Cancer Flashcards
(289 cards)
1
Q
What are the patterns of multisystem disease presentation?
A
Single organ involvement moving to multi organ involvement
Multi organ involvement from initial presentation
Multisystem diseases can remain focal in individual patients e.g. patients with sarcoidosis may have just lung involvement or can have lung, skin and gastrointestinal involvement
2
Q
What common processes underlie multisystem diseases?
A
Genetic defects (disorders of metabolism and processing) Autoimmune diseases Intracellular accumulations Infections Neoplasia Environmental and nutritional diseases
3
Q
What can be single gene causes of multi system disease?
A
Enzyme defects and their consequences: accumulation of a substrate e.g. Galactosaemia, Metabolic block with reduced amount of end product, Failure to inactivate a tissue damaging substrate e.g. alpha-1-antitrypsin
Defects in membrane receptors and transport systems: failure of transport and tissue damage e.g. cystic fibrosis
Alterations in the structure, function or quality of non-enzymic proteins e.g. collagen or proteins that regulate cell growth
4
Q
What chromosomal defects can cause multi system disease?
A
Structural abnormalities of chromosomes can underlie multisystem disease
Cytogenetic abnormalities can underlie multisystem disease e.g. Down’s Syndrome
5
Q
What complex multi genetic disorders can cause multi system disease?
A
Combinations of multiple polymorphisms and external exposures: multiple diseases of the same type e.g. HLA in autoimmune diseases
Can be disease specific e.g. chronic idiopathic inflammatory bowel disease
6
Q
How can autoimmune diseases lead to multi system disease?
A
Antibody formation: mimic or block exogenous ligand causing abnormalities in function of tissue e.g. Grave’s Disease
Immune complex mediated damage: Antibodies reacting within tissues to form complexes e.g. antibodies to normal structural tissue components e.g. the basement membrane in Goodpasture’s Disease
Deposition of circulating antigen-antibody complexes
CD4+ T cell mediated damage e.g. Rheumatoid Arthritis
7
Q
Describe the Mechanisms underlying abnormal intracellular accumulations
A
Inadequate removal of a normal substance due to defect in intracellular handling of substance e.g. steatosis (fatty change)
Abnormal endogenous substance builds up e.g. alpha-1-antitrypsin.
Abnormality caused by a problem with: Folding, Packaging, Transport, Secretion
Failure to degrade a metabolite due to an inherited enzyme deficiency e.g.storage diseases
Deposition and accumulation of an abnormal exogenous substance due to lack of necessary machinery
8
Q
What substances can accumulate in cells?
A
Lipids e.g. steatosis
Proteins e.g. reabsorption droplets in the kidneys
Glycogen e.g. in macrophages in glycogen storage disease
Pigments e.g. haemosiderosis with iron overload
Pathological calcifications e.g. Dystrophic calcification at sites of cell injury and necrosis, Metastatic calcification of normal tissues due to hypercalcaemia
9
Q
How can infection cause multi system disease?
A
infection being present at multiple sites
Infection causing a systemic inflammatory response with potential malfunction of multiple organ systems
10
Q
How can neoplasia lead to multi system disease?
A
Secretion of hormones: both indigenous and ectopic
Secretion of inflammatory mediators e.g. TNF leading to cachexia -> Evidence of systemic inflammation, Elevated basal metabolic rate, Equal loss of both fat and lean muscle
Paraneoplastic syndromes: Ectopic hormone production, Production of other humoral factors e.g. parathyroid hormone-related protein causing hypercalcaemia
Metastasis to multiple organs with: Destruction of tissue mass and loss of function, Blockage of drainage of material
11
Q
How can environmental diseases cause multi system problems?
A
poisons are: absorbed into system via skin, blood, gut etc
accumulate in the body or are excreted
effect cellular molecules e.g. receptors or enzymes and cause toxicity and dysfunction
12
Q
Which vitamin deficiency will lead to impaired wound healing?
A
Vitamin C
13
Q
What is multi system disease?
A
disease that affects a number of tissues or the body as a whole
No dominant system affected in every patient
three or more systems involved: GI, MSK, Mucous membrane, Renal, Hepatic, Hematologic, CNS
14
Q
What is carcinogenesis?
A
origin or production of a cancer/malignant neoplasm
Carcinogen is an environmental agent participating in the causation
Carcinogenesis results from the accumulation of multiple, sub-lethal genetic mutations in a step wise fashion over time
15
Q
What steps are involved in the process of carcinogenesis?
A
Initiating mutation: carcinogen caused, cell is primed with stem cell like properties
Mutation affecting genomic integrity/stability: precursor with mutator phenotype
Acquisition of cancer hallmarks: additional driver mutations, becomes founder cancer cell
Further genetic evolution: additional mutations, emergence of subclones, genetically heterogenous cancer
16
Q
What abnormalities underlie Carcinogenesis?
A
Initial mutation may be caused by environmental exposure, inherited or spontaneous
Cancer will form from clonal expansion of single cell which has incurred a mutation. All daughter cells have same mutations
Four classes of normal regulatory genes are principle targets of
cancer-causing mutation: Proto-oncogenes, Tumour suppressor genes, Regulation of apoptosis, DNA repair genes
17
Q
What is a passenger mutation?
A
Mutation with no phenotypic consequence
18
Q
What accounts for tumour progression, acquisition of a more aggressive phenotype with time and changes in response to treatment with time?
A
Subclone formation
19
Q
What is a mutator phenotype?
A
cells have mutations in genes that normally function in maintenance of genetic stability, typically loss of function
20
Q
What do driver mutations do?
A
contribute to malignant phenotype e.g. initiating mutation
21
Q
What are the hallmarks of cancer?
A
Sustaining proliferative signalling Evading growth suppression Avoiding immune destruction Enabling replicative immortality Tumour promoting inflammation Activating invasion and metastasis Genome instability and mutation Resisting cell death Deregulating cellular energetics
22
Q
What is a proto oncogene?
A
normal (non-mutated) counterparts, physiological regulators of cell proliferation
23
Q
What is an oncogene? Give examples
A
Positive, accelerators
promote autonomous cell growth In absence of normal growth signals
Products are oncoproteins
Signals from outside the cell (e.g. GF), Receptors – EGFR/Her2, Coupling molecules - ras, Phosphorylation Reactions, Cyclin Dependent Kinases/Cyclin Complexes
24
Q
What are tumour suppressor genes?
A
Negative, brakes
Signals from outside the cell (e.g. GI)
Cyclin Kinase Inhibitors
Checkpoints
25
What is p53?
Acts at G1/S checkpoint
Surveillance in cell cycle, normally stops cell cycle progression of damaged cells or causes apoptosis in non-repairable DNA damage
Induces transcription of genes which repair DNA
Mutated in a large number of cancers (>50%), associated with invasion
Guardian of the genome
26
What genes other than oncogenes and tumour suppressor genes are involved in carcinogenesis?
DNA Repair: Excision repair, mismatch repair (XP,HNPCC)
Evasion of Apoptosis: p53, bcl family
Limitless replication (telomerase)
Angiogenesis
Genes involved in invasion and metastasis
27
What is RAS?
Oncogene
Mutation is most common abnormality of dominant oncogenes – 15-20% of tumours
Normally inactivated by hydrolysis of GTP
Blocked when mutated
28
What is c-Myc?
Oncogene
Transcriptional activator
Targets include cyclin D2
Translocation t(8,14) in Burkitt lymphoma, but also breast, colon & lung cancer
29
What is HER2?
Cell membrane receptor
Amplified in 25-30% of breast cancers
Trastuzumab (Herceptin) is a specifically targeted therapy for HER2 positive breast cancer
30
What are BRCA1+2?
tumour suppressor genes
Autosomal Dominant inheritance usual
Increased risk of early onset cancer of the breast, ovary (
31
What is FAP?
Familial adenomatous polyposis
Mutation in APC gene (Tumour Suppressor Gene)
Predominantly Autosomal Dominant
100s – 1000s of polyps present
100% chance of colorectal carcinoma by age 30 so prophylactic colectomy performed
32
What is Hereditary Non-Polyposis Coli?
