Unit 2 - Traditional Therapies Flashcards
Who first had the idea of radiation therapy in cancer and who first showed that it could be used after surgery to minimise the radicalness of the surgery
Emil Grubbe
Fisher and Veronesi
What radioactive molecules were among the first two be used in cancer treatment?
Radon gas and radium capsules
Describe the history of chemotherapies
- Originally with Paracelsus in the 1500’s use of arsenic, lead and mercury (see also Pare’s La method)
- Paul Ehrilich 1st researcher looking at selectivity in drugs in many diseases using dyes and postulated the magic bullet idea
- Goodman and Gilman -> toxic mustard gasses from WWI to be used in lymphoma/leukaemia and went onto develop cyclophosphamide
- Sidney Faber rationalised use of anti-folates like aminopterin (block dihydrofolate reductase in nucleotide synthesis) -> many similar molecules work in a similar way like methotrexate and 5-FU
Who were the first people to use combinations of chemotherapies – what agents did this include?
Frei and Freireich – VAMP regime (60’s/70’s) – Vincristine, amethopterin, 6-mercaptropurine and prednisone in childhood leukaemia
Who were the first people to look at adjuvant chemotherapy
Bonnadona and Fischer used 5-FU, methotrexate and cyclophosphamide in breast cancer to improve survival and prevent relapse -> lead to development of neoadjuvant too
What was the first discovered oncogene and who discovered it?
Ras and Robert Weinberg
What is brachytherapy and how does it differ to other kinds of radiotherapy?
Brachytherapy is where the radiation is placed inside the body!! Although patients can be radioactive after treatment, so may have to isolate after therapy!!
What proportion of cancer patients have radiotherapy?
About 50%, generally more for radical intent but some cases are associated with palliative care (pain reduction, to improve breathing etc and uses a lower dose)
Describe some ways in which the targeted area is minimised in radiotherapy (within about 2mm)
- Using imaging techniques like MRI/CT/RNI to ensure only the specific region is targeted like CT’s – often a radiation plan is produced using 3 planes around an isocentre
- Minimise patient movement via immobilisation devices such as those for the head and neck or thorax monitoring devices which may be used to stop treatment when there is too much movement.
- Can use multiple planes/fields to reduce dose reaching sensitive tissues
- Certain radioactive substance which are specific to tissue (e.g., I-131 in thyroid)
- Intensity modulated radiotherapy and multi-leaf collimation can help shape the beam to with different intensities to prevent off-target effects
Describe the two types of ways brachytherapy can be given and for each of these describe how some examples of how it is used?
Sealed – sits within capsule (Ir-192)
Generally quite mobile devices. Given via intercavitary (existing cavity – ovarian cancer), intraluminal (catheter through the nose ->oesophagus) and interstitial (in a body cavity via an applicator which is computer controlled– such a breast and prostate) requiring many incisions.
Unsealed – is in form of liquid or gas (I-131) and dissipates throughout the body
Radioactive isotope therapy (given via IV/orally) – isotope will generally accumulate in a certain tissue to minimise off-target effects – not recovered- therefore radioactive and may need to isolate/minimise contact.
External beam – delivered by linear accelerators (Co-60) – directed outside the body, usually combined with a CT scanner to avoid other organs (image quality not as good)
What type of beam energies are used in radiotherapy and where would they be used?
Kilovoltage – uses electronic beam energy
Superficial X-rays (90-150kv) – X-rays on or near body surface
Deep X-ray therapy – 150-300kv – higher energy and penetrate deeper ( a few cm’s) – vertebrate metastatic disease
Megavoltage (6-10MVs) via a linear accelerator (large structures) in X-rays and particles. Can be used for deeper tumours. Will also have imaging panels attached to aid accuracy as well as light to guide the rays!
What are the acute and chronic side-effects of radiotherapy treatment?
Acute – damage to skins like erythema and dry desquamation (given emollients)
Chronic – telangiectasia, lymphedema, alopecia, anaemia, organ damage
Related to the dose used, the field size. The target organ and fractionation
List two types of particle radiotherapy
Electron radiotherapy and proton radiotherapy (require large particle accelerator which is expensive x10 vs radiotherapy)
Discuss the relationship of energy of electron radiotherapy and its intensity at different distances.
Electrons produced by linear accelerator – energies between 6-20MeV – which each having higher intensities at greater distances of penetration. 75% at skin surfaces – rises to a peak (2-6cm) deep and then a sharp drop-off – minimises off-target effects!!
How may radiotherapy cause damage to non-tumorous cells?
The ionising radiation can result in DNA damage, primarily SS/DS breaks – the higher the dose the more damage. This will result in cell cycle arrest at G1/S and G2/M if this damage is not repaired ->apoptosis!!!
The patient may not see damage immediately as cells go through the cell cycle at different times/rates.
Rank the four stages of the cell cycle in terms of radiosensitivity
Most sensitive: mitosis , G1/2, S-phase
What is a therapeutic ratio?
