BASIC RADIOBIOLOGY FOR RADIOTHERAPY

10cm
TOPIC 3
BASICS RADIOBIOLOGY
FOR RADIOTHERAPY

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Ref X-Ray Exp /
Radiation
Chemistry
01
Table of contents
Volume
Definition
Biological
Factors
Biological Effect of
Ionizing Radiation
02 03 04
Radiation
Response
05

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Radiation
Chemistry
01
3
Ref X-Ray Exp /

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RADIATION
EFFECT

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Photon ejects an
electron which produce
a biological damage on
the DNA
Indirect Action Direct Action
Electrons produce free
radicals which break
chemical bonds and
produce chemical changes
5
Radiation Chemistry
Ref X-Ray Exp /

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Ref X-Ray Exp /
Revision: Excitation and Ionisation
Ionizing radiation can dissipate its energy
by two methods:
1. EXCITATION
-Amount of energy absorbed raises an
electron in an atom/molecule to a higher
energy level without ejection of the
electron.
2. IONIZATION
-Occurs when the absorbed radiation has
enough energy to eject one or more
orbital electrons from the atom/molecule.

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1) DIRECT ACTION
9
1. Radiation may
impact the DNA
directly. The atoms of
the target itself may
be ionized or excited
leading to the chain of
physical and chemical
events that eventually
produce the biological
damaging.
2. It is a fairly uncommon
occurrence due to the small
size of the target; the
diameter of the DNA helix
=2 nm.
Ref X-Ray Exp /
3. Dominant process in the
interaction of high LET
particles such as neutrons
or alpha particles with
biological material.

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2) INDIRECT ACTION
10
1. The radiation
interacts with non-
critical target atoms or
molecules, usually
water.
3. These free radicals can
then attack critical targets
such as the DNA. Damage
from indirect action is much
more common than damage
from direct action
Ref X-Ray Exp /
2. This results in the
production of free radicals,
which are atoms or
molecules that have an
unpaired electron and thus
are highly reactive

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Volume
Definition
02
11
Ref X-Ray Exp /

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Volume Definition (ICRU)
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Clinical Target
Volume (CTV)
Gross Tumour
Volume (GTV)
Organs At Risk
(OAR)
Treated Volume
(TV)
01
02
03
04
Planning Target
Volume (PTV)
05

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GTV – Gross Tumour Volume
CTV – Clinical Target Volume
PTV – Planning Target Volume
OAR – Organ at Risk
TV – Treated Volume
IV – Irradiated Volume
13
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Gross Tumour Volume (GTV)
14
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The gross palpable, visible and demonstrable
extent and location of the malignant growth
(ICRU Report No. 50)
As the term suggests, tumors have a length, breadth and
depth, and the GTV must therefore be identified using
orthogonal 2D or 3D imaging (computed tomography (CT),
magnetic resonance imaging (MRI), ultrasound, etc.),
diagnostic modalities (pathology and histological reports,
etc.) and clinical examination.

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Clinical Target Volume (CTV)
15
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“The clinical target volume (CTV) is the tissue
volume that contains a demonstrable GTV and/or
sub-clinical microscopic malignant disease, which
has to be eliminated. This volume thus has to be
treated adequately in order to achieve the aim of
therapy, cure or palliation” (ICRU Report No. 50)
This volume may not be defined separately but considered
when defining the planning target volume (PTV) (e.g. CTV =
GTV + 1 cm margin)

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Planning Target Volume (PTV)
16
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“The planning target volume (PTV) is a geometrical
concept, and it is defined to select appropriate
beam arrangements, taking into consideration the
net effect of all possible geometrical variations, in
order to ensure that the prescribed dose is actually
absorbed in the CTV” (ICRU Report No. 50)
The PTV includes the internal target margin (ICRU Report No. 62)
and an additional margin for the set-up uncertainties, machine
tolerances and intratreatment variations
It fully encompasses the GTV and CTV (e.g : PTV = CTV + 1 cm).

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Treated Volume (TV)
17
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The volume of tissue enclosed by an isodose
surface selected and specified by the clinician
as being appropriate to achieve the aim of
treatment.
For example, this may be the volume
encompassed within the 95% isodose surface
(with 100% in the centre of the PTV) for a
curative treatment plan.

