote proliferation, inhibit apoptosis
11
Q
How can proto-oncogenes cause cancer?
A
Usually only activated during periods of tissue development or remodelling
Tightly controlled
Loss of control following mutation
12
Q
What are two examples of tumour suppressor genes?
A
p53 Retinoblastoma protein (Rb)
13
Q
What do tumour suppressor genes normally do?
A
Prevent uncontrolled proliferation
14
Q
What do tumour suppressor genes act like?
A
Brake pedal
15
Q
What needs to occur for tumour suppressor function to be lost?
A
Both copies of the gene need to be mutated/deleted/silenced
16
Q
What are the two types of mutation that can contribute to oncogenesis?
A
Gain of function mutations - oncogenes
Loss of function mutations - tumour suppressor genes
17
Q
What two ways can genes be changed to contribute to oncogenesis?
A
Mutations - insertion, deletion, missense
Chromosomal reaarangements
18
Q
What do chromosomal rearrangements induce?
A
Dysregulated gene expression
19
Q
What must accumulate before a malignant cell can develop into a significant tumour?
A
Multiple mutations - usually around 10-12
20
Q
How does a malignant cell progress into a tumour?
A
Cell proliferates
Only grows locally as can’t metastasize or ivade
Mutations inactivate DNA repair genes
More mutations accumulate, more genetic instability therefore more malignant potential
Malignant cells invade neighbouring tissues, enter blood vessels and metastasize to different sites
21
Q
What are the ten hallmarks of cancer?
A
Sustaining proliferative signalling Evading growth suppressors Activating invasion and metastasis Enabling replicative immortality Inducing angiogenesis Resisting cell death Deregulating cellular energetics Avoiding immune destruction Tour promoting inflammation Genome instability and mutation
22
Q
What is the traditional anti-cancer therapy method?
A
Poison the tumour more than you poison the host
23
Q
What are the advantages of combination chemotherapy?
A
Attacks the cancer on several biological fronts at once
Reduces dose of each agent
Less adverse effects on healthy cells
24
Q
How do cancer cells sustain proliferative signaling?
A
Become independent of host regulatory mechanisms
Become self sufficient
25
What are the three ways that a cancer cell becomes self sufficient?
Makes its own growth factors - act autocrine or paracrine
Alters receptors - activating mutations so receptor is constantly activated, receptor becomes overly expressed to respond to low ligand levels
Mutates signaling molecules - activating mutations switch on proliferation regardless of receptor activation
26
What is an example of a cancer where the receptors of the cell are altered?
MCT and KIT (stem cell factor receptor) mutations
27
What percent of canine MCT include KIT gene mutations?
30-50%
28
How does a KIT mutation cause uncontrolled proliferation?
Mutation in juxtamembrane region
Results in autophosphorylation
Cell signalling pathways acitvated
Cell survives and proliferates
29
What can be used to help treat MCT invloving these KIT mutations?
Receptor tyrosine kinase inhibitors
30
What is the difference between p53 and Rb, tumour suppressor molecules?
Rb - transduces growth inhibitory signals, determines whether cell cycle progression should proceed
p53 - receives iput from intracellular systems, halts cell cylce if viability is suboptimal, can trigger apoptosis
31
What breed has a germline p53 mutation and what does it predispose them to?
Bull Mastiffs
| Predisposed to lymphoid neoplasia
32
What are the two major circuits that regulate cell death?
Extrinsic pathway - receives and processes extracellular death-inducing signals
Intrinsic pathway - senses and integrates a variety of signals of intracellular origin
33
What do both cell death pathways result in?
Activation of the Caspase cascade which executes apoptosis
34
How do cancer cells resist cell death?
Downregulate the death receptors
| Up regulate members of the Bcl-2 family
35
What is cellular senescence primarily associated with?
Erosion of telomeres that protect the ends of chromosomes
36
How do cancer cells enable reproductive immortality?
