Week 10 Flashcards

(55 cards)

1
Q

Objectives of cancer treatment

A

Cure the patient (kill or remove all cancer cells)
Prolong patient survival (kill most cancer cells)
Palliate symptoms (kill some cancer cells)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Chemotherapy: clinical contexts

A

For advanced disease:
-where no other treatment exists
Adjuvant chemotherapy:
-systemic treatment following local radiotherapy or surgery
-to control microscopic metastases
Primary or neo-adjuvant chemotherapy:
-chemotherapy as initial therapy for locally advanced cancer
-to render it more amenable to subsequent surgery
-improve cosmesis/function
-to control micro metastasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Principles of chemotherapy

A

Cell cycle
G0 G1: microtubule inhibitors, topoisomerase inhibitors, alkylating agents
S: anti-metabolites, topoisomerase inhibitors
G2: platinum analogues
M: micro tubule inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Cell cycle specific drugs

A

Acts on cells in cell cycle and inhibits cell growth at specific phases
More effective against tumours with higher percentage of cell that are replicating

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Cell cycle non specific drugs

A

Acts on resting and cycling cells
Useful against tumours with low or high percentage of replicating cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Chemotherapy

A

Assumptions made in the use of cytotoxic chemotherapy:
-tumour growth proceeds exponentially independent of growth homeostasis but:
—a proportion are non dividing cells
—growth fraction may vary as a function of tumour size
-each dose results in the same proportional log kill but:
—proportional kill may also relate to growth fraction
—tumours are heterogeneous, and large tumours may be more likely to contain drug resistance clones
-intensity of dose influences outcome:
—cytotoxic drugs are given at close to the maximum tolerated dose
-different drugs have different kill properties

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Log-kill kinetics model

A

Every dose of chemo kills cells by fixed proportion
Between cancer cells can grow again
With time go down to zero cells, uncommon, mixed cell population

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Tumour kinetics

A

Gompertzian growth curve
Not until high number of cells is it clinically detected
Below that it’s a clinically undetectable tumour
Above that graph plateaus- death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Dose intensity

A

Norton-Simon. Hypothesis
-delivering treatments at a greater rate (“dose density”) could optimise chemotherapy efficacy
—minimising the regrowth of cancer between doses of therapy
—increase the cumulative cell kill
—achieving greater clinical benefit
Dose reductions for toxicity can reduce chance of cure
Dose delays enable fast growing micro metastases to recover

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Chemotherapy agents

A

Alkylating agents
Platinum agents
Antimetabolites
Topoisomerase inhibitors
Antimicrotubular agents
Other agents
Molecular targeted agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Alkylating agents

A

Diverse group of anti cancer agents
Covalently transfer alkyl groups to DNA bases
-base alkylation- monofunctional DNA adducts, subsequent processing or repair of these lesions leads to single strand breaks in the DNA/mispairing of nucleotides
-two bases are linked together by an alkylating agent forming cross bridges. Cross linking prevents DNA from being separated for DNA synthesis or transcription
Limited cell cycle specificity- binds directly to DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Examples alkylating agents

A

Cyclophosphamide
Ifosfamide
Mephalan
Chlorambucil

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Platinum agents

A

Discovered electric current delivered to bacterial culture via platinum electrodes led to inhibition of bacterial growth
Active compound found to be cisplatin
Bind covalently to purine DNA bases (N7 position)
Bifunctional intra strand crosslinks
Prevents DNA double strand from separating
Not S phase specific
Nephrotoxicity and resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Antimetabolites

A

Acts at level of DNA synthesis
Interfere with incorporation of nucleic acid bases
Purine or pyrimidine analogues:
-inhibits formation of normal nucleotides
-often inhibit enzymes essential for DNA and RNA synthesis
Prevent formation of reduced folate:
-essential for transfer of methyl groups in DNA synthesis
Usually S phase specific
Acts on cancer and normal cells that are dividing rapidly
-can cause significant bone marrow and GIT toxicity
No late carcinogenesis
-does not interact directly with DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Examples Antimetabolites

A

Purine Antimetabolites:
-fludarabine
-cladrabine
Pyrimidine Antimetabolites:
-5FU
-capecitabine
-cytosine arabinoside (ara-C)
-gemcitabine
Antifolates:
-methotrexate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Topoisomerase inhibitors

A

DNA topoisomerases: ubiquitous nuclear enzymes
Relax supercoiled double stranded DNA to allow DNA replication and RNA transcription
Topoisomerase I- single strand nicks
Topoisomerase II- double strand nicks
Swivelling of supercoiled DNA occurs at nicks followed by re-ligation to relive torsional strain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Topoisomerase I inhibitor