Associated with numerous polyps in colon
DNA mismatch repair gene defect e.g. MSH 1 or 2
Increases risk colon carcinoma (HNPCC)
33
What is neurofibromatosis?
NF-1 codes for a protein involved in RAS signalling (Tumour suppressor gene)
NF1 product neurofibromin normally switches off RAS, if mutated does not > increased growth promoting signals
Autosomal dominant
Increased risk of malignant peripheral nervesheath tumours (sarcomas)
34
What is retinoblastoma?
RB is a tumour suppressor gene
Autosomal dominant pattern of inheritance of mutation usual
2 hit hypothesis: Inherit one defective copy of RB gene, 2nd hit = spontaneous mutation > retinoblastoma (& osteosarcomas)
RB protein normally binds E2F, When E2F released cell can enter cycle (at G1 phase)
Tumour of retina in children. 40% of cases familial, 60% sporadic
Familial cases occur younger (1yr age) and can be bilateral
35
What is Xeroderma pigmentosum?
Autosomal Recessive
Deficiency of DNA repair enzymes
Young children develop skin atrophy & cancers, normally seen in elderly
people
Death often due to metastatic squamous cellcarcinoma or melanoma
Fewer than 40% survive beyond 20 years
36
What is Ataxia Telangiectasia?
Autosomal Recessive
Deficiency of DNA repair enzymes (ATM)
1 in 40,000 to 100,000
Progressive cerebellar ataxia beginning between ages one and four years
Increased risk of leukaemia and lymphoma
Unusually sensitive to ionizing radiation
37
What are the stages of carcinogenesis?
Initiation results from exposure to a carcinogen and means it is potentially capable of neoplasia formation
Permanent DNA damage means that there is ‘memory’ of agent, irrespective of when promoter is applied
Promoters induce tumours in initiated cells but are not capable of
tumour genesis in non-initiated cells, Have to be applied AFTER initiation: Not affecting DNA, Not permanent
38
What substances can act as carcinogens?
Radiation
Chemical Carcinogens including: Exogenous hormones, Occupational exposures
Microbes especially viruses
39
Except carcinogens, what can increase risk of mutations forming?
Reparative proliferation e.g. chronic inflammation or tissue injury and by immunodeficient states
40
How does UV radiation act as a carcinogen?
Forms pyrimidine dimers in DNA, which overwhelm normal DNA repair mechanisms
Skin cancers more common on sun exposed areas of fair skinned individuals
Melanoma (superficial spreading type) & Basal cell carcinomas associated episodes of sunburn
41
How does ionising radiation act as a carcinogen?
Causes DNA damage: chromosome breakage, translocations and point mutations
Increases risk of the following: myeloid leukaemias, thyroid (only in young), breast, lungs and salivary gland
42
What types of chemical carcinogen are there?
Direct Acting: require no metabolic conversion to be carcinogenic e.g. Alkylating agents
Indirect Acting: require metabolic conversion to become carcinogenic e.g.polycyclic and aromatic hydrocarbons, aromatic amines and dyes
43
How do chemicals act as carcinogens?
Act on DNA and are mutagenic
| highly reactive electrophile groups that directly damage DNA
44
How do promoters work?
stimulating cellular proliferation e.g.chronic inflammation and increased risk of neoplasia
45
When are you at risk of exposure to polycyclic aromatic hydrocarbons? And what do they cause?
Smoking
Chimney sweeps
Skin exposure to tar
Squamous cell carcinoma
46
When are you at risk from nitrosamines? And what do they cause?
Rubber workers
| Mouth, oropharynx and oesophageal cancers
47
What does asbestos exposure cause?
Lung cancer
| Mesothelioma
48
When are you at risk of Aromatic amines exposure and what do they cause?
Rubber and dye workers
| Transitional cell carcinoma - bladder
49
What cancer can androgens and anabolic steroids cause?
Hepatocellular carcinoma
50
Give some examples of microbiological carcinogens
Hepatitis B (&C): chronic inflammation and repair
HPV (human papilloma virus) 16 and 18 most active/high risk serotypes: inactivate p53 and RB
EBV (Epstein Barr virus): Promote B cell growth and transformation
Helicobacter pylori: chronic inflammation and repair
Aflatoxins (produced by Aspergillus flavus (fungus)): p53 mutations
Schistosoma haematobium: chronic inflammation and repair
51
What host factors can determine the risk of a tumour developing?
```
Race / environmental factors
Diet
Age
Constitutional factors: Gender, Inherited risks (e.g. Xeroderma pigmentosum)
Premalignant lesions & conditions
Transplacental exposure
```
52
Describe geographical variation in tumour incidence
High incidence of Burkitt Lymphoma in sub-Saharan Africa -
EBVirus/malaria/other
High incidence of skin cancers in Australia - UV radiation
Thyroid cancer in Russia – Chernobyl: radiation
Hepatocellular Carcinoma in Asia and Africa. Aflatoxins and HBV
Oesophageal Carcinoma in China - diet
53
What symptom sets may cancer present with?
Local symptoms
Due to metastasis
Catastrophic symptoms
Para neoplastic syndromes
54
How can asymptomatic cancers present?
Screening
| Incidental findings
55
What local symptoms may present from cancer?
```
Lump
Pain
Mark / ‘lesion’ on skin
Bleeding
Cough
Dysphagia
Discharge
```
56
What symptoms may present from metastasis?
```
Lump
Pain
Headache
Confusion
Fit
Cough
```
57
What catastrophic symptoms may result from cancer?
```
Cord compression
SVCO
Fit / stroke
Fracture
Bleed
```
58
What endocrine para neoplastic syndromes are there?
```
Low sodium (hyponatraemia)
High calcium (hypercalcaemia)
Low sugar
Cushings
Hyperaldosteronism
```
59
What neurological para neoplastic syndromes are there?
Eaton-Lambert myasthenia: autoimmune reaction to presynaptic voltage gated sodium channels
Encephalomyelitis
Cerebellar degeneration
Polymyositis: muscle inflammation
60
What mucocutaneous para neoplastic syndromes are there?
Acanthosis nigricans: darkened, thickened patches of skin develop in armpit and around groin and neck
Dermatomyositis: polymyositis with skin involvement
61
What haematological para neoplastic syndromes are there?
Polycythemia: high conc of Hb
| Trousseau sign: spontaneous venous thrombosis, suggestive of visceral carcinoma esp lung and GI tract
62
What are the two types of cancer treatment intent?
Radical
| Palliative
63
What types of cancer treatment sequencing are there?
Neo adjuvant: before surgery
| Adjuvant: after
64
What factors are involved in decision making with regards to treatment options for cancer?
```
Multidisciplinary team meeting
Staging (clinical / histopathological)
Pathology
Patient co-morbidity and performance status
Patient preference
```
65
56 female, Fit and well, 1,2cm right breast mass detected on national screening mammogram, History – no significant PMH. No FH of cancer. No medications NKDA, Examination NAD lump not palpable. Biopsy confirms Grade 1 lobular breast carcinoma
Oestrogen receptor positive, Progesterone receptor positive
HER2 IHC negative for amplification
Axillary USS no nodal disease
What do you do now?
Wire guided wide local excision and sentinel lymph node biopsy
Adjuvant Radiotherapy to breast
Adjuvant Tamoxifen hormone therapy for 5 years (oestrogen receptor antagonist in breast tissue)
66
Frail, Performance status 2, Presents with painful 10cm breast mass, History –two years know worsening mass. PMH T2DM on
insulin, Ex-smoker, IHD. Polypharmacy penicillin allergy
Examination Large mass obviously palpable with axillary nodes.
Biopsy confirms Grade 2 lobular breast carcinoma
Oestrogen receptor positive, Progesterone receptor positive
HER2 IHC negative for amplification
Axillary disease evident on imaging, Staging CT no distant mets
What now?
Patient too frail for surgery
Primary palliative radiotherapy
Palliative Hormone therapy Letrozole (aromatase inhibitor – inhibits peripheral conversion of androgens to oestrogen)
67
What is Letrozole?