Upregulate telomerase
Adds new telomeres`
Avoids apoptosis and senescence
37
Why must a cancer cell induce angiogenesis?
Reaches a size where it is at risk of hypoxia-induced cellular necrosis
Requires a dedicated blood supply to contiue growing
38
How do tumour cells induce angiogenesis?
Secrete angiogenic factors - VEGF
Acts on adjacent endothelial cells
Stimulates development of new blood vessels into the tumour
39
Why can receptor tyrosine kinase inhibitors help prevent angiogenesis induction?
VEGF is a receptor tyrosine kinase
40
How does invasion and metastasis of tumour cells usually begin?
Invade into nearby lymph or blood vessels
41
What can tumour cells do that can aid in invasion and metastasis?
Produce matrix metalloproteinases - disrupt surrounding tissues, allows invasion
Alter cell adhesino molecules - allows to detach and migrate
42
How do tumour cells reprogram energy metabolism?
Limit metabolism largely to glycolysis
Upregulate GLUT1 transporters
More efficient uptake of glucose into malignant cells
43
How can a tumour cell avoid immune destruction?
```
Alters altered self antigens
Alters expression of MHC
Kill tumour infiltrating lymphocytes
Produce immunosuppressive mediators
Induce tolerance
```
44
How do tumour cells increase the rate of mutation?
Increase sensitivity to mutagenic agents
| Breakdown one or several components of the genome maintenance machinery
45
Why is invasion of immune cells into a tumour counter-productive?
Enhance tumorigenesis as supplies: growth factors, imunosuppressive cytokines, angiogenic mediators
46
Why is the prevalence of cancer in pets increasing?
Pets are living longer - increased chance of developing cancer
Diagnostic techniques improving
47
Why is there a greater demand for cancer care in pets?
Owner awareness is increasing
| May owners have a personal experience of cancer
48
How should pets with cancer be approached?
```
Good communication vital
Positive yet realistic approach
Compassion
Well-informed advice to aid decision making
Seek help if out of your depth
```
49
What is the first step when presented with a patient with a mass lesion?
Decide if it is cancer or not
50
What are the differential diagnoses with a mass lesion?
Inflammatory lesions - abscess, granuloma
Haemoatoma
Seroma
Cyst
51
What is it important to do with a mass lesion?
Make a diagnosis
| Don't wait and see if it grows
52
What should be considered in history and physical examination when examining a mass lesion?
```
How long has it been present?
Growth?
Any trauma?
Hot, red or painful?
Solid or fluid filled?
Well-defined or ill-defined?
```
53
What two samples can be taken of a mass lesion to assist diagnosis?
Cytology - fine needle aspiration
| Histopathology - biopsy
54
What are the advantages of cytology in mass lesions?
Quick, cheap and easy
Distinguish inflammatory and neoplastic lesions
Gives information on cell type and morphology
Useful for analysis of effusions and bone marrow
55
How can inflammatory lesions be differentiated from neoplastic lesions on cytology?
Inflammatory - neutrophils, mixed cell poplation
| Neoplastic - one cell type dominates
56
What does cell morphology help deterine with a ass lesion?
If it is benign or malignant
57
What does cytology not tell us about mass lesions?
Tissue architecture
Mitotic index
Invasion of vasculature/lymphatics
Tumour grade
58
What is the gold standard for diagnosis of mass lesions?
Histopathology
59
What does histopathology tell us about a mass lesion?
```
Whether inflammatory or neoplastic
Cell type and morphology
Tissue architecture
Mitotic index
Invasion of vasculature/lymphatics
Degree of necrosis
Tumour grade
```
60
What should the next question be if a lesion is neoplastic?
What is the cell type/tissue of origin?
61
What are sometimes required to make/refine a diagnosis o cell type in a mass lesion?
Special stains
| Immunohistochemistry
62
Why is a definitive diagnosis essential in mass lesions?
Different tumour types have different biological behaviour
| Require different treatments
63
What are some features of malignancy in cells?
