Presentation Radiation Protection in Radiotherapy.ppt

This presentation discusses radiation protection in radiotherapy, focusing on safety principles for patients, healthcare workers, and the public. It explains radiation risks, protective measures, international standards, and the importance of quality assurance in radiotherapy practice. Suitable for medical students, radiation therapists, medical physicists, and professionals in oncology.

1. Radiation Protection inRadiation Protection in
RadiotherapyRadiotherapy
Part 3Part 3
Biological EffectsBiological Effects
Lecture 2: High Doses in Radiation TherapyLecture 2: High Doses in Radiation Therapy
IAEA Training Material on Radiation Protection in Radiotherapy

2. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 2
OverviewOverview

Radiobiology is of great importance for Radiobiology is of great importance for
radiotherapy. It allows the optimization of radiotherapy. It allows the optimization of
a radiotherapy schedule for individual a radiotherapy schedule for individual
patients in regards to:patients in regards to:

Total dose and number of fractionsTotal dose and number of fractions

Overall time of the radiotherapy courseOverall time of the radiotherapy course

Tumour control probability (TCP) and normal Tumour control probability (TCP) and normal
tissue complication probability (NTCP)tissue complication probability (NTCP)

3. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 3
ObjectivesObjectives

To understand the radiobiological background To understand the radiobiological background
of radiotherapyof radiotherapy

To be familiar with the concepts of To be familiar with the concepts of tumour tumour
control probabilitycontrol probability and and normal tissue normal tissue
complication probabilitycomplication probability

To be aware of basic radiobiological models To be aware of basic radiobiological models
which can be used to describe the effects of which can be used to describe the effects of
radiation dose and fractionationradiation dose and fractionation

4. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 4
ContentsContents
1. Basic Radiobiology1. Basic Radiobiology
2. The linear quadratic model2. The linear quadratic model
3. The four ‘R’ s of radiotherapy 3. The four ‘R’ s of radiotherapy
4. Time and fractionation4. Time and fractionation

5. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 5
1. Basic Radiobiology1. Basic Radiobiology

The aim of radiotherapy is to kill tumor cells The aim of radiotherapy is to kill tumor cells
and spare normal tissuesand spare normal tissues

In external beam and brachytherapy one In external beam and brachytherapy one
inevitably delivers some dose to normal tissueinevitably delivers some dose to normal tissue
patient
tumor
Beam 3
Beam 2
Beam 1
Brachytherapy sources

6. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 6
Basic Radiobiology: Basic Radiobiology: targettarget

The aim of radiotherapy is to kill tumour cellsThe aim of radiotherapy is to kill tumour cells - they - they
may be in a bulk tumor, in draining lymph nodes may be in a bulk tumor, in draining lymph nodes
and/or in small microscopic spread.and/or in small microscopic spread.

Tumour radiobiology is complexTumour radiobiology is complex - the response - the response
depends not only on dose but also on individual depends not only on dose but also on individual
radiosensitivity, timing, fraction size, other agents radiosensitivity, timing, fraction size, other agents
given concurrently (given concurrently (e.g.e.g. chemotherapy), … chemotherapy), …

Several pathways to tumour sterilization existSeveral pathways to tumour sterilization exist ( (e.g.e.g.
mitotic cell death, apoptosis (= programmed cell mitotic cell death, apoptosis (= programmed cell
death), …)death), …)

7. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 7
Survival curvesSurvival curves

8. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 8
Radiobiology: Radiobiology: tumortumor

Irradiation kills cellsIrradiation kills cells

Different mechanisms of cell killDifferent mechanisms of cell kill

Different radio-sensitivity of different Different radio-sensitivity of different
tumourstumours

Reduction in size makes tumourReduction in size makes tumour

better oxygenatedbetter oxygenated

grow fastergrow faster

9. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 9
Radiobiology: Radiobiology:
micrometastasismicrometastasis
Tumours may spread first through Tumours may spread first through
adjacent tissues and lymph nodes adjacent tissues and lymph nodes
nearbynearby

Need to irradiate small deposits of Need to irradiate small deposits of
clonogenic cells earlyclonogenic cells early
Less dose required as each fraction of Less dose required as each fraction of
radiation reduces the number of cells by radiation reduces the number of cells by
a certain factora certain factor

10. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 10
The target in radiotherapyThe target in radiotherapy

The bulk tumourThe bulk tumour

may be able to distinguish may be able to distinguish
different parts of the tumour different parts of the tumour
in terms of radiosensitivity in terms of radiosensitivity
and clonogenic activityand clonogenic activity

Confirmed tumour spreadConfirmed tumour spread

Potential tumour spread Potential tumour spread

11. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 11
ReminderReminder

Palpable tumour (1cmPalpable tumour (1cm
33
) = 10) = 10
99
cells !!!cells !!!

