Week 10 Flashcards

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)

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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

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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

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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

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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

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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

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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

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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

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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

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10
Q

Chemotherapy agents

A

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

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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

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12
Q

Examples alkylating agents

A

Cyclophosphamide
Ifosfamide
Mephalan
Chlorambucil

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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

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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

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15
Q

Examples Antimetabolites

A

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

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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

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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

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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

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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

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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

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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

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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

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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
Q

Response to chemotherapy: what it really means

A

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
Q

Hallmarks of cancer

A

Self sufficiency in growth signals
Insensitivity to anti growth signals
Tissue invasion and metastasis
Limitless replicative potential
Sustained angiogenesis
Evading apoptosis

27
Q

New signal transduction inhibitors

A

Growth factor antibodies:
-bevacizumab anti VEGF
Growth factor receptor antibodies:
-trastuzumab anti HER2
-cetuximab anti HER1
Receptor antagonists:
-imatinib, gefitinib, erlotinib

28
Q

Selection of targets for the development of novel cancer drugs

A

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
Q

Targeted drugs, chemotherapy

A

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
Q

Radiotherapy

A

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
Q

X-rays

A

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
Q

Direct and indirect interaction

A

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
Q

DNA damage

A

Double strand breaks lethal damage
Single strand breaks Potentially lethal damage
Sublethal damage

34
Q

Oxygen effect

A

Oxygen actually required shortly after irradiation at between 2us and 5ms
Oxygen acts to “fix” radiation damage between free radicals

35
Q

Basic radiobiology

A

Repair
Reoxygenation
Reassortment or redistribution
Repopulation
Radio sensitivity

36
Q

Types of radiotherapy

A

External beam
Brachytherapy
Radioactive isotopes

37
Q

Role of radiotherapy

A

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
Q

UK wide standard schedules

A

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
Q

Clinical delivery of radiotherapy

A

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
Q

Side effects

A

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
Q

Organs at risk

A

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
Q

Volumes

A

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
Q

Superficial radiotherapy- KV and electrons

A

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
Q

Bracytherapy internal radiotherapy

A

Cervix and endometrium- intrauterine or vaginal stock
Implanted seeds- prostate

45
Q

Radioisotopes

A

I131
-hyperthyroidism
-thyroid cancer

46
Q

Megavoltage photons

A

Otherwise known as external beam
Makes up majority of RT
Simple fields, conformal volumes, IMRT/tomo, SABR and SRS

47
Q

Acute toxicity

A

Tiredness
Skin reaction
-erythema
-moist desquamation especially infra-mammary fold
Breast discomfort
Nausea rare

48
Q

Late toxicity

A

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
Q

RT planning scan

A

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
Q

Treatment delivery

A

Linac
Around 10 minutes of which 2 minutes is the actual treatment time
On treatment review to manage toxicity

51
Q

Palliative radiotherapy

A

Locally advanced disease
Bone metastases
Soft tissue eg lymphadenopathy, skin metastases
Cerebral metastases
-WBRT and SRS

52
Q

Oligometastatic disease

A

1 to 3 extra cranial metastases
Maximum size 4-5cm
SABR
UK CORE study

53
Q

Bone metastases

A

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
Q

Cerebral metastases

A

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
Q

Limitations of radiotherapy

A

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