Aromatase inhibitor – inhibits peripheral conversion of androgens to oestrogen
Used in post menopause breast cancer treatment
68
34 year old Female, 3 cm breast mass rapid onset, No PMH No meds NKDA. FH of breast and ovarian cancer. Non smoker. On examination obviously palpable mass in right breast no axillary nodes. Imaging shows 3.3cm mass in right breast. No axillary disease, Biopsy shows ductal breast carcinoma Grade 3. ER PR and HER2 negative
What now?
Patient has Neo-adjuvant Chemotherapy FEC-T (fluorouracil, epirubicin, cyclophosphamide, docetaxel
Marker guided WLE (wide local excision) and SLNB (sentinel lymph node biopsy)
Adjuvant radiotherapy to breast
69
What is cisplatin?
Chemo drug
| Bind and cause cross linking of DNA which triggers apoptosis
70
What is R CHOP?
```
Rituximab CD20 antibody on B cells
Cyclophosphamide
Doxorubicin
Vincristine
Prednisolone
```
71
What is the RECIST criteria?
Response Evaluation Criteria in Solid Tumours
define when tumours in cancer patients improve (respond), stay the same (stabilise), or worsen (progress) during treatment
72
In what cancers is a BRAF mutation significant?
Proto oncogene
Non Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, adenocarcinoma of the lung
73
How can chemotherapy be delivered?
Induction: treatment for advanced disease
Adjuvant: Systemic treatment after primary has been controlled by alternative method e.g. surgery/ radiotherapy, reduce risk of recurrence after local treatment alone
Neo Adjuvant/ Primary: initial rx of localised tumour
Direct/ Regional: into sanctuaries or by site directed perfusion of specific regions most affected by cancer
74
What is an advantage to intrathecal chemotherapy? And what is used to deliver it?
Higher concentrations of drug to localised tumour
| OMMAYA RESERVOIR
75
What are advantages of intraperitoneal chemotherapy? When might this be used?
Peritoneal cavity can be exposed to much higher concentrations of cytotoxics than with systemic delivery
Main indication: ovarian cancer
76
How do anti metabolite drugs work?
Analogues of natural components of normal metabolic pathways
Disrupt synthetic phase of cell cycle
Inhibit key synthetic enzymes by mimicking a natural substrate or co-factor
Become incorporated into natural molecules such as DNA &
RNA and disrupt function
Toxicity reflects effects on proliferating cells e.g. bone marrow and GI mucosa
77
Give examples of pyramidine anti metabolite drugs
5-Fluorouracil
Capecitabine
Cytosine arabinoside
Gemcitabine
78
Give examples of purine anti metabolite drugs
```
6-mercaptopurine
Thioguanine
Cladribine
Fludarabine
Pentostatin
```
79
Give examples of anti folate drugs
Methotrexate
Raltitrexed
Pemetrexed
80
How do tubular binding agents work as anti cancer drugs? And give some types
Inhibit polymerisation of tubulin
Inhibit microtubular disassembly, prevents normal growth and breakdown of tubules required for cell growth
Taxanes (Paclitaxel, Docetaxel) and vinca alkaloids (Vincristine, Vinblastine, Vinorelbine)
81
How do anthracyclines work as anti cancer drugs?
DNA binding: Planar ring intercalates with DNA, H bonds created between side chain and bases, Sugar moiety binds to minor groove
Topoisomerase II inhibition
Formation of free radicals: Damage to nuclear and mitochondrial DNA, Lipid membrane damage through peroxidation
82
Name some anthracycline drugs
Doxorubicin
Epirubicin
Caelyx/ Myocet
83
What are some toxic side effects of anthracyclines?
```
Myelosuppression
Alopecia
mucositis
Radiosensitizer
Radiation recall phenomen
Nausea and vomiting
Extravasation
soft tissue necrosis
CARDIOTOXICITY
```
84
What is PEG LD?
Pegylated liposomal doxorubicin
Anthracycline Encapsulation in liposomes alters pk of the drug
Different toxicity profile to unencapsulated doxorubicin
Less Myelosuppression & Cardiotoxicity
85
How do the platins work as anti cancer drugs?
Platin complexes form covalent bonds with electrophilic atoms
DNA -platin adducts: Cross Strand links to adjacent complementary guanines, adjacent guanine and adenine bases
Causing ssDNA and dsDNA breaks and stopping separation of strands for transcription and replication
86
Name some toxic side effects of cisplatin
```
Myelosuppression
Highly emetic, Mucositis
Alopecia
Azospermia
Nephrotoxicity – K and Mg wasting, acute tubular necrosis, renal
failure, worsened by other nephrotoxics
Neurotoxicity –Ototoxicity (high frequency loss), peripheral
neuropathy
Raynauds phenomen, Allergic reactions
```
87
What benefit is there of using carboplatin over cisplatin?
Less nephrotoxic
88
Name some toxic side effects of carboplatin
Myelosuppression – thrombocytopaenia
Nausea and vomiting (less than cisplatin)
Renal impairment
Anaphylaxis, Especially on second rechallenge to drug, Desensitisation can be tried in certain circumstances
89
How do alkylating agents work?
Form covalent bonds with DNA bases
Causes DNA breaks: ss DNA breaks/ ds DNA breaks
Cross linking of DNA prevents separation of complementary strands for transcription or for synthesis
90
Name some toxic side effects of alkylating agents
```
Myelosuppression
Alopecia
Nausea and vomiting
Mutagenesis & Carcinogenesis (AML, bladder Ca)
Veno-occlusive disease
Infertility
Pulmonary fibrosis
```
91
What is Extravasation in chemotherapy terms?
Infiltration of a vesicant drug from an I.V. line into surrounding tissue
92
What might be some signs and symptoms that Extravasation of a drug has occurred?
Oedema,swelling, blanching, and coolness
| Patient may complain of pain/feeling of tightness around the site
93
What could be consequences of drug Extravasation?
Necrotic ulcers, infection, disfigurement, reflex sympathetic dystrophy syndrome, and loss of function
94
What do you do if a drug has extravasated?
Elevate affected arm
For most extravasations, apply ice for 20 minutes at least four times a day for 24 to 48 hours
Treat extravasations from Vinca alkaloids and epipodophyllotoxins with heat
Photograph site, if possible
Topical hydrocortisone cream- mild reaction
If severe reaction, contact plastics
95
Define chronic disease
Persistent, long-standing, long-term, constantly recurring; incurable
Intrinsically indolent natural history, but ultimately incurable
Amenable to treatment that may afford control, rather than cure, & impacts on the natural history of disease, transform acute to chronic and prolongs survival
96
What is a cure?
Die of something completely different, having survived progression-free until that point
97
What is DCIS?
Ductal carcinoma in situ
98
What is an IHC ER Q-score?
Immunohistochemistry oestrogen receptor measure
99
What does FISH negative mean?
Fluorescence in situ hybridisation: done in breast cancer to look for HER2
100
What is an adnexal mass?
Mass in uterine appendages: ovaries and Fallopian tubes
101
What is Letrozole?
Aromatase inhibitor used as endocrine therapy in post menopausal women with breast cancer
102
What is a GIST?
Gastrointestinal stromal tumour
| Soft tissue sarcoma
103
What is imatinib? and give 2 uses
Tyrosine kinase inhibitor
Chronic myelogenous leukemia: Philadelphia chromosome +
Gastrointestinal stromal tumor: after surgical removal of cKIT-positive tumors to help prevent recurrence and unresectable cKIT-positive GISTs
104
What is Trastuzumab?
herceptin: monoclonal antibody with specificity for extracellular epitope of HER2, and trans-membrane ligand-less member of the EGFR family
105
What are implications of chronic disease?
Shorten survival
Compromise performance status
Curtail economic activity and impoverish
Degrade quality of life
Impact on friends and family
Require care and carers
Cause depression, anxiety, frustration & anger
Constitute an increasing financial burden to society
106
What ways should patients be educated on self management of chronic disease?
Information: knowledge as power, expert patient, autonomy, consumer groups
Guiding principle: expectation guiding
Physical: timing of therapeutic interventions
Psychological: relaxation, mindfulness
107
What is the Gompertzian Growth Curve?