Large mass (1kg) = 10Large mass (1kg) = 10
12 12
cells - need cells - need
three orders of magnitude more cell killthree orders of magnitude more cell kill

Microscopic tumour, micrometastasis = Microscopic tumour, micrometastasis =
around 10around 10
66
cell - cell -
need less doseneed less dose

12. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 12
Radiobiology: normal tissuesRadiobiology: normal tissues

Sparing of normal tissues is essential for Sparing of normal tissues is essential for
good therapeutic outcomegood therapeutic outcome

The radiobiology of normal tissues may be The radiobiology of normal tissues may be
even more complex as the one of tumours:even more complex as the one of tumours:

different organs respond differentlydifferent organs respond differently

there is a response of a cell organization there is a response of a cell organization
not just of a single cellnot just of a single cell

repair of damage is in general more repair of damage is in general more
importantimportant

13. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 13
Volume effectsVolume effects

The more normal tissue is irradiated in The more normal tissue is irradiated in
parallel organsparallel organs

the greater the pain for the patientthe greater the pain for the patient

the more chance that a whole organ failsthe more chance that a whole organ fails

Rule of thumb Rule of thumb - - the greater the volume the greater the volume
the smaller the dose should bethe smaller the dose should be

In serial organs even a small volume In serial organs even a small volume
irradiated beyond a threshold can lead irradiated beyond a threshold can lead
to whole organ failure (to whole organ failure (e.g.e.g. spinal cord) spinal cord)

14. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 14
Classification of radiation Classification of radiation
effects in normal tissueseffects in normal tissues

Early or acute Early or acute
reactionsreactions

Skin reddening, Skin reddening,
erythemaerythema

NauseaNausea

VomitingVomiting

TirednessTiredness

Occurs typically Occurs typically
during course of RT during course of RT
or within 3 monthsor within 3 months

Late reactionsLate reactions

TelangectesiaTelangectesia

Spinal cord injury, Spinal cord injury,
paralysisparalysis

FibrosisFibrosis

FistulasFistulas

Occurs later than 6 Occurs later than 6
months after months after
irradiationirradiation

15. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 15
Classification of radiation Classification of radiation
effects in normal tissueseffects in normal tissues

Early or acute Early or acute
reactionsreactions

Late reactionsLate reactions
Late effects can be a result
of severe early reactions:
consequential radiation injury

16. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 16
Radiobiological modelsRadiobiological models

Many models existMany models exist

Based on clinical experience, cell Based on clinical experience, cell
experiments or just the beauty or simplicity of experiments or just the beauty or simplicity of
the mathematicsthe mathematics

One of the simplest and most used is the so One of the simplest and most used is the so
called “linear quadratic” or “alpha/beta” model called “linear quadratic” or “alpha/beta” model
developed and modified by Thames, Withers, developed and modified by Thames, Withers,
Dale, Fowler and many others.Dale, Fowler and many others.

17. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 17
2. The Linear 2. The Linear
Quadratic ModelQuadratic Model

Cell survival:Cell survival:
single fraction: S = exp(-(αD + βD
2
))
(n fractions of size d: S = exp(- n (αd + βd
2
))

Biological effect:Biological effect:
E = - ln S = αD + βD
2
E = n (αd + βd
2
) = nd (α + βd) = D (α + βd)

18. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 18
Biological effectivenessBiological effectiveness
E/α = BED = (1 + d / (α/β)) * D = RE * D
BED = biologically effective dose, the dose
which would be required for a certain effect
at infinitesimally small dose rate (no beta
kill)
RE = relative effectiveness

19. Quick question???Quick question???
What is the physical unit for the a/b ratio?What is the physical unit for the a/b ratio?

20. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 20
BED useful to compare the effect of BED useful to compare the effect of
different fractionation schedulesdifferent fractionation schedules

Need to know a/b ratio of the tissues Need to know a/b ratio of the tissues
concerned.concerned.

a/b typically lower for normal tissues a/b typically lower for normal tissues
than for tumourthan for tumour

21. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 21
The linear quadratic modelThe linear quadratic model
0.001
0.01
0.1
1
0 2 4 6 8 10
Dose (Gy)
P
r
o
b
a
b
i
l
i
t
y

o
f

c
e
l
l

s
u
r
v
i
v
a
l
cell kill (low a/b)
cell kill (high a/b)

22. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 22
The linear quadratic modelThe linear quadratic model
0.001
0.01
0.1
1
0 2 4 6 8 10
Dose (Gy)
P
r
o
b
a
b
i
l
i
t
y

o
f

c
e
l
l

s
u
r
v
i
v
a
l
cell kill (low a/b)
cell kill (high a/b)
Alpha determines
initial slope
Beta determines
curvature

23. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 23
Rule of thumb for a/b ratiosRule of thumb for a/b ratios