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Organs At Risk (OAR)
18
Ref X-Ray Exp /
Organs adjacent to the PTV which are non-target; do
not contain malignant cells
The aim should therefore be to minimise irradiation
of OARs as they are often relatively sensitive to the
effects of ionising radiation and, if damaged, may
lead to substantial morbidity.
The OARs to be considered will vary greatly
according to the anatomical region being treated,
the size of the PTV and the location of the PTV in
these regions.
OARs
• Lung
• Spinal cord

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Biological Factors
(5 Rs)
03
20
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RADIATION DAMAGE CLASSIFICATION
Lethal damage
irreversible, irreparable
and leads to cell death
Sub lethal
damage
can be repaired in hours
unless additional sub
lethal damage is added to
it
Potentially
lethal damage
can be manipulated by
repair when cells are
allowed to remain in non-
dividing state
21
Ref X-Ray Exp /

FRACTIONATION
● Refers to division of total dose into no. of separate fractions over total treatment time
conventionally given on daily basis , usually 5 days a week.
● Size of each dose fractionation whether for cure or palliation depends on tumor dose as well as
normal tissue tolerance .
● e.g. if 40 Gy is to be delivered in 20 fractionation in a time of 4weeks then daily dose is 2Gy.

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Fractional Schedules
Standard Radiation
Therapy
Usually given as an outpatient,
five days a week for a given
period of time. Radiation has the
advantage of avoiding surgical
risk, possibly preserving organs
and therefore organ function, as
well as being able to easily treat
large areas of tumors or potential
tumor involvement that might
otherwise be difficult to reach
with surgery and result in greater
post-operative defect and
dysfunction.
Accelerated
Fractionation
is treatment with multiple daily
fractions of approximately
standard size to about the
same total dose, but is given in
a shorter overall time.
Hyperfractionated
Radiation Therapy
is the use of multiple radiation fractions
(doses) per day of smaller than
conventional size but to a higher total
dose, with little or no change in overall
treatment time. The rationale for this
type of therapy is that it allows less time
in between treatments for the tumor
cells to recover from the radiation
damage. However, there is a greater risk
of acute radiation-associated side effects
with this form of treatment.
23
Ref X-Ray Exp /

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5 R’s
The biological factors that influence the
response of normal and neoplastic tissues
to fractionated radiotherapy
24
Repair Repopulation
Reoxygenation
Redistribution
Ref X-Ray Exp /
Radiosensitivity

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1. Repair
25
Ref X-Ray Exp /
All cells repair radiation damage
Repair is very effective because DNA is damaged significantly more due to
‘normal’ other influences (e.g. temperature, chemicals) than due to radiation
The half time for repair, tr, is of the order of minutes to hours
It is essential to allow normal tissues to repair all repairable radiation damage
prior to giving another fraction of radiation.
This leads to a minimum interval between fractions of 6 hours
Spinal cord seems to have a particularly slow repair - therefore, breaks
between fractions should be at least 8 hours if spinal cord is irradiated.

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2. Repopulation
26
Ref X-Ray Exp /
In both tumors and normal tissues, proliferation of surviving cells may occur
during fractionated treatment.
As cellular damage and cell death occur during the treatment, the tissue may
respond with an increased rate of cell proliferation.
The effect of this cell proliferation during treatment, known as repopulation or
regeneration (increase the number of cells during the treatment and reduce
the overall response to irradiation)
Repopulation must be considered when protracting/prolong radiation e.g. due
to scheduled (or unscheduled) breaks such as holidays.
So longer a radiotherapy course lasts, more difficult it becomes to control
tumor & may be detrimental
Thus, fractionation must be controlled so as not to allow too much time for
excessive repopulation of tumor cells at the same time not treating so fast that
acute tolerance is exceeded

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3. Reoxygenation
27
Ref X-Ray Exp /
Oxygen is an important enhancement for radiation effects
(“Oxygen Enhancement Ratio” (OER)
Cells at the center of tumor are hypoxic and are resistant
to low LET radiation.
One must allow the tumor to re-oxygenate, which
typically happens a couple of days after the first
irradiation
Phenomenon by which hypoxic cells become oxygenated
after a dose of radiation is termed reoxygenation.
Hypoxic cells get reoxygenated occurs during a
fractionated course of treatment, making them more
radiosensitive to subsequent doses of radiation.

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3. Reoxygenation
28
Ref X-Ray Exp /
When a tumor outgrows its blood supply, the cells in the center of the tumor
do not get enough oxygen.
As the tumor shrinks during radiation treatment, the hypoxic cancer cells in
the center of the tumor come closer to the blood supply.
They then become oxygenated and more sensitive to the next dose of
radiation.