Mathematical model for a time series, where growth is slowest at the end of a time period
Slow initial growth, Rapid subclinical growth, threshold for clinical detection, slower clinical growth, death of patient
108
What is the self seeding concept of cancer growth?
Primary tumor cells released to enter the circulation to:
Self-seed back to primary
Metastasise to a distant secondary site such as lung, brain, bone
From which they return to primary tumor mass
109
What factors attract circulating tumour cells?
Tumour-derived inflammatory cytokines IL-6 and IL-8 attract
| CTCs, promote accelerated growth, angiogenesis, and recruitment of myeloid cells into the stroma
110
What are protective factors against ovarian cancer?
Increasing parity, oral contraceptive use, and oophorectomy
111
What are treatment options for ovarian cancer?
Adjuvant radical chemotherapy curative intent for early stage
Palliative but survival-prolonging intent for advanced stage, before or after surgery
112
What factors may contribute to survival of ovarian cancer?
Tumour’s platinum sensitivity
Stage
Operability
113
Which chemo drug is often used in ovarian cancer?
Cisplatin
114
When is second line therapy appropriate in cancer treatment?
Second-line therapy is never curative, therefore palliative
Palliation means symptom control
Chemotherapy has nasty side effects
Second-line therapy in absence of disease-related symptoms is therefore a nonsense
Good practice therefore means defer Rx until their advent
Longer platinum-free interval, since first-line treatment, higher the response rate
115
What do prognosis and treatment related toxicity in patients with advanced solid tumours depend on?
Tumour burden & performance status
116
What may be the first symptom of relapse of ovarian cancer?
Bowel obstruction
117
Which women are most likely to survive ovarian cancer?
Women
118
Why is VEGF a promising target for cancer therapy?
Vascularisation essential for tumour growth
Ovarian cancer secretes VEGF protein to stimulate blood vessel growth
VEGF makes vessels leaky – ascites
119
What difference does a BRCA mutation have on ovarian cancer?
Present earlier, and may be more chemosensitive
120
What is PARP-1?
Key enzyme involved in the repair of single-strand DNA breaks
121
What happens if you inhibit PARP1?
Increased double-strand DNA damage
122
What factors need to be considered along a surgical route of approach?
Avoidance of key structures e.g. neurovasculature
Minimal damage
Provide sufficient field of view and access and option to increase size of access
Fascial, avascular & aneural planes
Lymph drainage routes
Embryological routes of travel/remnants
123
What structures are at risk at the primary incision site and during biopsy procedures?
Cutaneous nerves
124
What structure is at risk with a posterior triangle biopsy?
Cranial nerve XI
125
What structure is at risk with a submandibular gland/node biopsy?
Cranial nerve VII mandibular branch
126
What structure is at risk with a vastus approach to the knee?
Infrapatellar branches of saphenous nerve
127
What are langers lines? And what are they useful for?
Lines of tension/cleavage which help guide the orientation of surgical incisions
Determined by direction of travel of collagen fibres in the skin
128
What are benefits of z plasty incisions?
Enable adequate exposure whilst enabling alignment of scars with tension lines
129
How should a muscle be split?
Direction of travel of their fibres
130
What is a neoplasm?
Abnormal mass of cells, growth of which exceeds and is uncoordinated with normal growth control mechanisms of tissues
131
Differences between benign and malignant neoplasm
Malignant neoplasm has ability to invade surrounding tissues and metastasise
Both can cause death
132
What are the two tissue types that make up all tumours (and all tissues!)? What does each type determine about the tumour?
Parenchyma: determines biological behaviour of neoplasm and name of neoplasm
Stroma: supporting tissue, has important role in determining how quickly tumour can grow
133
What is differentiation?
Extent to which neoplasm looks and functions like the parenchymal cells they are differentiating towards
134
What is dysplasia?
Disorderly proliferation of cells, but does not represent cancer. Loss in uniformity of cells and orderly maturation, but no breech of basement membrane (most dysplasia involves epithelium)
135
What is the other term for severe dysplasia in epithelia?
Carcinoma in situ
136
Can you think of a time when a benign neoplasm might rapidly expand?
When it is hormone dependent and level of that hormone goes up suddenly e.g. leiomyomas and oestrogen during pregnancy
137
Other than differentiation, what things could limit the rate of growth of a malignant neoplasm?
Inadequate or limited blood supply and pressure from the surrounding tissue e.g. if it is in a boney cavity
138
Why might a malignant neoplasm suddenly increase in size?
Subclone in tumour which more proliferative
More commonly tumours undergo necrosis and possible
haemorrhage into their centres as their growth outstrips their blood supply
139
Why are many malignant neoplasms firmer than the adjacent tissues e.g. breast cancers and prostate cancers?
Tumour invades adjacent connective tissue
Firm form of stroma can form in neoplasm: desmoplastic stroma, which gives some neoplasms hard craggy feeling characteristic of cancer on palpation
140
When malignant neoplasms are resected, surgeons look to get a clear resection margin, why?
Malignant neoplasms infiltrate, invade and often destroy surrounding tissues. So unless they have a clear margin of normal tissue around the malignant neoplasm they can’t be sure they have removed it all, which would increase the chance of recurrence of the neoplasm dramatically
141
What is a metastasis?
Secondary implant of a neoplasm discontinuous with the primary neoplasm
142
What are the routes of metastasis?
Transcoloemic, haematogenous, lymphatic and direct through tissues
143
What do metastases mean for the aims of a patients treatment?
In general if metastases are present then all treatments are aimed at prolonging life and not curing the patient
Some exceptions to this rule exist e.g. renal cell carcinoma with isolated liver mets
144
Why are the liver and the lungs the most common sites for metastases?
Because they drain blood from the abdominal viscera (liver) and the rest of the body (lungs). Any tumour cells will get trapped in the capillary beds and form metastatic deposits if they are able
145
What is a sentinel lymph node? What does a negative node mean for the patient?
Sentinel node is first node in the regional lymphatic group to receive lymph drainage from the neoplastic tissue
Negative node means no other lymph nodes should be
involved and no further lymph gland removal should be necessary
There are few tumours which show consistency in drainage patterns, breast and melanoma being the ones for which this sampling technique is used clinically currently
146
Which genes of cell proliferation are affected in cancerous cells?
Growth promoting proto-oncogenes
Growth inhibiting tumour suppressor genes
Genes controlling apoptosis
Genes involved in DNA repair
147
Malignant neoplasms represent clonal expansions, how does heterogeneity develop in neoplasms?
A single cell will give rise to a neoplasm, but as neoplastic cells proliferate they undergo further mutations, some which will offer a survival advantage to cells e.g. increased ‘aggressiveness’ and these cells will flourish producing a subclone. Other
mutations e.g. a highly immunogenic cell forms will not survive
148
What is the key first step in initiating Go to G1 transition i.e. entry to the cell cycle? What happens inside the cell as a result?
Cells normally enter cell cycle upon binding of a growth factor to a cell surface receptor
Transiently activated receptor activates intracellular signal transduction proteins
Series of second messengers activated which culminate in transduction molecules signalling nucleus which induce and activate nuclear regulatory factors to initiate DNA replication
149
What are the stages of the cell cycle?
```
G0- resting or quiescent
G1- Gap 1
S-DNA synthesis
G2- Gap 2
M- Mitosis
```
150
What are positive controls on the cell cycle?
Accelerators are growth factors from outside cell and phosphorylation reactions catalysed by cyclin dependent kinase and cyclin complexes
151
What are the negative / inhibitory controls on the cell cycle?
Brakes on cell cycle are applied by cyclin kinase inhibitors and checkpoints
152
Where are the key cycle checkpoints? What do they look for?
G1/S: DNA damage before DNA is replicated and that environment is favourable
G2/M: looking for damaged or unduplicated DNA and checking that the cell is big enough before mitosis
153
How do cyclins and cyclin dependent kinases (CDK) work?
Cyclins show cyclical variation in levels during the cell cycle
There are several cyclins, which have key roles at different points of the cycle
Cyclins bind to cyclin dependent kinases (CDK) (constant levels throughout cycle but variably active) to form a complex, which activates CDK
Activated complex phosphorylates target proteins which drive the cell forward through cell cycle
154
What are the negative controls of CDKs?