Large a/b ratiosLarge a/b ratios

a/b = 10 to 20a/b = 10 to 20

Early or acute Early or acute
reacting tissuesreacting tissues

Most tumoursMost tumours

Small a/b ratioSmall a/b ratio

a/b = 2a/b = 2

Late reacting Late reacting
tissues, tissues, e.g.e.g. spinal spinal
cordcord

potentially prostate potentially prostate
cancercancer

24. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 24
The effect of fractionationThe effect of fractionation
0.001
0.01
0.1
1
0 2 4 6 8 10
Dose (Gy)
P
r
o
b
a
b
i
l
i
t
y

o
f

c
e
l
l

s
u
r
v
i
v
a
l
cell kill (low a/b)
cell kill (high a/b)
fractionated (low a/b)
fractionated (low a/b)

25. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 25
Fractionation Fractionation

Tends to spare late reacting normal Tends to spare late reacting normal
tissues - the smaller the size of the tissues - the smaller the size of the
fraction the more sparing for tissues fraction the more sparing for tissues
with low a/bwith low a/b

Prolongs treatmentProlongs treatment

26. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 26
A note of cautionA note of caution

This is only a modelThis is only a model

Need to know the radiobiological data Need to know the radiobiological data
for patientsfor patients

Important assumptions:Important assumptions:
There is full repair between two fractions
There is no proliferation of tumour cells -
the overall treatment time does not play a
role.

27. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 27
3. The 4 Rs of radiotherapy 3. The 4 Rs of radiotherapy

R Withers (1975)R Withers (1975)
Reoxygenation
Redistribution
Repair
Repopulation (or Regeneration)

28. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 28
Reoxygenation

Oxygen is an important enhancement for Oxygen is an important enhancement for
radiation effects (“Oxygen Enhancement radiation effects (“Oxygen Enhancement
Ratio”)Ratio”)

The tumour may be hypoxic (in particular in The tumour may be hypoxic (in particular in
the center which may not be well supplied the center which may not be well supplied
with blood)with blood)

One must allow the tumour to re-oxygenate, One must allow the tumour to re-oxygenate,
which typically happens a couple of days which typically happens a couple of days
after the first irradiationafter the first irradiation

29. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 29
Redistribution

Cells have different radiation sensitivities in Cells have different radiation sensitivities in
different parts of the cell cycledifferent parts of the cell cycle

Highest radiation sensitivity is in early S and Highest radiation sensitivity is in early S and
late G2/M phase of the cell cyclelate G2/M phase of the cell cycle
G1
G1
S (synthesis)
M (mitosis)
G2

30. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 30
Redistribution

The distribution of cells in different The distribution of cells in different
phases of the cycle is normally not phases of the cycle is normally not
something which can be influenced - something which can be influenced -
however, radiation itself introduces a however, radiation itself introduces a
block of cells in G2 phase which leads block of cells in G2 phase which leads
to a synchronizationto a synchronization

One must consider this when irradiating One must consider this when irradiating
cells with breaks of few hours.cells with breaks of few hours.

31. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 31
Repair

All cells repair radiation damageAll cells repair radiation damage

This is part of normal damage repair in the This is part of normal damage repair in the
DNADNA

Repair is very effective because DNA is Repair is very effective because DNA is
damaged significantly more due to ‘normal’ damaged significantly more due to ‘normal’
other influences (other influences (e.g.e.g. temperature, chemicals) temperature, chemicals)
than due to radiation (factor 1000!)than due to radiation (factor 1000!)

The half time for repair, tThe half time for repair, t
rr, is of the order of , is of the order of
minutes to hoursminutes to hours

32. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 32
Repair

It is essential to allow normal tissues to repair It is essential to allow normal tissues to repair
all repairable radiation damage prior to giving all repairable radiation damage prior to giving
another fraction of radiation.another fraction of radiation.

This leads to a minimum interval between This leads to a minimum interval between
fractions of 6 hoursfractions of 6 hours

Spinal cord seems to have a particularly slow Spinal cord seems to have a particularly slow
repair - therefore, breaks between fractions repair - therefore, breaks between fractions
should be at least 8 hours if spinal cord is should be at least 8 hours if spinal cord is
irradiated.irradiated.

33. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 33
Repopulation
Cell population also grows during radiotherapyCell population also grows during radiotherapy
For tumour cells this repopulation partially For tumour cells this repopulation partially
counteracts the cell killing effect of counteracts the cell killing effect of
radiotherapyradiotherapy

The potential doubling time of tumours, TThe potential doubling time of tumours, T
pp
((e.g.e.g. in head and neck tumours or cervix in head and neck tumours or cervix
cancer) can be as short as 2 days - therefore cancer) can be as short as 2 days - therefore
one loses up to 1 Gy worth of cell killing when one loses up to 1 Gy worth of cell killing when
prolonging the course of radiotherapyprolonging the course of radiotherapy

34. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 34
Repopulation

The repopulation time of tumour cells The repopulation time of tumour cells
appears to vary during radiotherapy - at the appears to vary during radiotherapy - at the
commencement it may be slow (commencement it may be slow (e.g.e.g. due to due to
hypoxia), however a certain time after the first hypoxia), however a certain time after the first
fraction of radiotherapy (often termed the fraction of radiotherapy (often termed the
“kick-off time”, T“kick-off time”, T
kk) repopulation accelerates.) repopulation accelerates.

Repopulation must be taken into account Repopulation must be taken into account
when protracting radiation when protracting radiation e.g.e.g. due to due to
scheduled (or unscheduled) breaks such as scheduled (or unscheduled) breaks such as
holidays.holidays.

35. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 35
Repopulation/
Regeneration

Also normal tissue repopulate - this is an Also normal tissue repopulate - this is an
important mechanism to reduce acute side important mechanism to reduce acute side
effects from effects from e.g.e.g. the irradiation of skin or the irradiation of skin or
mucosamucosa

Radiation schedules must allow sufficient Radiation schedules must allow sufficient
regeneration time for acutely reacting tissues.regeneration time for acutely reacting tissues.

36. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 36
The 4 Rs of radiotherapy: Influence on The 4 Rs of radiotherapy: Influence on
time between fractions, t, and overall time between fractions, t, and overall
treatment time, Ttreatment time, T
Reoxygenation
Redistribution
Repair
Repopulation (or
Regeneration)

Need minimum TNeed minimum T

Need minimum t Need minimum t

Need minimum t for Need minimum t for
normal tissuesnormal tissues

Need to reduce T for Need to reduce T for
tumour tumour

37. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 37
The 4 Rs of radiotherapy: Influence on The 4 Rs of radiotherapy: Influence on
time between fractions, t, and overall time between fractions, t, and overall
treatment time, Ttreatment time, T
Reoxygenation
Redistribution
Repair
Repopulation (or
Regeneration)

Need minimum TNeed minimum T

Need minimum t Need minimum t

Need minimum t for Need minimum t for
normal tissuesnormal tissues

Need to reduce T for Need to reduce T for
tumor tumor
Cannot achieve all at once -
Optimization of schedule
for individual circumstances

38. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 38
4. Time, dose and fractionation4. Time, dose and fractionation

Need to optimize fractionation schedule Need to optimize fractionation schedule
for individual circumstancesfor individual circumstances

Parameters:Parameters:

Total doseTotal dose

Dose per fractionDose per fraction

Time between fractionsTime between fractions

Total treatment timeTotal treatment time

39. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 39
Extension of LQ model to include Extension of LQ model to include
time:time:
E = - ln S = n * d (α + βd) - γT
γ equals ln2/T
p with T
p the potential doubling
time

note that the γT term has the opposite sign to
the α + βd term indicating tumour growth
instead of cell kill

40. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 40
The potential doubling timeThe potential doubling time

the fastest time in which a tumour can
double its volume

depends on cell type and can be of the order
of 2 days in fast growing tumours

can be measured in cell biology
experiments

requires optimal conditions for the tumour
and is a worst case scenario

41. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 41
Extension of LQ model to include Extension of LQ model to include
time:time:
E = - ln S = n * d (α + βd) - γT
Including T
k ("kick off time") which allows for
a time lag before the tumour switches to the
fastest repopulation time:
BED = (1 + d / (α/β)) * nd - (ln2 (T - T
k)) / αT
p

42. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 42
Evidence for “kick off” timeEvidence for “kick off” time

43. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 43
Use of the LQ model in Use of the LQ model in
external beam radiotherapy:external beam radiotherapy:

Calculate ‘equivalent’ fractionation Calculate ‘equivalent’ fractionation
schemesschemes

Determine radiobiological parametersDetermine radiobiological parameters

Determine the effect of treatment Determine the effect of treatment
breaksbreaks

e.g.e.g. Do we need to give extra dose for the Do we need to give extra dose for the
long weekend break?long weekend break?

44. Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 44
SummarySummary
Radiobiology is essential to understand the Radiobiology is essential to understand the
effects of radiotherapyeffects of radiotherapy

It is also important for radiation protection of It is also important for radiation protection of
the patient as it allows minimization of the the patient as it allows minimization of the
radiation effects in healthy tissuesradiation effects in healthy tissues

There are models which allow to estimate the There are models which allow to estimate the
effect of a given radiotherapy scheduleeffect of a given radiotherapy schedule

Caution is necessary when applying a model Caution is necessary when applying a model
to an individual patient - clinical judgement to an individual patient - clinical judgement
should not be overruledshould not be overruled

45. Any questions?Any questions?