Increased N:C ratio
Abnormal mitotic figure
Hyperchromatic nucleus
Prominent nucleolus
64
What should be decided after cell/tissue of origin with a mass lesion?
Is it benign or malignant
65
Why is it important to decide whether a mass is benign or malignant?
Predict biological behaviour
Plan appropriate treatment
Advise the owner about the prognosis
66
What are the differences between a benign and malignant tumour?
Benign - grow slowly by expansion, dont invade surrounding tissues, dont invade lymph or vasculature, don't metastasize, not life threatening, can often be cured
Malignant - grow more rapidly, invade and disrupt surrounding tissues, invade lymph and vasculature, metastasize to other parts o the body, treatment is more difficult, can be life threatening
67
What is tumour grade used to predict?
Behaviour of certain tumours - MCT, STS
68
What does the tumour grade depend on?
```
Mitotic index
Degree of cellular differentiation
Invasion of surrounding tissues
Invasion of vasculature/lymphatics
Amount of necrosis
```
69
What are the three tumour grades?
Low grade
Intermediate grade
High grade
70
What are tumour grades important for?
Treatment planning
Prognosis
Communication when comparing outcomes
71
What system is used for mast cell tumours?
Patnaik grading systems - roman numerals for grade
72
What is the Kiupel system for gading MCTs?
Divides them into low grade and high grade
73
What should be assessed on histopathology if a tumour has been excised?
Margins
| Ensure all tumour has been removed
74
What does clinical staging assess?
Extent of the disease in the patient
75
What does clinical cancer staging involve assessment of?
Primary tumour
Drainage lymph nodes
Distant metastatic disease
76
What is clinical staging important in?
Treatment planning
Prognosis
Communication
77
What system is often used for clinical staging?
TNM - primary tumour, node, distant metastasis
78
What is assessed for the T part of the TNM system?
```
Size
Mobility
Ulceration
Relationship to surrounding tissues
Ulceration
```
79
What is assessed for the N part of the TNM system?
Drainage lymph nodes - size, mobility, relationship to surrounding tissues, texture, consistency
80
What is used for internal lymph node assessment?
Imaging
81
What is an FNA used to decide when clinically staging tumours?
Assess if lymph node metastasis is present or not
82
What is the M part of the TNM system usually assessed via?
Imaging - radiography, ultrasound, CT, MRI
83
What is the most common site for metastasis in small animals?
Lungs
84
What can give clues whether distant metastasis has occurred?
History and physical examination
85
Describe the 5 stages in the WHO system for staging lymphoma
Stage I - involvement limited to single node or lymphoid tissue in a single organ
Stage 2 - involvement of more than one lymph node in a regional area
Stage III - generalised lymph node involvement
Stage IV - liver and/or spleen involvement
Stage V - manifestation in the blood and involvement of bone marrow and/or other organ systems
86
What are the substages of the WHO system for staging lymphoma?
a - without systemic signs
| b - with systemic signs
87
What are paraneoplastic syndromes?
Systemic effects of a tumour
| Occur at a distant site to the tumour
88
What can cause paraneoplastic syndromes?
Secretions of: hormones, hormone like-substance enzyme
Cytokine production
Immune mediated mechanisms
89
What might concurrent illnesses affect in a cancer patient?
Treatment plan
| Prognosis
90
What are the four baseline tests used to assess a cancer patient?
Haematology/CBC
Biochemistry
Urinalysis
Coagulation parameters (when indicated)
91
Why is haematology essential prior to starting any chemotherapy?
Need for a baseline
| Many chemotherapy drugs are myelosuppressive - affect ability to produce new blood cells
92
What three things should be checked for on haematology?
Anaemia - common, occurs for many reasons
Cytopenias - might reflect myelophthsis or immune-mediated disease
Abnormal cells
93
What is biochemistry used to assess in a cancer patient?
General health status
94
What do we assess on a biochemistry in a cancer patient?
Organ damage/function
95
Why do we need to assess organ damage/function in a cancer patient?