The therapeutic index describe the difference in susceptibility of damage to target (tumour) cells compared to non-target cells at a given dose.
What are the three phases in a radiation event- describe each of these in detail?
Physical phase – very quick
Incoming photon interacts with orbital electrons – ionisation – and the photon is scattered to interact with another atom (Compton Scatter)
Chemical damage – within 1ms
Primary target is water, radiolysis results in ROS like hydroxyl free radical – SS/DB breaks and 8-Oxo-G
Biological phase – over longer periods (months)
Where the DNA damage can be (or not) repaired – this stage looks at the repair by enzymes or the subsequent cell cycle arrest/apoptosis – which can result in side-effects (anaemia/alopecia/lymphedema/erythema…)
What is the oxygen effect in radiotherapy?
The amount of oxygen present plays a significant role in the effectiveness of radiotherapy, decreasing amount decreases efficiency!!
This is because most DNA damage in radiotherapy which interact a free-radical which interacts with oxygen to form free-radical species (short half-life) – hence hypoxia will result in less of these species hence less direct damage to DNA.
A large proportion of tumours are actually hypoxic (can changes over time)– which means these regions will likely survive treatment and be able to allow tumour recurrence.
What ways can we enhance the oxygen enhancement ratio to aid radiotherapy?
- Supplying additional oxygen to the patient
- Improve patients own oxygen delivery (exercise/health)
- Monitor levels of haemoglobin to suspend treatment to ensure most effective efficacy – Cherenkov excited luminescence imaging
- Oxygen mimic drug (nitroimidazoles)
- Selectively targeting hypoxic cells via hypoxia activated prodrugs like mitomycin C
- Increase oxygen flow by oxygen carriers
- Target DNA repair pathway – 5-FU or ATR/Chk1 inhibitors in early development
- Vasodilation (nicotinamide)
- Anti-angiogenic agents
- Hyperbaric chambers
But if they will actually increase oxygen at permanent hypoxic areas may effect efficiency!! Onion peel model!! – But they may help to reduce the dose required to reduce impact on non-tumorous tissue
Using the 5R’s describe the impact of fractionation on radiotherapy results?
Radiosensitivity
Each cell has its own radiosensitivity – some cells are very radioresistant like melanoma so there is no point using it here. The amount of radiation per fraction and number of fractions is based on the radiosensitivity of the cells.
Reoxygenation
Increased oxygen concentration increases the susceptibility to radiation damage and will prevent recurrence due to (temporary) hypoxia – hence fractionation reduces this impact and increases the chances of ‘catching’ the tumour cells when they are not hypoxia (only temporary)
Reassortment
Efficacy also depends on the stage of the cell cycle, those in M-phase are more sensitive – hence like above – increased fractionation means that over the entire regime it is likely you will catch these cells in their most sensitive cell cycle state – again to prevent recurrence
Repopulation
The space between doses will allow tumours to proliferate and re-populate the tumour – meaning an increasing dose would then be required – which could be a disadvantage – this could be due to the enriched nutrient supply to these tumours. But normal tissue has more time to recover. Accelerated radiotherapy protocols can be used for some tumours with fast repopulation rates
Recovery
Where cells sustain sub-lethal damage, the longer period between radiotherapy can increase the chance of recovery and a higher dose is required.
In radiotherapy, what is the tolerance dose?
This is the maximum amount of radiation a tissue can receive before becoming permanently damaged – it depends how much of the organ is present in the radiation field (although shielding can sometimes reduce this). The TD is given as X/Y – X is the % probability of complication after Y years!!
What side-effects are most chemotherapies associated with and why?
Chemotherapies are usually associated with blocking certain stages of the cell cycle – of which all cells progress through. These agents preferentially target rapidly dividing cells, which will include tumour cells, but also other fast-dividing cells like red blood cells (anaemia), white blood cells (immune deficiency), gastrointestinal issues and hair loss.
What factors can influence the efficacy of a chemotherapy?
- Tumour cell burden
- Sensitivity – do they up-regulate MDR1 or other pro-survival genes (DNA repair for alkylating agents)
- Dose intensity
- Treatment schedule
- Proportion of tumour population that is actively dividing
- Location of the tumour (BBB)
What is the fractional kill hypothesis and why does this explain why chemotherapy is given in cycles?
At a given a proportion of tumour cells will be dividing – so only a few of the cells will be targeted by these agents – hence only a proportion of the tumour population will be killed (growth fraction) – also treatment schedule, dose intensity, sensitivity and tumour cell burden are important.
Therefore, sustained chemotherapy will mean that not all tumour cells will be killed and there are increased side-effects to the patient. Hence it is given in cycles.
This is a cycle of treatment and cessation for the normal cells (as well as some tumour cells) to recovery to maximise tumour cell death whilst minimising damage to normal cells!!
What does neoadjuvant chemotherapy mean?
That chemotherapy is given before surgery to shrink the tumour and perhaps make the surgery less complex.