Cyclin dependent kinases are inhibited by cyclin dependent kinase inhibitors, which help quickly decay CDK when it is no longer needed
155
What are the molecular hallmarks of cancer (Hanahan and Weinberg)?
```
Replicative immortality
Tumour promoting inflammation
Activation of invasion and metastasis
Induction of angiogenesis
Genome instability and mutation
Resistance to cell death
Dysregulation of cellular energetics
Sustained proliferating signalling
Evasion of growth suppressors
Avoidance of immune destruction
```
156
What are the normal genes that promote cell growth? What are their mutated forms called? What are their products called?
Normal growth promoting genes in cells are proto-oncogenes Code for proto-oncoproteins
Mutated forms of the gene in cancer are called oncogenes and they code for oncoproteins
157
How do oncogenes differ from proto-oncogenes?
Promote cell cycle in absence of normal growth factors necessary for proto-oncogene transcription etc
158
How many alleles of a proto-oncogene need to be mutated for neoplastic transformation? Why?
Mutation of proto-oncogenes behaves in a dominant fashion i.e. a single allele of the gene needs to be mutated to enable neoplastic transformation
Its product promotes cell cycle and so any increase it the level will accelerate the cell cycle
159
What mode of signalling do growth factors normally use? How is this changed in cancer?
Normally growth factor signalling is via paracrine signalling, but some cancers set up an autocrine loop to ensure a constant growth factor supply
160
How are growth factor receptors altered to enable self sufficiency in growth signals?
Growth factors can be altered in two ways: Mutated so they are active even without a ligand
Overexpressed so very low levels of the growth factor (that would normally be insufficient to trigger proliferation) stimulate proliferation e.g. Her2 in breast cancer and EGFR in lung cancers (both treatment targets)
161
What do normal signal transduction pathways of growth factor receptors involve? How could they be mutated to provide self-sufficiency in growth signals?
Second messengers or cascade of phosphorylation leading to signal transduction into the nucleus
Mutations in RAS and ABL involve permanent activation of GPCR and translocation of gene there is unregulated expression of its tyrosine kinase respectively
162
What is the normal role of nuclear transcription factors? How can they be mutated to allow self-sufficiency in growth signals?
Regulate transcription of DNA e.g. growth promoting genes Show cyclical expression, however can remain high throughout cell cycle which leads to inappropriate expression of growth promoting genes e.g. CDKs and down regulation of growth inhibition genes e.g. CDK inhibitors
163
What form of abnormalities in the cyclins/CDK/CDKI system would enable self-sufficiency in growth signals?
Mutations that dysregulate expression and activity of the cyclins and CDKs or mutations that inhibit or render inactive CDKIs will lead to uncontrolled cell cycle progression
164
What is meant by the terms promoters and caretakers in terms of tumour suppressor genes?
Promoters e.g. p53 and RB release breaks on cell cycle if they become mutated
Caretakers are responsible for integrity of genome, mutations in these indirectly allow malignant transformation by allowing the survival of cells with DNA damage leading to the potential accumulation of widespread DNA damage
165
How many copies of the TSGs alleles need to be mutated to enable a malignant phenotype to emerge? Why?
Tumour suppressor genes require mutations in both alleles to enable a malignant phenotype
Normal allele will continue to produce the regulatory protein at a certain level
166
What happens when a normal TSG is activated by DNA damage?
TSGs encode growth inhibitory proteins
Cell cycle will be arrested whilst attempts are made to repair DNA
If unsuccessful then cells will become senescent (permanently enter G0)
167
When is retinoblastoma protein activate and inactive?
Active when it is hypophosphorylated
| Inactive when hyperphosphorylated
168
Explain the two hit hypothesis of which accounts for the sporadic and familial retinoblastoma tumour formation
Tumour suppressor genes behave in a recessive manner i.e. both must be mutated for a malignant phenotype to emerge
In familial cases of retinoblastoma, children inherit a single mutant copy and then acquire a somatic mutation leading to loss of heterozygosity of the gene. In sporadic cases two somatic mutations have to occur for both alleles to become mutant. Familial retinoblastoma is an autosomal dominant disease
169
Where in the cell cycle is RB key?
RB is key for the G1/S checkpoint transition, beyond which mitosis is obligatory
170
How does RB regulate the G1/S checkpoint transition step of the cell cycle?
Transcription factor E2F is key for expression of cyclin E.
Cyclin E/CDK complex is necessary for DNA synthesis i.e. S phase of the cell cycle. Active RB binds to E2F and thus blocks transcription of cyclin E
171
How is RB inhibition of the G1/S checkpoint transition step released?
Cyclin D and CDK4 complex phosphorylates RB (makes it inactive), this releases E2F, which enables cyclin E expression
172
How could the inhibitory effects of RB be lost?
RB itself could be mutated/lost or the genes that control its phosphorylation could be affected to you lose the inhibitory effect
173
What does p53 do?
Activation of temporary cell cycle arrest (quiescence)
Induction of permanent cell cycle arrest (senescence)
Trigger apoptosis
174
What can trigger the expression of p53?
Anoxia, inappropriate oncogene expression and damaged DNA. Once it is triggered it up-regulates expression of repair proteins e.g. MDM2
175
When in the cell cycle does p53 induce cell cycle arrest? What does it do?
Late in G1 phase- remember once into the S phase the cell is committed to mitosis and so if it was any later all the cells in which p53 was activated would have to undergo apoptosis.
p53 induces cell cycle arrest by inhibition of phosphorylation of RB i.e. the RB remains active
176
Why do some cells undergo apoptosis and some cells become senescent?
Depends on the degree of chromatin damage and the type of chromatin change
177
Describe TGF beta pathway involvement in the cell cycle
Potent inhibitor of proliferation as it causes activation of CDKIs and suppresses growth promoting genes
Mutations in this pathway are seen in the vast majority of colon and pancreatic cancers
178
Describe the Β-Catenin Pathway, APC (Adenosis Polyposis Coli) in FAP
APC gene is a tumour suppressor gene, a mutant allele is inherited in those with Familial Adenomatous Polyposis (FAP). APC regulates intra-cellular expression of β-catenin, which helps to bind E-Cadherin. β-catenin also signals via the WNT signalling
pathway to activate proliferation. Loss of APC means unregulated β-catenin expression and thus unregulated proliferation
179
How does FAP present?
Patients with FAP have hundreds of adenomatous polyps in their colons and a guarantee that one of these will become malignant
180
What is the function of E-Cadherin?
E-Cadherin binds cells together i.e. it is intercellular glue, it is dysregulated in virtually all cancers
181
What effect would loss of E-Cadherin have on cells?
Loosen intercellular bridges, cells more mobile, and cells would loose polarity as they are no longer anchored in place
182
What is apoptosis?
Programmed cell death, via activation of the caspase cascade
183
What are the two methods of activating apoptosis?
Intrinsic (mitochondrial permeability) pathway and the extrinsic (death receptor) pathway
Intrinsic cascade relies on a balance between pro-apoptotic molecules and anti-apoptotic molecules
Extrinsic cascade relies on a ligand binding to death receptor.
Process of apoptosis involves proteolytic cleavage of the caspase enzyme cascade
184
Mutations in what targets would lead to evasion of apoptosis?
Mutations to prevent activation of caspases, mutations in death receptor (extrinsic pathway), mutations to increase pro-apoptotic molecules and problems with p53 mediated apoptosis
185
Follicular lymphomas contain a translocation which renders them resistant to apoptosis. Would you expect this to be a slow or fast growing tumour?
Tumour growth relies on lack of cell death rather than rapid proliferation the tumour should be slow growing
Many follicular lymphomas follow this trend, however other mutations can supervene which increase the rate of proliferation secondarily
186
How much replication can cells undergo before they become senescent?
60-70 rounds
187
What structure on the ends of chromosomes limits the number of replications? How does it work?
Telomeres on end of chromosomes get shorter during each round of proliferation. At a critical point they are identified as double stranded DNA breaks and cell enters senescence
188
How can telomeres be altered to allow for limitless replicative potential?