Drugs metabolised and excreted via liver and kidneys
Damage could affect choice and dose of drugs
Important prior to general anaesthetic and chemotherapy
96
What else is it important to look for in a biochemistry of a cancer patient?
Paraneoplastic effects of the tumour
97
What are three examples of paraneoplastic effects that can be seen on a biochemistry?
Hypercalcaemia - tumour production of PTH-rp, untreated will cause renal damage
Hypoglycaemia - insulin secretion, secretion of insulin-like growth factors
Hyperglobulinaemia - excessive antibody production
98
What is urinalysis used for in a cancer patient?
Baseline screening for underlying renal problems
99
When would you do a coagulation profile in a cancer patient?
If they have bleeding tendencies
100
What abnormalities in coagulation can cancers cause?
Thrombocytopenia
Hypercoagulability
Hypocoagulability
101
What might cancer patients present as instead of a mass presence?
Clinical signs relating to a paraneoplastic syndrome
102
What are ten examples of paraneoplastic effects that a cancer patient may present with?
```
Hypercalcaemia
Hypoglycaemia
Hyperviscosity
Gastric ulceration/vomiting
Endocrine problems
Pyrexia
Immune-mediated problems
Hypertrophic osteopathy
Dermatologic manifestations
Cancer cachexia
```
103
What is essential when discussing cancer treatment with owners?
Good communication
104
What should be covered when assessing owners expectations and goals?
Whether the cancer can be cured
Induction of remission for a time period
Is the aim to reduce tumour burden or control disease
Is treatment just palliative
105
What must be maintained throughout cancer treatment?
Good quality of life
106
What ethical and physiological issues need to be considered when discussing cancer treatment?
Owner's personal experience with cancer
Concerns about complications/adverse effects - surgery has cosmetic appearance, chemotherapy lower doses in animals so less severe adverse effects, radiation has less intensive schedules than people but need general anaesthetic
107
What nine things should be considered when discussing cancer treatment?
```
Owner's expectations
Quality of life
Psychological factors
Patient temperament
Patient general health status
Possible complications
Time commitment/logistics
Cost
Prognosis
```
108
What are seven cancer treatment options?
```
Surgery
Radiation treatment
Chemotherapy
Molecular targeted drug therapy
Anti-angiogenic therapy
Immunotherapy
Others - photodynamic, electrochemotherapy etc.
```
109
What are the most common options for cancer treatment?
Surgery
Radiation
Chemotherapy
110
What is surgery the treatment of choice for with cancer?
Primary carcinomas
Sarcomas
Mast cell tumours
111
What is radiation treatment the primary treatment for?
Nasal tumours
| Localised, radiosensitive, non-resectable tumours
112
What is radiation therapy frequently used as?
Adjunctive therapy - follow incomplete resection of other tumours
Neo-adjuvant surgery - shrink tumours prior to surgery
113
What is chemotherapy indicated for in cancer patients?
Treatment of systemic disease - lymphoma, leukaemia, myeloma, systemic mast cell disease, disseminated histiocytic sarcoma
114
What can chemotherapy be used for in highly metastatic cancers?
Adjunctive treatment
| Used following surgical removal of the primary tumour
115
What is essential when providing supportive care to a cancer patient?
Ensuring good quality of life
| Anticipate and prevent adverse effects
116
What six things should be considered when giving supportive care to a cancer patient?
Nutrition- monitor BCS/weight, ensure adequate intake
Dehydration - IVFT
GI problems - patients getting chemotherapy, consider gut protectants, anti-emetics or appetitie stimulants
Antibiotics - if neutropenic
Analgesia - short and long term, NSAIDs
Physiotherapy
117
What can cytotoxic drugs interfere with?
Cell growth
| Cell division
118
What can chemotherapy drugs be?
Carcinogenic
Mutagenic
Teratogenic
119
Who shouldn't handle chemotherapy drugs or body fluids from chemotherapy patients?
Pregnant women
| Children
120
What should not be done with cancer tablets/capsules?