A

Bind to and stabilise the DNA-topoisomerase I adducts
Inhibits religation of DNA strands
Single strand breaks in DNA
Examples:
-camptothecin
-irinotecan
-topotecan

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Topoisomerase II inhibitors

A

Forms a complex with topoisomerase II after cleavage of DNA
Inhibits religation of DNA strands
Single and double strand breaks in DNA
Examples:
-etoposide
-anthracyclines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Antimicrotubular agents

A

Prevent spindle formation
-essential for sorting and moving of chromosomes following replication at end of mitosis
Vinca alkaloids:
-vincristine
-vinblastine
-vinorelbine
Binds to tubulin, preventing polymerisation of microtubules
-inhibits cell cycle progression
Taxanes: paclitaxel, docetaxel
-binds to tubulin (different site to vinca alkaloids)
—prevents microtubular disassembly
-disrupts normal microtubule dynamics that’s required for cell divisions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Combination chemotherapy

A

Provides maximum cell kill within the range of toxicity that can be tolerated for each drug
Provides a broader range of coverage of resistant cells in a heterogeneous tumour population
Prevents or slows the development of drug resistant cells
Select cytotoxic drugs:
-with different mechanisms of action
-with different dose limiting toxicities to minimise damage to any one organ system
-in optimum dose and schedule
-with minimum interval between cycles
-monitoring response, performance status and toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Toxicity

A

Low therapeutic index
Toxicity to normal cells is major limiting factor
Careful dose calculation
-body surface area or derived from renal function
-individual dose adjustment based on prior dose toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

‘Reversible’ chemotherapy toxicities

A

Affects rapidly dividing cells:
-bone marrow- myelosuppression
-GIT- mucositis, diarrhoea
-hair follicles- alopecia
-germinal epithelium
-skin
NB ‘reversibility’ reflects compartment repopulation by recruitment of resting stem cells and this dictates time for recovery between treatment cycles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

‘Irreversible’ cumulative toxicities

A

Target slow growing cells:
-kidney
-nerves
-heart
-lung
These effects probably reflect the individual physicochemical properties of different classes of drugs
Dictate maximum safe cumulative exposure
Monitor and stop treatment if toxicity too severe

24
Q

Assessment of response

A

Stable response RECIST:
-<30% decrease
-<20% increase
-in sum of defined measurable disease (unidimentional)

Disease progression:
->20% increases in sum of all measurable lesions or new lesions