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4. Redistribution/ Reassortment
29
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Cells have different radiation sensitivities in different
parts of the cell cycle
Redistribution of proliferating cell populations
throughout the cell cycle increases cell kill in
fractionated treatment relative to a single session
treatment.
Cells are most sensitive during M & G2 phase & are
resistant during S phase of cell cycle .
Redistribution can be a benefit in fractionated course
of Radiotherapy if cells are caught in sensitive phase
after each fraction .
“Sensitization due to re-assortment” causes
therapeutic gain.

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Ref X-Ray Exp /
● G1 phase. The cell grows.
● S phase. The cell makes copies of its
chromosomes. Each chromosome now
consists of two sister chromatids. Most
radiation resistant phase. Cellular repair
mechanisms are active
● Increases repair of radiation damage
● G2 phase. The cell checks the duplicated
chromosomes and gets ready to divide.
● M phase. The cell separates the copied
chromosomes to form two full sets (mitosis)
and the cell divides into two new cells
(cytokinesis). Repair mechanisms are shut
down
● The period between cell divisions is known
as 'interphase'.
● Cells that are not dividing leave the cell cycle
and stay in G0.

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But…..
Repair and Repopulation tend to make the tissue more
resistant to second dose of radiation.
Reassortment and Reoxygenation tend to make it more
sensitive.
The overall sensitivity of the tissue depends on:
The Fifth 'R' : Radiosensitivity

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5. Radiosensitivity
32
Ref X-Ray Exp /
For a given fractionation course (or for single-dose irradiation), the
haemopoietic system shows a greater response than the kidney, even
allowing for the different timing of response.
Similarly, some tumors are more radioresponsive than others to a
particular fractionation schedule, and this is largely due to differences in
radiosensitivity.
Muscle
Bones
Nervous system
Skin
Liver
Heart
Lungs
Bone Marrow
Spleen
Thymus
Lymphatic nodes
Gonads
Eye lens
Lymphocytes
(exception to the RS
laws)
Low RS
Medium RS
High RS

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Summary
33
Ref X-Ray Exp /
Reassortment, Repair, Reoxygenation are all benefits of fractionation.
Repopulation is the negative associated with fractionation of radiation.
Repair occurs in normal cells and tumor cells.
Reassortment occurs in cycling cells—mostly tumor but some normal cells
Reoxygenation occurs only in tumor cells.
Repopulation occurs in the tumor cells.

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Biological Effect of
Ionizing Radiation
04
34
Ref X-Ray Exp /

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Biological Effect
DETERMINISTIC
EFFECTS
STOCHASTIC
EFFECT

Biological effects of radiation
in time perspective
Time scale
Fractions of seconds
Seconds
Minutes
Hours
Days
Weeks
Months
Years
Decades
Generations
Effects
Energy absorption
Changes in biomolecules
(DNA, membranes)
Biological repair
Change of information in cell
Cell death
Organ Clinical
death changes
Mutations in a
Germ cell Somatic cell
Leukaemia
or
Cancer
Hereditary
effects

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Consequence of DNA damage
37
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Dose Response Curve
38
Ref X-Ray Exp /
Line 2:
Threshold is
assumed,
response
expected at lower
doses.
(Radiotherapy)
Line 1:
No level of radiation
can be considered safe.
(Diagnostic Imaging)
Line 3:
Nonlinear
dose response
Deterministic Effect
Stochastic Effect

Erythema
Skin Breakdown
Cataracts
Death
2
1. DETERMINISTIC EFFECTS
(High Dose)
Acute effect/ short
term effect/ early
effect
4
Specific to
particular tissues
6
Have a dose
threshold (above
500–1000 mSv)
1
Due to cell killing
(high dose given
over short period)
3
Severity of harm is
dose dependent
5

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1. Deterministic Effect
40
Ref X-Ray Exp /

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ACUTE
RADIATION
SYNDROME
(ARS)

ACUTE
RADIATION
SYNDROME
(ARS)
the most notable deterministic effect of
ionizing radiation
Signs and symptoms are not specific for
radiation injury but collectively highly
characteristic of ARS
Combination of symptoms appears in
phases during hours to weeks after
exposure
prodromal phase, latent phase, ,
manifest illness, - recovery (or death)
01
02
03
04

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Acute radiation syndrome (ARS)
45
Ref X-Ray Exp /

-cancer induction (Somatic
effect)
-hereditary effects
2
2. STOCHASTIC EFFECT
(Low Dose)
Late effect /
Chronic effect)
4
Probability of effect
increases with dose
6
No dose threshold -
applicable also to very
small doses (below
several tens or 100–200
mSv)
1
Due to cell changes and
proliferation towards a
malignant disease
3
Severity (example
cancer) independent of
the dose
5

