Radiobio part 4 Flashcards
Lethal damage
Hits to critical sites/targets are sufficient to cause death at the next mitosis.
Irreversible & irrepairable damage leads to clonogenic death.
Direct effect of High LET radiation
Sublethal damage
hits to critical sites/targets are not sufficient to cause “death”.
Repairable if given time, nutrients & o2 unless additional radiation dose is given (inc further SLD).
corresponds to shoulder gradient of survival curve.
Indirect effect of radiation /low LET radiation.
A potential difference between normal/cancer cells to be exploited. Normal cells usually have intact repair pathways.
Potentially Lethal Damage
Hits are sufficient to cause death but may be repairable if mitosis is delayed by sub optimal growth conditions, may become fatal if mis-repair occurs.
Damage that can be repaired under certain conditions such as the presence of favourable environmental features or cell cycle arrest.
A potential difference between normal/cancer cells to be exploited. Cancer cells have defective cell cycle controls and may not be able to halt progression through the cycle.
Early Repair
Time to onset not influenced by extent of damage
Influenced by overall treatment time (longer = better)
Typically transient (but consequential damage may occur)
Late Repair
Time to onset IS influenced by extent of damage
(more damage = shorter latency)
Not influenced by overall treatment time
Typically progresses with time and is permanent (some compensation may occur)
Describe effect of cell cycle on radiation sensitivity
Radiosensitivity is cell cycle dependent
- Cells in G2/M phase are most radiosensitive due to imminent mitosis.
- S phase is most radioresistant as by this point DNA has been copied and so cells have a template which can be used for HR repair.
Cells in G1 do not have a template and so will depend on NHEJ
Dividing dose into several fractions spares normal tissues (because repair of sublethal damage between dose fractions and repopulation of cells if time is long enough). Tumour damage is increased because of reoxygenation & redistribution of cells into radiosensitive phases of cell cycle
Repopulation
= an increase in the surviving fraction resulting from cell division during fractionation of radiotherapy
If interval between fractions is from 10-12 hours because this exceeds the length of the cell cycle in these rapidly proliferating cells. Leads to regrowth of normal and malignant cells - counteracting the cell loss from ongoing treatment.
In some cases repopulation can exceed the cell kill induced by radiation leading to improvement of early effects during treatment or alternatively inability cure a malignacy.
Accelerated repopulation
Known that RT can directly activate EGFR
EGFR then activates PI3k-AKT, ERK & JAK/STAT pathways leading to cell survival & proliferation. Hence there is a time presure to complete RT treatment once started.
Cell survival curve as the basis for fractionation
Increasing the no. of fractions increases the “shoulders” of the cell survival curve.
This leads to an increase in the dose required to have the same RBE.
Cell survival curve shows how fractionation can increase:
normal tissue repair from sublethal damage, normal tissue repopulation, tumour cell reoxygenation, tumour cell cycle redistribution.
Dose fractionation increases the therapeutic window between normal and tumour cell kill.
Prolonged treatment times spares early reactions and allows tumour reoxygenation, but if too long can enable tumour repopulation.
Cellular sensitivity
- a
- B
- SF2
alpha = indicates sensitivity to low doses of radiation
b = indicates sensitivity to high doses of radiation
SF2 = surviving fraction at a dose of 2Gy.
- is a clinically useful assessment of sensitivity
- Does not predict SF2 at other doses
- If SF2 is low - suggests RADIOSENSITIVITY
D0 = the dose required to give 1 lethal event per cell/to reduce the surviving fraction down to 0.37 of its original value.
Mean inactivation dose= relates to the clinical radiosensitivity of a specific tumour and has a set specific value.
A/B ratio for tumours & acute and late responding tissues
Typical a/b ratio for early (acute) repsonding normal tissues (e.g bone marrow) is 10Gy
Typical a/b ratio for late responding normal tissues (e.g. lens of eye) is 3GY
Exception to this is brain & spinal cord which is around 2 Gy.
Typical a/b ratio for most tumours is around 10 Gy.
a/b ratio is due to the intrinisc properties of the tissue i.e. less proliferation and more time in G0/G1 in late responding normal tissues (more NHEJ)
Fractionation spares late responding tissues = small difference in dose can have major biologiacl effects.
Early adverse effects are relatively insensitive to fraction size.
Late adverse effects ARE sensitive to fraction size.
Tumour cure is limited by late toxicity.
- Late normal effects have low a/b ratios (3Gy) but most tumours have high a/b ratios (10Gy)
- Radical treatments are given in 2Gy fractions to exploit this fact
A/B does not define radiosensitivity.
BED
= theoretical biological total dose that produces the same effect (e.g. level of cell kill) - if the treatment were given as an infinite no. of very small dose fractions.
Can compare the effects of different dose regimens on the tumour and normal tissue.
BED = D [1 + d/(a/b)]
D = total dose
d = dose per faction
BED = total dose x relative dose effectiveness - repopulation factor (K x (T-T delay))
T = overall treatment time
EQD2
= equivalent dose in 2Gy Fractions
EQD2 = D [( d + a/b) / (2 + a/b) ]
Fractionation dosing
@2Gy there is more effect on tumour than late responding tissue
@4Gy this flips over so more effect on late responding tissue than the tumour
As the dose per fraction is increased there is more of a difference between tumour and late responding tissue (curves diverge)
2Gy is a compromise between giving the treatment in a reasonable amount of time and for each fraction of treatment to have more of an effect on tumour than the late responding normal tissue.
hence use 2Gy/fraction for tumours with high A/b ration - case for most tumours.
Exception- Breast (4.5Gy), prostate (1.5Gy) - they have low a/b ratios so sensitive to changes in dose per fraction as the surrounding tissue. Using 2Gy per fraction would spare the tumour as much as the normal tissues.
Time interval between fractions
Multiple fractions per day associated with increased biological effect unless the interval is long enough to allow full repair
Recovery T1/2 is approx 4 hours, therefore 50% recovery in 4 hours and 75% in 8 hours, recovery is not complete by 8 hours
Fractionation