Telomerase, an enzyme normally only expressed in utero, can elongate telomeres and thus allow for an infinite number of replications
Telomerase expression is seen in several cancers
5-15% of cancers without telomerase use an alternative telomere lengthening strategy
189
Above what size do tumours need their own blood supply?
1-2mm
190
What properties do blood vessels have which are created in tumours?
Leaky, dilated and have a haphazard pattern of connection
191
How can a tumour be vascularised?
Vascularisation could occur via angiogenesis (buds from adjacent capillary sprouts) or vasculogenesis (recruitment of stem cells from bone marrow)
192
What does vascularisation of the tumour facilitate?
Supply of nutrients and oxygen and removal of waste products
Provision of growth factors from endothelial cells
Access to vascular supply for haematogenous dissemination
193
What growth factor is key to vascularisation of a tumour? What stimulates its production?
VEGF
Induced by hypoxia and involves a switch in tissues from production of angiogenic inhibitors to pro-angiogenic factors
Tumour invades extra-cellular matrix then growth factors can be released from these stores as well
194
What are the two types of extracellular matrix? What are the major components?
Basement membrane and interstitium
| Comprise collagens, glycoproteins and proteoglycans
195
What four things does a cell need to do to invade the ECM?
Cell needs to detach from adjacent cells
Degrade the ECM
Attach to novel ECM ligands
Migrate through the ECM
196
How does detachment from adjacent cells occur in cancer?
Cells bind to each other using cadherins, notably E-cadherin. Reduced expression means loss of this intercellular adhesion and detachment
197
How does degradation of the ECM occur when cancer cells are invading?
Epithelial cells need to clear a path through basement membrane and interstitium
This is done via production of proteases e.g. MMPs (with reduced TIMPs).The proteases come from the tumour cells and the connective tissue
198
How does attachment between cells and ECM change during invasion?
Normally cells bind to ECM via integrins and loss of this anchoring induces apoptosis
Neoplastic cells are resistant to apoptosis and when they digest the ECM new attachment sites are revealed which help stimultate migration
199
How is locomotion induced in the neoplastic cells?
Tumour cell derived cytokines act via cell surface receptors on actin to enable movement
200
How do tumour cells protect themselves from immune mediated destruction in the vessels?
Tumour cells form emboli with each other and with the hosts’ platelets and some leukocytes to protect a core of cells
201
What determines the site of vascular or lymphatic drainage of a tumour?
Metastasis will be carried in blood or lymphatics to natural point of drainage of the tissue until they adhere to a cell and leave the vascular supply
In haematogenous dissemination this occurs in small capillary beds, where the tumour emboli get stuck
202
What is meant by the term organ tropism? How does it occur?
Attraction of a tissue/substance to a particular organ
In neoplasms this reflects the type of adhesion molecules expressed by the tissues and the tumour e.g. breast commonly metastasises to bones
203
What is the triple assessment of breast?
Clinical Brest examination
Radiological: mammogram/USS
Pathological: fine needle aspiration cytology
204
How are the different parts of a triple assessment of a breast graded?
Clinical P1-5
Radiological R/U1-5
Pathology C1-5, B1-5a and 5b
2 = Benign 5 = Malignant
205
What things may be discussed at an MDT meeting with regards breast tumour?
```
Surgery or primary endocrine therapy?
Axillary involvement?
Breast conservation or mastectomy?
Reconstruction?
Chemotherapy?
Radiotherapy?
Patient preference
Comorbidities
Family history (?genetics referrall)
```
206
What can be initial therapy options for breast tumours?
Neoadjuvant chemotherapy
Surgery: Breast conserving operation/Mastectomy
Axillary surgery
207
What is a WLE?
Wide local excision, can be done wire guided
208
What are sentinel lymph nodes and how can they be used in breast surgery to minimise surgery?
Sentinel node is considered to be the first node in the tumor drainage path
SLNBx is an acceptable alternative to complete axillary dissection
Identified by presence of radioactive blue dye that is injected within the breast parenchyma
if sentinel node is negative for metastasis there is no need for further axillary node clearance thereby reducing the morbidity
209
After a breast tumour removal surgery, what things might be discussed at an MDT meeting?
```
Report discussed
Further surgery needed? (shaves, Axillary node clearance) Staging scans?
Chemotherapy?
Radiotherapy?
Hormones?
Herceptin therapy?
Follow up
```
210
Name some benign breast diseases
Fibrocystic disease: breast pain, tenderness, lumpiness
Intraductal Papillomas: wart like lump in ducts, small lump or discharge from nipple
Sclerosing lesions: hardening of the breast tissue
Epithelial hyperplasia (without atypia): breast cell proliferation
Inflammation: acute, duct ectasia, fat necrosis
Benign tumours: Fibroadenoma and hamartoma
Developmental disorders: supernumerary nipples or breasts; accessory axillary breast tissue; congenital inversion of nipple
211
Give some risk factors for breast cancer
Increasing age
Hormonal factors: Early menarche, late menopause, Nulliparity or increasing age at birth of first child, HRT
Proliferative breast disease
Diet High levels of fat, moderate to heavy alcohol consumption
Obesity
Ethnicity
• Radiation Undergoing radiation therapy for Hodgkin: 20 - 30% risk at 10 - 30years after therapy
212
What genetic link is there to breast cancer?
5 - 10% of cases are attributed to inheritance of an autosomal
dominant gene
BRCA1 - tumor supp gene, younger age, 30-60% risk of ovarian cancer by age 70, greater incidence of medullary carcinoma and higher grades of tumour
BRCA2 - tumor supp gene, older age, male breast cancer, ovary, bladder, prostate, pancreas
Woman with 1 affected 1st degree relative has double risk of breast cancer of a woman with no family history; two (or more)relatives affected, risk increases further. Risk is higher if relative is diagnosed aged under 50
213
What are the different types of breast cancer?
Invasive: Ductal carcinoma, Lobular carcinoma (10% approx)m Tubular, Mucinous, Adenoid cystic
Non invasive / in situ: Ductal carcinoma in situ (DCIS), Lobular
carcinoma in situ (LCIS)
Paget’s disease of the nipple: skin of one nipple, eczema-like symptoms, itchy, red rash on nipple that can extend to the areola small ulcer or dry, red, flaky patches of skin similar to psoriasis
214
What is the Nottingham prognostic index (NPI)?
Size of tumour in cm x 0.2 + Grade + Score for nodes (negative =1, 1 - 3 nodes =2, 4 or more nodes =3)
Prognostic scale from excellent to poor
215
Name some local effects of the presence of a malignant lesion
Palpable mass and disfigurement
Destruction of adjacent tissue and loss of function
Destruction of adjacent tissues with subsequent infection e.g ulceration and infection or haemorrhage
Compression of adjacent tissue, particularly hollow tubes
216
What is cancer cachexia?
Individuals with cancer commonly suffer progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia, referred to as cachexia
Cancer cachexia is associated with: Equal loss of both fat and lean muscle, Elevated basal metabolic rate, Evidence of systemic inflammation
217
What are paraneoplastic effects?
Some cancer-bearing individuals develop signs and symptoms that cannot readily be explained by anatomic distribution of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose
These occur in about 10% of people with cancer
218
Why are paraneoplastic effects important to remember about?
They may be the earliest manifestation of an occult neoplasm
Can cause significant clinical problems and may even be lethal
They may mimic metastatic disease and therefore confound treatment
219
Give some examples of paraneoplastic effects
Endocrinopathies: ACTH secreting small cell carcinoma causing Cushings
Nerve and muscle disorders: Myasthenia caused by bronchogenic carcinoma caused by immune mechanisms
Osseous, Articular, and Soft Tissue Changes: clubbing of the fingers in bronchogenic carcinoma via an unknown mechanism
Vascular and Hematologic Changes: Non-bacterial thrombotic endocarditis in advanced cancers associated with hypercoagulability
Nephrotic syndrome: various cancers secreting tumour antigens and immune complexes
220
When will cancer develop?