Crush or break tablets
Open capsules
Reformulated if necessary by special pharmacy
121
What needs to be worn when administering cancer tablets?
Gloves
| Wash hands afterwards
122
What should cancer tablets be dispensed in?
Child-proof container
Clearly labelled as containing cytotoxic drugs
Blister packs into strips and put into childproof container
123
What must be done with excess cytotoxic drugs?
Returned to practice
| Destroyed by incineration
124
What should injectable cytotoxic agents be drawn in?
Syringes in a cytotoxic safety cabinet
| Phaseal equipment
125
What should be worn when administering injectable cytotoxic drugs?
Protective clothing - chemotherapy gloves, waterproof long-sleeved gown, face mask and goggles
126
Describe administering intravenous chemotherapy
Good restraint
Firmly tape catheter in place
Use designated, quiet area of the hospital with no through traffic
Luer-locking connections
Flush catheter before and after drug with 0.9% saline
Work over an absorbent pad
127
Why must body waste/excreta of cancer patients be handled with care?
Small traces of drug may be present in the body waste for prolonged periods
128
What are some sensible precautions when handling body waste/excreta from cancer patients?
Wearing gloves to clean up
Double bag faeces/cat litter/kennel waste
Designate toileting area if possible
Avoid contact with saliva
129
What is the definition of neoplasia?
Uncontrolled proliferation of cells
Continues in absence of inciting cause
Neoplastic cells originate from a single cell which has undergone mutation and lost the ability to control its division
130
What is fundamental to accurate diagnosis of neoplasia?
Good communication between the clinician and the pathologist
131
What are the gross features of a benign tumour?
```
Growth by expansion
Low to moderate growth rate
Well demarcated from surrounding tissue
Compresses surrounding tissue
Smooth in gross outline
Surrounding connective tissue capsule
Freely mobile on palpation
Homogenous cut surface
Little haemorrhage or necrosis
Surgical removal often easy
No recurrence if completely excised
No metastasis
```
132
What are the microscopic features of benign tumours?
```
Similar to tissue of origin
Well organised
Endocrine tumours can be functional producing hormones affecting other parts of the body
Surrounding connective tissue capsule
Doesn't broach the capsule
Few or no mitoses
Generally no haemorrhage or necrosis
```
133
What are the gross features of malignant tumours?
```
Growth by invasion
Not encapsulated
Not mobile on palpation
Complete removal often difficult
Often recurs after excision
Ulcerates if on skin or mucosal surface
Internal necrosis and haemorrhage
Can metastasise to local lymph nodes and lungs
```
134
What are the microscopic features of malignant tumours?
Variable cell size and shape - pleomorphism
Variable nuclei size and shape - anisokaryosis
Increased N:C ratio
Prominent nucleoli
Presence of normal/abnormal mitoses
Loss of cohesiveness and structure
Malignant fusion leading to formation of multinucleated cells
Secondary changes - necrosis, fibrosis, inflammation
Not usually encapsulated
135
What word describes a benign tumour of the surface epithelia?
Papilloma
136
What word describes a benign tumour of glandular epithelia?
Adnemoa
137
What is a malignant tumour of epithelial origin?
Carcinoma
138
What are malignant tumours of glandular epithelia termed?
Adenocarcinoma
139
What is a granuloma?
Organised type of chronic inflammation
140
How do you describe tumours of mesenchymal origin
Benign add -oma to tissue of origin
| Malignant add -sarcoma to tissue of origin
141
What is a lymphoma?
Tumour of the lymphoid system
| Usually malignant
142
What is a melanoma?
Tumour of melanocytes
| Can be benign or malignant
143
What are leukaemias?
Tumours derived from the cells of the bone marrow which circulate in the blood
144
What are teratomas?
Germ cell tumours with elements of ectoderm, endoderm and mesoderm
145
What are sarcoids?
Low grade fibrosarcomas commonly seen in horse skin
146
What are the four ways a tumour can metastasize?