25
Response to chemotherapy: what it really means
Complete response CR: -prerequisite (but not sufficient) for cure -implications for improved survival Partial response PR: -palliative value only offset by drug toxicity effects -more modest impact on survival Stable response: -any impact on survival limited to conscious ie non toxic, therapy Quality of response may be defined by: -performance status -quality of life measurements -relapse- free survival from time all treatment discontinued
26
Hallmarks of cancer
Self sufficiency in growth signals Insensitivity to anti growth signals Tissue invasion and metastasis Limitless replicative potential Sustained angiogenesis Evading apoptosis
27
New signal transduction inhibitors
Growth factor antibodies: -bevacizumab anti VEGF Growth factor receptor antibodies: -trastuzumab anti HER2 -cetuximab anti HER1 Receptor antagonists: -imatinib, gefitinib, erlotinib
28
Selection of targets for the development of novel cancer drugs
Mutant oncogene products commonly found in tumours but not in normal tissues Tumour induced alterations of the micro environment necessary for cancer progression (eg angiogenesis) Must have a causal role in cancer development Genetics and biology must be well established Suitable for in vitro based assays Suitable for pharmacological intervention
29
Targeted drugs, chemotherapy
Targeted drugs: -target abnormalities typical of cancer cells -act selectively against cancer cells -limited toxicity -often orally available -chronic treatment may control cancer for a long time Chemotherapy: -targets common cell growth mechanisms -equally affects normal and cancer cells -often very toxic -usually given IV -given only for a limited number of cycles (6-10)
30
Radiotherapy
RT is the use of ionising radiation to treat tumours Key discoveries in late 19th century- Röntgen and becquerel-discovery of X-rays and demonstrated the spontaneous emission of nuclear radioactivity Marie curie- discovery of radium and polonium working with Pierre curie and becquerel Remains the principle non surgical cancer treatment
31
X-rays
Electrons are accelerated by a potential difference (voltage) across a vacuum when the e-hit a target x rays are produced. The penetrating power of an X-ray is proportional to V Energy of beams usually described in terms of generating voltage eg 250kV, 5MV, 10MV etc Radiotherapy dose measured in gray Gy=1J/kg Radiation exposure= dose in gray x biological conversion factor= sievert Sv
32
Direct and indirect interaction
Direct action: electron interacts with DNA directly Indirect action: electron interacts with a water molecules to produce hydroxyl radical which produces damage to the DNA
33
DNA damage
Double strand breaks lethal damage Single strand breaks Potentially lethal damage Sublethal damage
34
Oxygen effect
Oxygen actually required shortly after irradiation at between 2us and 5ms Oxygen acts to “fix” radiation damage between free radicals
35
Basic radiobiology
Repair Reoxygenation Reassortment or redistribution Repopulation Radio sensitivity
36
Types of radiotherapy
External beam Brachytherapy Radioactive isotopes
37
Role of radiotherapy
Radical: -first definitive treatment eg head and neck cancer, prostate cancer -preoperatively eg rectal cancer, oesophageal cancer -adjuvant eg breast cancer Palliative: -high dose palliation -local control -symptom control
38
UK wide standard schedules
Worked out empirically initially More recently tested in the context of national phase 3 studies eg start A and B in breast cancer, HD trials in Hodgkin’s lymphoma
39
Clinical delivery of radiotherapy
Generally given as series of daily treatments called fractions Typical schedules Radical 66Gy/33fractions/6.5weeks. 55Gy/20fractions/4weeks Palliative: 8Gy/1 fraction. 30Gy/10fractions/2week
40
Side effects
Acute: -fatigue, nausea, dermatitis, mucositis -problems with eating/drinking, communicating, pain/mucus Late: -due to scarring -puckering/mishapen breasts -in oesophageal- problems with lung function -bones more fragile increased risk of fractures
41
Organs at risk
Dependent on dose per fraction as well as total dose Tolerance of different organs to radiotherapy -lens -6Gy across a course of radical radiotherapy -spinal cord 44Gy in 2 Gy fractions -brachial plexus 50Gy in 2 Gy fractions -kidney -lungs -heart
42
Volumes
GTV: gross tumour volume: size cancer after imaging/biopsies CTV: clinical target volume: takes into account any microscopic spread of the tumour that we cant see via imaging/biopsies PTV: planning target volume (95%-107% ICRU 50 definition) radiotherapy not always 100% precise Field edge: 50% penumbra
43
Superficial radiotherapy- KV and electrons
Used for skin cancers (BCC, SCC, skin lymphoma) Clinical mark up Custom made lead cut out or end plate to shape field Margins- KV versus electrons
44
Bracytherapy internal radiotherapy
Cervix and endometrium- intrauterine or vaginal stock Implanted seeds- prostate
45
Radioisotopes
I131 -hyperthyroidism -thyroid cancer
46
Megavoltage photons
Otherwise known as external beam Makes up majority of RT Simple fields, conformal volumes, IMRT/tomo, SABR and SRS
47
Acute toxicity
Tiredness Skin reaction -erythema -moist desquamation especially infra-mammary fold Breast discomfort Nausea rare
48
Late toxicity
Chest wall pain- costochondritis Rib fracture Pneumonitis- lung volume Lymphoedema -arm -breast Brachial plexus injury- field matching Cardiac- rare with modern RT Second malignancy- contralateral breast:avoid splash
49
RT planning scan
Immobilisation -breast board -arms above head into arm rests DIBH -CT in free breath and DIBH Surface guided RT with AlignRT not tattooed Clinician contours tumour bed and creates tumour bed PTV-surgical clips and surgical changes Places beam to cover breast tissue
50
Treatment delivery
Linac Around 10 minutes of which 2 minutes is the actual treatment time On treatment review to manage toxicity
51
Palliative radiotherapy
Locally advanced disease Bone metastases Soft tissue eg lymphadenopathy, skin metastases Cerebral metastases -WBRT and SRS
52
Oligometastatic disease
1 to 3 extra cranial metastases Maximum size 4-5cm SABR UK CORE study
53
Bone metastases
Pain relief- single fraction Pathological fracture-actual or pending -surgical fixation especially weight bearing areas with post operative RT Spinal cord compression -oncology emergency -surgical decompression, stabilisation and RT -primary RT
54
Cerebral metastases
Solitary- consider surgery Solitary- fully resected- observation vs whole brain RT Role for SRS Selecting patients for whole brain RT -response to Dexamethasone -performance status RT technique -lateral fields -dose: 20Gy in 5 fractions -Hippocampal sparing- study
55
Limitations of radiotherapy
Volume of therapy limited by normal tissue tolerance Disease outside treated volume will not be treated Some tumours are not sufficiently radio sensitive to be eradicated but safe RT doses eg glioblastoma Normal tissue tolerance precludes radical treatment for local recurrence