When cells acquire non-lethal mutations in their genetic material
221
Describe radical (curative) cancer treatment
Maximise successful eradication
Preserve function
Maintain form/cosmesis
Adjuvant: given alongside primary treatment, reduce risk of recurrence
Chemotherapy and radiotherapy (adjuvant) to breast after breast-conserving surgery
Neo-adjuvant: downstaging cancer BEFORE radical/definitive treatment. Improve chances of success, no residual cancer left behind after surgery, Preserve organ which would otherwise need removing / sacrificing, chemo and/or radiotherapy, or hormone therapy
Hormone tablets to shrink estrogen-sensitive large breast cancer
Chemoradiotherapy to a bulky rectal cancer before attempting surgery
222
Describe the aims of palliative cancer treatment
```
Symptom control
Delay progression
Prolong survival
Quality & quantity of life
Aim for least complications
Convenience and tolerability to patient important
```
223
Name some members of the MDT which may be involved in the care of a cancer patient
```
Clinical nurse specialist
Palliative care team
Clinical trials unit
Oncologists
Pharmacist
Radiologists
Surgeons
Pathologists
```
224
If a cancer has metastasised, why might surgery still be useful?
Removing (debulking) primary tumour may improve survival
In incurable/advanced disease, surgery can also be useful in removing
tumours that are causing bleeding/ compression/obstruction
225
Describe the use of radiotherapy in cancer treatment
Use of ionising radiation, usually high energy x-rays
Treat cancer. Rarely on benign tumours /condition
Bigger dose you give, more likely you will kill tumour cells
Cells that don’t die off will repair themselves and survive
Normal healthy cells have a good DNA repair system (more likely to repair and recover)
Cancer cells faulty DNA repair system, more likely to die or mutate
Ionising radiation from radiotherapy causes damage to DNA in cancer cells, which cannot repair DNA well and die
226
What limits how much radiotherapy you can give?
How much the normal tissue/organ can withstand (before they fall apart)
227
What tissues will be affected acute and late onset by side effects of radiotherapy treatment?
Acute: rapidly dividing tissues (e.g. mouth/gut lining, skin) - inflammation
Late: slowly/non-dividing tissues (e.g. spinal cord, optic nerve, saliva glands, bowel) –scarring/fibrosis
228
What is dose fractionation with regards to radiotherapy?
Splitting total RT dose into a smaller dose over many sessions (e.g. over 1-7wks)
Reduces harmful toxicity to healthy cells (by giving time to recover between each fraction)
Allows higher total dose of radiation to be given (more effective)
229
As a radical treatment option, what are benefits of radiotherapy?
Organ preservation
| Avoid disfiguring surgery
230
What are the 2 types of radiotherapy?
External Beam: delivered by using radiation sources from outside of the body.Usually high energy x-rays, sometimes electrons
Internal Radiotherapy: Brachytherapy (Insert tubes/needles (attached to radioactive source) allow a radioactive source to dwell inside the
tube in patient for a specific time - extremely high dose radiation delivered to the organ/tissue of contact) cervix, uterus, prostate, esophagus
Radioisotope (Drink/inject radioactive liquid, which emits radiation particles to short distances to destroy nearby tissues) eg Thyroid Radio-iodine
SIRT – Selective Internal RT: Liver metastases from bowel Ca
Interventional radiologist threads a guidewire from groin to hepatic arteries, Radioactive beads delivered to the liver mets
231
Name some acute side effects of radiotherapy
Fatigue
Nausea
Diarrhoea, cystitis, rectal bleed (pelvis)
Mucositis, oral secretions, dry mouth, taste change (head & neck)
Skin breakdown (radiation dermatitis) – neck, groin and perineum
Pneumonitis, esophagitis (lung, esophagus)
232
Name some late side effects of radiotherapy
Scarring, fibrosis, adhesions, fistulae
Impaired function (dysphagia, incontinence, permanent colostomy)
Xerostomia (dry mouth due to saliva gland dysfunction)
Osteoradionecrosis of jaw
Myelopathy
Secondary cancer (breast cancer from previous wide-field RT for lymphoma as a child/teenager)
Sterility/infertility
Skin changes (telangiectasia, pigmentation)
Lymphoedema (esp. after axilla or groin surgery)
Cataract, cognitive impairment, loss of vision, pituitary malfunction, myelopathy (brain/spine)
233
How do chemotherapy drugs work?
Interrupting processes or inhibiting substances necessary for cellular replication and life. Cytotoxic
234
What are goals of cancer chemotherapy?
Cure (some leukemias, lymphomas, germ cell tumours e.g. testicular Ca)
Reduce risk of recurrence (adjuvant treatment)
Prolong survival (palliative)
Improve symptoms (palliative)
Radiosensitiser (concurrent chemoradiotherapy)
235
Name some modes of chemotherapy administration
```
IV: cannula; indwelling central venous line (Hickman/Picc/Groshong line)
Oral e.g. hydroxyurea
Subcutaneous
Intracavity e.g bladder
Intrathecal (into CNS). Can be fatal
```
236
What factors determine the choice of treatment for cancer?
```
Types of cancer and its stage
Purpose of treatment
Pre-morbid health of patient
Risk v Benefit
Patient choice: Social impact, Spiritual beliefs, Quality of life
```
237
How might treatment modalities be modified depending on the stage of a tumour?
Stage I: wide local excision/resection, small-field radical RT
Stage II: primary surgery/RT, adjuvant chemo/RT/hormones
Stage III: multi-modality treatment -neoadjuvant chemo/RT+ radical surgery or radical chemo RT + adjuvant chemo/RT/hormones
Stage IV (metastatic): palliative surgical/interventional radiology procedures (excision/bypass/stent), palliative RT (pain, spinal cord compression, haemoptysis/bleeding, fungating growth), palliative chemo and/or hormone treatment
238
What factors likely contribute to whether a cancer is likely to relapse?
TNM stage, cancer grade, prognostic biomarkers, patient age
239
What are treatment options for early stage low grade prostate cancer?
Watch & wait: treat when Ca symptoms appear (elderly frail men) – live with Ca (more likely to die of sth else)
Active surveillance: careful and frequent monitoring with PSA blood test/MRI scan/repeat biopsy, treat with aim of cure (surgery/RT) when cancer becomes more active, good for men who want to avoid side effects of treatment until it deemed necessary
Radical treatment straight away: those who psychologically don’t feel comfortable with ‘having a cancer in my body’ or stress of frequent tests/scans; accept treatment might be over-treatment
240
How does personalised medicine apply to cancer treatment?
Additional genetic/molecular test to see how sensitive your cancer is to chemo (and therefore how likely you will benefit from having chemo)
Oncotype DX test in breast Ca (adjuvant chemo)
241
What is a performance status and how does it change treatment choice for cancer?
WHO/ECOG Performance Status 0-4. 0- normal, 1- mild symptoms, 2-50% time in bed, 3-need assistance, 4-cannot perform self care, in bed all day
For radical & adjuvant Rx: usually require PS 0-1/2
For palliative treatment: up to PS 3
PS 4: keep comfortable / palliative only
242
What co morbidities need to be assessed for with relation to fitness for treatments?
Fitness for surgery: anaesthetic risk, one-off big assault
Fitness for systemic treatment (chemo): serial knocks over many months/years
Fitness for radiotherapy: contraindications e.g. previous RT in same region, pregnancy, radiation sensitivity
243
Describe the cell cycle
G1 phase: cell prepares for DNA synthesis
S phase: cell generates complete copy of genetic material
G2 phase: cell prepares for mitosis
M phase: replicated DNA is condensed and segregated into chromosomes
G0 phase: resting state
244
Describe differences between schedule dependent and dose dependent chemotherapy
```
Agents with major activity in a particular phase of cell cycle
schedule dependent (e.g. every 3 weeks; weekly)
Agents with significant activity in multiple phases, dose dependent
```
245
Chemotherapy drug combinations have what characteristics?
```
Different mode of action (more effective)
Different toxicity (can tolerate)
Reduces chance of cancer resistance
```
246
Chemotherapy drug toxicity depends on what factors?
Drug dosing and schedule
Patient
Disease
247
Name some common toxicities of chemotherapy
Neutropenia, anemia, thrombocytopenia (myelosuppression/bone marrow suppression) – neutropenic sepsis can be fatal
Mucositis, diarrhea (GI toxicity)
Nausea and vomiting
Alopecia
Sterility/Infertility (especially sterility in males)
248
Which cell types are likely to be most and least affected by chemotherapy side effects?