Lymphatics - carcinoma
Vascular - sarcoma
Trans-cavity - mesothelioma
Local - multiple tumour types
147
What are multicentric tumours?
Multiple tumours that present at first presentation
| Difficult to determine primary site
148
What are some examples of malignant tumours that metastasize rapidly and constantly?
```
Tonsillar carcinomas
Pancreatic carcinomas
Osteosarcomas
Oral and digital melanomas
Mammary carcinomas - cats
```
149
What are some examples of tumours that metastasise slowly or rarely?
Squamous cell carcinomas - invade extensively before metastasis
Fibrosarcomas - recur at site of excision
150
What are some examples of things used in immunohistochemistry that can assist identification?
Cytokeratin - epithelial marker, carcinoma
Vimentin - mesenchymal marker, sarcoma
CD3 - T cell marker, T cell lymphoma
CD79a - B cell marker, B cell lymphoma
151
What is tumour grading a measure of?
Differentiation
152
What does not always correlate with tumour grade?
Prognosis
153
What four ways are there of tumour grading?
Light microscopy
Immunophenotyping
Detection of genetic mutations
Use of proliferation markers
154
Describe tumour grading using light microscropy
High grade - poorly differentiated
| Low grade - well differentiated
155
How does tumour grading on immunohistochemistry work?
Tumours become poorly differentiated - high grade
| Lose expression of expected tissue markers
156
What is standard practice for grading lymphomas in people?
Detection of specific mutations using cytogenetics
157
What is valuable for mast cell tumour grading in dogs?
Detection of proliferation markers - Ki-67
158
How can the pathologist help the clinician?
```
Help obtain definitive diagnosis
Shortlist likely differential diagnoses
Estimate a prognosis
Formulate a treatment plan
Client education
Clinical audit
```
159
What should you consider when choosing a pathologist?
```
Service
Quality
Confidence
Cost
Location
```
160
What should a biopsy report contain?
```
Signalment and clinical history
Gross description
Clear concise histological description
Diagnosis or list of DDx
Comments on biological behaviour and prognosis
```
161
What should a histological description from a pathologist include?
Cellular morphology
Mitotic index
Tissue or lymphatic invasion
Adequacy of surgical margins
162
What are the three requirements the pathologist needs from the clinician?
Representative sample
Correctly submitted sample
Full clinical history
163
Describe a representative sample
```
Incisional or excisional biopsy
Include marign of normal tissue
Avoid necrotic and cavitated areas - not bone tumours need sample from that area
MNark margins of interest
Identify samples from different sites
```
164
Describe a correctly submitted sample
Fix promptly in a large vlume of neutral buffered formalin
Intact tissue specimens should be no greater than 2cm
Larger specimens can be submitted unfixed if close to laboratory
Follow Royal Mail guidelines for sending specimens
Labels should be indelible
Names - practice, owner and animal
Sample site
165
What is chemotherapy?
Treatment of cancer with cytotoxic drugs
166
How do cytotoxic drugs work?
Interfere with cell growth or cell division
Target rapidly dividing cells
Not specific to cancer cells and can affect body's normal rapidly dividing cells
167
What is required with cytotoxic drugs?
A balance between efficacy and toxicity
168
What are the major differences between veterinary and human chemotherapy?
Lower doses of drugs used in animals
Less intensive schedules in animals
Often trying to control disease than cure in animals
Lack of intensive facilities for management of complications in animals
Quality of life is still paramount
169
For what six things is chemotherapy indicated?
Primary treatment for disseminated disease
Adjuvant therapy following surgery
Certain tumours following complete resection
Neo-adjuvant chemotherapy
Treatment of chemosensitive tumours where surgery or radiation is not possible
Primary treatment for transmissible veneral tumour
170
When should chemotherapy not be used?
When surgery or radiation treatment is a more effective alternative
171
What are the routes of administration for cytotoxic drugs?
```
Oral
IV
Sub cutaneous
Intra-cavitary
Intra-lesional
```
172
When is cytotoxic chemotherapy most likely to be effective?
