1.8 Radiotherapy fractionation Flashcards
What is Sublethal Damage?
Caused by indirect effect of radiation
- Damage not sufficient to cause death
- Damage that can be repaired before lethal chromosome aberrations occur
- Curve on the cell survival graph
What is lethal damage?
direct effect of high LET radiation
- Damage sufficient to cause cell death at next mitosis
- Not repairable or reversible
- Leads to clonogenic death
What is potentially lethal damage?
An experimental finding in petri dish.
- Sufficient to cause death
- Can be repair in the right situation e.g. if mitosis is delayed
- Cells can survive if maintained in a non-growth state
Not really any clinical relevence
What are the 5 R factors in fractionated radiotherapy?
- Repair - sublethal damage is repaired in normal cells and tumours, differences in repair rate can be useful
- Repopulation - between fractions
- Reoxygenation - fractionation allows time for tumour cells to die which improves oxygenation to the remainin g
- Redistribution - the distribution of cells in each stage of the cell cycle has time to change with each fraction
- Radiosensitivity
How does fractionation increase survival of normal tissues?
- Repair half time for late responding tissues is 3-6 hours so gives chance to repair
- Reduced late toxicity
However, could lead to reduced probabiliy of tumour control
What are the clinical implications of Sub Lethal Damage Repair?
- Need at least 6 hours between fractions to ensure repair is able to be completed in late responding normal tissues
- Tissues that are better able to do SLDR are more sensitive to fractionation (get more benefit from fractionation()
What is Sub Lethal Damage Repair?
Recovery of sublethally damaged cells between fractions before lethal chromosome abberations can occur
What does fractionation do to the late responding curve?
Flattens the curve
Which stages in the cell cycle are Radiosensitive and why?
G2 and M
Mitosis imminent
Which stage of the cell cycle is radioresistant and why?
Late S phase
DNA repplication has already occured and repair proteins are active at this point
How does fractionation relate to the cell cycle?
The cells have time to move from radioresistant phase to more radiosensitive phase
What does fractionation result in? What is it’s goal?
- Spare normal tissue
- Increase tumour damage due to:
- Reoxygenation
- Redistribution/reassortment of cells from radioresistant phase to radiosensitive phase
What is Repopulation in tumour cells?
Proliferation of surviving tumour cells after radiotherapy
How does length of treatment course affect repopulation in tumours?
Increased risk with prolonged RT schedules (>3-4 weeks) - survivng tumour accelerate repopulation to compensate for loss of cells making treatment less effective
How does treatment scheduling affect repopulation?
Fractionation over several weeks aims to exploit the difference in repopulation rates between tumour and normal tissues
How do delays in radiotherapy treatments impact effectiveness?
With delays the liklihood that the tumour has time to repopulate increases
What tissues and tumours repopulate quickly?
Early responding normal tissues
Tumours e.g. small and NSCLC, H&N, cervical, oesophageal, anal, bladder
What is Tdelay?
Delay time from first day of treatment before the onset of accelerated repopulation
e.g. 28 days for H+N SCC
What is K(Gy/day)?
approximate dose requried to offset one days worth of repopulation
K is inversley proportional to tumour radiosensitibity and tumour doubling time
If tumour is radioresistant and fast growing will need high K
What is Accelerated repopulation?
Rate of tumour cell division increases, often after around 3-4 weeks (lag-phase) of radiotherapy
This can signficiantly impact treatment efficacy
How does accelerated repopulation occur within the cells?
EGFR is associated with radioresistance
Radiotherapy can activate EGFR
EGFR activates: PI2K-AKT, ERK, and JAK/STAT
These increase cell survival
How is accelerated repopulation overcome?
With accelerated radiotherapy - deliver the total dose over a shorter period, to minimise time tumour cells have to repopulate
What are the mechanisms that allow for accelerated repopulation?
- Radiation kills some of the clonogenic cells in the tumour, surviving clonogenic cells are stimualted to divide more rapidly.
- Fewer cells competing for resources, so conditions are favourable for the surviving cells to proliferate
- Damaged and dying tumour cells release cytokines and mitogenic signals
- ‘Survival of the fittest’ - cells that are naturally more radioresistant are more likely to sruvive and so cells with this trait proliferate
- Tumour stem cells are more likely to survive RT due to their efficeint repair mechanisms
What needs to be avoided in RT treatment to reduce chance of accelerated repopulation?
- Longer treatments may reduce probability of tumour control
- Interruptions need to be avoided
However, reducing treatment duration could increase liklihood of acute toxicity
How does fractionation affect the cell survival curve?
The shoulder of the curve reflects the capacity of cells to repair sub-lethal damage
Fractionation increases the shoulder of the cell survival curve
What does fractionation do to the cell survival curve?
Increases the ‘shoulder’
How does fractionation help normal tissue?
- Increases cell repair
- Increases repopulation
How does fractionation kill tumour cells?
- Allows time for reoxygenation
- Increased redistribution of cells to radiosensitive phase
How is dose affected by fractionation?