Bone marrow, GI tract, hair follicles - rapidly multiplying
| Central nervous system, bone – slow multipliers
249
What are some limitations of chemotherapy?
Drug Resistance
Drug toxicity
Inability to suppress metastasis
250
Cancers acquire resistance to anti-cancer drugs by
```
Alteration of drug targets
Expression of drug pumps
Expression of detoxification mechanisms
Reduced susceptibility to apoptosis
Increased ability to repair DNA damage
Altered proliferation
```
251
How does methotrexate resistance develop?
Dihydrofolate reductase: Mutated or overexpressed
252
How do resistance to vinca alkaloids develop?
Mutations in tubulin or microtrubule associated proteins
253
Describe differences between chemotherapy and targeted therapy
Chemo: effects cells that are doubling, not very specific, mostly IV, cytotoxic
Targeted: inhibit specific target, mostly oral, mix of cytostatic and cytotoxic
254
List some signal transduction inhibitor drugs and what their targets are
Everolimus/sirolimus: mTOR inhibitors
Trastuzumab: HER receptor inhibitor
Gefitinib/afatinib: EGFR inhibitors
255
What is Imatinib? And what is it used to treat?
Protein kinase inhibitor
| Used to treat CML and GIST
256
What is a Philadelphia chromosome?
Translocation of chromosome 22: unusually short
| Associated with chronic myelogenous leukemia
257
What are Erlotinib and Gefitinib?
Highly specific tyrosine kinase inhibitor associated with EGFR
Used as second line for NSCLC (non small cell lung cancer)
258
What are Sunitinib and Sorafenib? And what are they used for?
Inhibit multiple receptor tyrosine kinases e.g.VEGFR and c-kit
Used in advanced RCC (renal cell carcinoma)
259
What is Vemurafenib? And when is it used?
BRAF inhibitor
Used in inoperable melanoma
V600E mutations in BRAF kinase gene must be present which constitutively activate BRAF kinase, turns on cell proliferation in absence of GF
260
What is Bortezomib? And when is it used?
Proteasome inhibitors
Prevents degradation of proteins in proteasome
Protein accumulation and cell death
Myeloma treatment
261
Describe how monoclonal antibodies are named
Letters before suffix indicate source e.g. o for mouse, u for human, xi for chimeric
Internal letter or symbol indicates use e.g. tu for tumours, vi for virus, c or ci for circulation
Eg Rituximab: Chimeric antibody used to treat tumours
262
What is bevacizumab?
Antibody that specifically inhibits VEGF so prevents angiogenesis
263
What is Rituximab?
Anti CD20 antibody. Against B cells
| Used in lymphomas, leukaemia, autoimmune disorders
264
What is tamoxifen?
Oestrogen antagonist used in breast cancer treatment
265
What is Anastrozole?
Aromatase inhibitor used hormone in post menopausal oestrogen sensitive breast cancer
266
What is leuprolide?
GnRH agonist, inhibits LH and therefore testosterone
| Used to treat prostate cancer
267
Why is granulocyte-colony stimulating factor given in some chemotherapy regimens?
Injections given in some chemo regimen to boost neutrophil count to reduce risk of neutropenic sepsis
268
How can chemo lead to nausea and vomiting?
Drug stimulates enterochromaffin cells of the GI system which leads to serotonin release. This stimulates the vagus nerve which signals to the chemoreceptor trigger zone which then triggers the vomiting centre. This leads to salivation, increased respiratory rate and pharyngeal, GI and abdominal muscle contractions
269
What is Tumour Lysis Syndrome?
Occurs due to rapid cell lysis & large amounts of cell metabolites in blood
Seen usually in leukemia/lymphoma/bulky small-cell solid cancers within 12-48hrs of starting chemo, lead to acute renal failure, cardiac arrest and death
270
Which group of chemotherapy drugs can lead to irreversible heart failure?
Anthracyclines
271
What is hand food syndrome?
Also called palmar plantar erythrodyesthesia
Side effect of some chemo
Causes redness, swelling, paresthesia and pain on palms of feet and hands
Graded 1-3
272
What is Concurrent/synchronous chemoradiotherapy?
Chemotherapy or targeted agents act as radiosensitiser, increasing efficacy of radiation
Chemo drug is given at a lower dose than if it was used alone
specifically to mop up disease
Commonly used chemo drugs for radiosensitiser purpose: cisplatin 5FU/capecitabine, mitomycin, cetuximab
273
How do endocrine/ hormone therapies work to treat cancer?
Slow or stop the growth of hormone-sensitive tumours
| Act by either preventing hormone production or interfering with action of the hormone
274
Why might a bilateral orchidectomy be used in prostate cancer?
Stunts prostate cancer growth as it will reduce testosterone levels
275
What is an Antibody-Drug Conjugate?
Very toxic chemo/radioactive substance, packaged in an
antibody shell that recognises only cancer target
Binds to tumour cell, gets taken up, toxin gets released only inside the target cell, causing death
Vast majority of normal healthy cells gets no damage
276
What are some side effects of targeted therapy for cancer?
Skin problems (rash, dry skin, nail changes), EGFR-related, Cetuximab
Diarrhoea
Blood clot (thrombosis) and wound healing, VEGF-related, Bevacizumab
Hypertension, VEGF-related, Bevacizumab
Gastrointestinal perforation, VEGF-related
277
What is Ipilimumab?
Anti-CTLA4 antibody used to treat melanoma
CD8 T cells lead to cellular immune attack on tumour antigens
CTLA4 is the off switch in this, block this CTLA4 off switch, T-cell will do its job again and attack tumour cells/antigen
278
What is Nivolumab?
Anti-PD1/PDL1 used in melanoma, lung Ca
PD-1 dampens anti tumor immunity, and cancer cells have hijacked this system. Anti–PD-1 drug selectively blocks PD1, thereby restoring T-cell anti tumor function
279
What are some common sites for cancer metastasis?
```
Brain
Lungs
Lymph nodes
Liver
Bone
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280
How do prostatic vertebral metastasis appear on radiological imaging?
Metastases are either osteoblastic/sclerotic or osteolytic
Prostate cancer has a primarily osteosclerotic pheontype
On x-ray, sclerotic lesions will be white
On CT scan sclerotic lesions appear hyperdense and irregular but are unlikely to extend beyond the vertebrae
On MRI the signal intensity of the metastatic deposits will vary according to the degree of mineralisation
281
What clinical features of spinal compression may be present with bony metastases?
Lumbar vertebral lesions have the potential to cause problems in the cauda equina
Acute onset lower back pain, localised tenderness, nocturnal,
unremitting pain, sciatica type pain, muscular weakness, abnormality in bladder emptying
282
How can a vertebral metastasis cause spinal cord compression?
Almost all metastatic spinal cord compressions are caused by an epidural compression from a tumour or a bony fragment from the collapsed vertebra affected by the metastasis
283
How urgently would the symptoms of spinal cord compression need to be treated if they manifested? Why?
Urgently, if delayed functionality would be lost permanently
284
What is CTLA4 and what does it do?
Immune checkpoint which down regulates the immune system
| On surface of T cells and acts as an off switch when bound to APCs
285
Name some check point inhibitor drugs and describe their mechanism of action
Anti-CTLA-4: Ipilimumab
PD-1 inhibiting antibodies: nivolumab
Up-regulate T cell activation
T cell proliferation
286
Name some side effects of check point inhibitor drugs
Dermatologic - rash
Gastrointestinal- colitis
Hepatic - hepatitis
Endocrine - pituitary, thyroid and adrenal
287
What are check point inhibitors used for?
Metastatic melanoma
288
What is Lenalidomide used for? And how does it work?
Multiple myeloma, melanoma, myelodysplastic syndromes
Increases p21 expression
Prevents entry into cell cycle
Decreased angiogenesis by decreasing VEG-F
Decreased osteoclast formation
Decreased anti TNF
289
What are side effects of Lenalidomide?
Foetal risk (thalidomide analogue)
Haematological toxicity
Thromboembolism (venous and arterial)