When disease burden is low
173
When is the best time to treat cancer with cytotoxic drugs?
Early in the disease course
If using as adjuvant let the wound heal first
With tumours with a high mitotic index
174
What is the cell kill hypothesis?
Tumour cell kill follows first order kinetics
| A dose of drug will kill a fixed percentage of the tumour population as opposed to a number of cells
175
Describe cytotoxic drug dosing
Should be used at maximum tolerated dose
Multiple doses usually required
Pulse dosing often used
176
What are the principles of combination chemotherapy?
Use drugs that: have been shown to be effective individually, have different modes of action and don't interfere with each other, act at different stages of the cell cycle, don't have overlapping toxicities
177
What are most cytotoxic drugs dosed on?
mg/m2 basis
178
What are the four stages of chemotherapy?
Induction - initial treatment protocol, fairly intense, aim to induce remission
Maintenance - only in some protocols, follows induction, less intense, aim to maintain remission
Re-induction - when tumour relapses, return to initial protocol, aim to re-induce remission
Rescue - when tumour becomes resistan to current therapy, use different drugs that tumour hasn't been exposed to
179
What are two alternatives to conventional cytotoxic chemotherapy?
Metronomic chemotherapy/continuous low dose chemotherapy
| Receptor tyrosine kinase inhibitors
180
What is the aim in metronomic chemotherapy?
Slow growth by inhibiting angiogenesis
| Decrease circulating regulatory T-cells
181
What are the effects of receptor tyrosine kinase inhibitors?
Inhibit angiogenesis
Reduce proliferation
Promote apoptosis
182
What four factors affect the success of chemotherapy?
Tumour type - some highly sensitive, others resistant
Penetration of drug - depends on blood supply and natural barriers
Development of resistance - mutations occur creating resistance, drug exposure selects for resistance
Multi-drug resistance
183
What are the four main adverse drug reactions to cytotoxic drugs?
Myelosuppression
GI toxicity
Poor hair growth/whisker loss
Drug extravasation
184
What can myelosuppression by chemotherapy result in?
Neutropenia
| Thrombocytopenia
185
What is the dose limiting cytotoxic effect of many agents?
Neutropenia
186
When is the lowest level of neutrophils often observed?
One week after chemotherapy dose
187
What should be done to avoid myelosuppression?
Monitor CBC regularly in animals
Take CBC prior to each administration of myelosuppressive drug
Monitor neutrophil nadir
Reduce dose if low neutrophils or sepsis occurs
188
What should be done if neutropenic and pyrexic/sick?
Give IV broad spectrum antibiotics
189
What can occur with cytotoxic drugs in the GI tract?
Anorexia
Vomiting
Diarrhoea
190
What can GI adverse effects have a major effect on?
Quality of life
191
What should be done if GI AEs are experienced after drug administration?
Take prophylactic measures next time
192
What should be done when vomiting is a GI AE?
Bland diet
Gut protectants
Anti-emetics
193
What should be done if diarrhoea is a GI AE?
Bland diet
| Metronidazole for immunomodulatory effects
194
What shuold be done if anorexia is a GI AE?
Maropitant if nauseous
Appetite stimulants
Feeding tubes
195
What can many IV chemotherapy drugs cause if extravasated?
Irritation
| Blistering (vesication)
196
What should be done if extravasation occurs?
Leave catheter in place
Withdraw as much drug as possible
Apply heat packs or ice
Seek specialist advice
197
What toxicity effects does Doxorubicin have?
Cardiotoxicity in dogs - dysrhythmias during administration, chronic toxicity more significant, more likely to occur at cumulative doses
Mast cell degranulation - wheals, urticaria, pruritus, oedema, vomiting, diarrhoea, dyspnoea, hypovolaemic shock
Nephrotoxicity in cats
Vesicant if injected perivascularly
198
How can Doxorubicin toxicity be prevented?