An increased dose is required to have the same radiobiological effects
e.g.
16Gy in 1 fraction will kill all the cells (but the normal tissue won’t be able to recover)
= 22Gy in 2#
= 34Gy in 5#
= 45Gy in 10#
= 60Gy in 20#
What does the statement “Effective dose-survival curve for multi-fractionation = exponential function of dose” mean in radiotherapy?
In multi-fractionated radiotherapy, the cumulative cell survival decreases exponentially with the total dose
aka
In tumours multiple fractions exponentially decreases tumour cell survival
In normal tissue sub-lethal damage is repaired between fractions
What is the Linear Quadratic Model?
A model that describes how cells respond to radiation
What is the equation for the LQ model?
What is αD - the linear component of the linear quadratic model?
- Directly proportional to dose (linear)
- Shoulder width reflects sublethal damage
- Reflects cell death caused by single radiation event causing a ‘double hit’ e.g. a single photon causing lethal damage to both DNA strands with one hit
- Dominates at low radiotherapy doses
- Represents direct, irreperable DNA damage - radiosensitivity
- Important in high LET radiation
What is βD^2 - the quadratic component of the linear quadratic model?
- Directly proportional to dose squared (exponential)
- Reflects cell death caused by ‘two single hits’ independent radiation events which interact e.g. 2 different photons which cause damage that combines to kill the cell
- Dominates at higher doses
- Represents damage that requires multiple hits to become lethal - can repair
- Important in low LET radiation
What is SF2?
Surviving fraction at 2Gy
if SF2 low then tissue is radiosensitive
What is Dq?
Quality threshold dose - the dose at which extrapolation of the exponential portion of the cell survival curve (at high) doses, would intersect the y axis at 1 (100% survival)
Measures the width of the shoulder of the survival curve - reflects the cell’s ability to accumulate and and repair SLD
Larger Dq = bigger shoulder = cells better able to repair SLD and survive
What is D0?
Dose required to give 1 lethal event per cell to reduce SF to 0.37 of original value
What is mean activation dose?
Area under the radiation survival curve
What is the α/β ratio?
The dose at which the number of cells killed by linear (radiosensitivity) and quadratic components (repair) are equal
Measure of intrinsic radiosensitivity
when αD=βD2
Determines how bendy the curve is - the lower the α/β ratio the more curved
At what dose is α/β ratio high?
> 10Gy - rapidly proliferating tumours
At what dose is α/β ratio low?
2-3Gy - late-responding normal tissues
What type of cell killing occurs in high α/β ratio?
- Linear
- Single-hit damage dominates
What type of cell killing occurs in low α/β ratio?
- Quadratic
- Accumulation of sublethal injuries
How sensitive are cells with high α/β ratio to radiotherapy?
Very sensitivive
How sensitive are cells with low α/β ratio to radiotherapy?
Not very sensitive
Which α/β ratio cells can repair the damage?
Low
What are the shapes of the graphs for high and low α/β ratio?
High = linear
Low = curved/parabolic
What does ‘sensitive’ to fractionation mean?
The cancer cells are more sensitive to changes in fractionation, this means that small fractions may not be an advantage
Which α/β ratio type (high or low) benefits from very fractionated radiotherapy?
High α/β ratio
Which α/β ratio type (high or low) benefits from fewer fractions of radiotherapy?
Low α/β ratio
Increasing the number of fractions (with smaller doses) allows time for low α/β ratio tumours to recover and therefore reduces cell killing
Why do high α/β ratio tumours benefit from increased fractionation?
Reduces normal tissue toxicity without signficiantly impairing tumoru lethality
Which α/β ratio type (high or low) is more at risk of accelerated repopulation?
High α/β ratio - if treatment is prolonged accelerate repopulation can occur
Can overcome this with increasing total dose e.g. hyperfractionation or shortening treatment time e.g. accelerated schedule
A tumour with a high α/β ratio is most sensitive to…
Overall treatment time
(but not fractionation)
How is low α/β ratio affected by changes to dose and treatment time?
Affected by dose
but
not affected by overall treatement time
Which type of α/β ratio (high or low) tumour control is more impaired by treatment breaks?
High α/β ratio
What type of normal tissues have high α/β ratio?
Early responding
What type of normal tissues have low α/β ratio?
Late responding
What toxicities are seen in tissues/tumours with high α/β ratio?
Acute toxicities
e.g. skin damage, mucositis, lymphocyte reduction
What toxicities are seen in low α/β ratio?
Late toxicities
e.g. lung fibrosis, cardiomyopathy, nephropathy
What tumour types have high α/β ratio?
Most tumours
head + neck 10.5
lung 8.2
oesophagus 4.9
cervix, bladder, lymphoma, testicular
What is the formula for BED?
n = number of fractions
d = dose per fraction
α/β = sensitivity of tissue (from the LQM)
What is the formula for EQD?
n = number of fractions
d = dose per fraction
x = reference fose per fraction - usually 2Gy per fraction so usually = 2
What is the formula for RBE?