Administer over 20-30 minutes
Monitor shortening by echocardiography for contractilty decreases
Use with care in breeds predisposed to heart disease
199
What toxicity effects does cyclophosphamide have?
Haemorrhagic cystitis in dogs - rare in cats
200
How can cyclophosphamide toxicity be prevented?
```
Allow free access to fresh water
Dose in the morning
Allow plenty of opportunity to go out
Divide dose over two days if high
Avoid prolonged courses of administration
Treatment difficult
```
201
What toxicity effects does Vincristine have?
Peripheral neuropathies
Ileus/constipation in cats
Skin sloughs if injected perivascularly
202
What toxicity effects does Lomustine have?
Hepatotoxicity - particularly dogs, monitor ALT prior to dose, consider SAMe
Nephrotoxicity - monitor USG, dipstick for glucosuria
203
What toxicity effects do Platinum drugs have?
Nephrotoxicity
Cisplatin causes vomiting via CTZ - give antiemetics
Irritants if injected perivascularly
204
What drugs should not be given to cats?
Cisplatin - fatal pulmonary oedema
| 5-FU - extreme neurotoxicity
205
What do some herding breeds have an increased sensitivity to?
Vinca alkaloids
| Doxorubicin
206
How do alkylating agents work?
Substitute an alkyl group for H+ ion
Causes cross linkage and breaking of DNA
Interferes with DNA replication and transcription
207
What are some examples of alkylating agents?
```
Cyclophosphamide
Lomustine
Melphalan
Chlorambucil
Procarbazine
Dacarbazine
```
208
How to mitotic spindle inhibitors work?
Bind to tubilin
Prevent normal assembly of microtubules
Cause mitosis to stop in metaphase
Only affects G2/M phase
209
What are some examples of mitotic spindle inhibitors?
Vincristine
Vinblastine
Vinorelbine
Taxanes
210
How do anti-metabolites work?
Mimic normal substrates in nucleic acid metabolism
Inhibit enzymes
Lead to production of non-functional molecules
Interfere with DNA synthesis
Specific to S phase
211
What are some examples of anti-metabolites?
```
Cytosine arabinoside/cytarabine
Methotrexate
Hydroxycarbamide
5-fluorouracil
Gemcitabine
Azathioprine
```
212
How do anti-tumour antibiotics work?
```
Prevent DNA and RNA synthesis
Inhibits topoisomerase II (untangles DNA strands)
Breaks DNA strands
Cross-links DNA
Free radical oxidative damage
```
213
What are some examples of anti-tumour antibiotics?
Doxorubicin
Epirubicin
Mitoxantrone
Actinomycin-D
214
How do platinum compounds work?
Similar to alkylating agents
Inter- and intrastrand crosslinks in DNA
Interferes with DNA synthesis and transcription
215
What are some examples of platinum compounds?
Cisplatin
| Carboplatin
216
How do corticosteroids help fight cancer?
Cause apoptosis of lymphoid and mast cells
217
What are two examples of cancer treating corticosteroids?
Prednisolone
| Dexamethasone
218
What are the adverse effects of corticosteroids?
```
Polydipsia
Polyuria
Polyphagia
Excessive panting
Muscle weakness
Slow wound healing
Immunosuppression
```
219
How does L-asparaginase work in cancer treatment?
Breaks down L-asparagine
Reduces amount present
Neoplastic lymphoid cells can't synthesise
Extracellular supply diminished so die
220
What is a possible side effect of L-asparaginase?
Allergic/anaphylacitc reaction
221
How do NSAIDs help in cancer treatment?
```
Thought to involve COX-2 inhibition
Inhibit angiogenesis
Promote apoptosis
Anti-inflammatory
Analgesic
```
222
What are NSAIDs used in for cancer treatment?
Continuous low-dose chemotherapy protocols
| Metronomic chemotherapy protocols
223
How do receptor tyrosine kinase inhibitors work against cancer?
Interfere with cell signaling
| Inhibit signaling through KIT receptors