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2. Stochastic Effect
47
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2. Stochastic Effect
48
Ref X-Ray Exp /

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Stochastic Effect VS Deterministic
Effect
49
Ref X-Ray Exp /

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Stochastic Effect VS Deterministic Effect
50
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Somaticeffects
These effects are observable either
relatively soon after individuals have been
irradiated ("early" or "short-term" effects),
or after periods of a few months to several
years ("late" or "long-term" effects)

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Radiation Response
05
52
Ref X-Ray Exp /

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1. LINEAR ENERGY TRANSFER (LET)
defining the quality
of an ionizing
radiation beam
01
The linear rate of energy
absorption by absorbing
medium as charged
particle traverses the
medium
(dE/dl, KeV/mm)
02

gamma rays
deep therapy
X-rays
soft X-rays
alpha-particle
HIGH LET
Radiation
LOW LET
Radiation
Separation of ion clusters in relation to
size of biological target
4 nm
The Spatial Distribution of Ionizing Events Varies with
the Type of Radiation and can be defined by LET

• A dose of 1 Gy will give 2x103
ionization events in 10-10 g (the
size of a cell nucleus). This can be
achieved by:
– 1MeV electrons
• 700 electrons which give 6
ionization events per m.
– 30 keV electrons
• 140 electrons which give
30 ionization events per
m.
– 4 MeV protons
• 14 protons which give 300
ionization events per m.
• The biological effectiveness
of these different radiations
vary!
-ray
’-ray
excitation
ionization
 particle
excitation and ionization

Repairable Sublethal Damage
X- or -radiation is sparsely ionizing; most damage can be
repaired
4 nm
2 nm

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Single lethal hit
Also known as - type killing
4 nm
2 nm
Unrepairable Multiply Damaged Site
It is hypothesized that the lethal
lesions are large double strand
breaks with Multiply Damaged
Sites (MDS) that can not be
repaired. They are more likely to
occur at the end of a track

At high dose, intertrack
repairable Sublethal Damage may
Accumulate forming
unrepairable, lethal MDS
Also known as - type killing

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Photon ejects an
the DNA
chemical bonds and
59
Ref X-Ray Exp /

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Oxygen Enhancement Ratio
Oxygen is a powerful
oxidizing agent and
therefore acts as a
radiosensitizer if it is
present at the time of
irradiation (within msecs).
The presence or absence
of molecular oxygen within
a cell influences the
biological effect of ionizing
radiation: the larger the
cell oxygenation above
anoxia, the larger is the
biological effect until
saturation of the effect of
oxygen occurs, especially
for low LET radiations
Its effects are
measured as the
oxygen enhancement
ratio (O.E.R.)

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The effect is quite
dramatic for low LET
(sparsely ionizing)
radiations, while for high
LET (densely ionizing)
radiations it is much less
pronounced
The ratio of doses without
and with oxygen (hypoxic
vs. well-oxygenated cells)
to produce the same
biological effect is called
the oxygen enhancement
ratio (OER).
O.E.R. =
D(anox)/D(ox)

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Photon ejects an
the DNA
chemical bonds and
62
OER
Ref X-Ray Exp /

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For densely ionizing
radiation, such as low-
energy α-particles, the
survival curve does not
have an initial shoulder
In this case, survival
estimates made in the
presence and absence of
oxygen fall along a
common line; the OER is
unity – in other words,
there is no oxygen effect

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RELATIVE BIOLOGICAL EFFECTIVENESS (RBE)
Equal doses of different
LET radiation DO NOT
produce equal biological
effects
A
A term relating the ability
of radiations with different
LETs to produce a specific
biologic response
B
RBE is defined as the
comparison of a dose of
some test radiation to the
dose of 250 kV x-rays that
produces the same biologic
response
C
250 kV x-rays or
1.17/1.33 MeV 60Co as
the standard radiation
D

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Fractionated doses of dense vs. sparse ionizing beam:
The RBE of high LET beam becomes larger when the fraction number is increasing.
04
65
Ref X-Ray Exp /
RELATIVE BIOLOGICAL EFFECTIVENESS (RBE)

Radiation
Energy
WR (also RBE or
Q)
x-rays, gamma
rays, electrons,
positrons, muons 1
neutrons < 10 keV 5
10 keV - 100 keV 10
100 keV - 2 MeV 20
2 MeV - 20 MeV 10
> 20 MeV 5
protons > 2 MeV 2
alpha particles,
nuclear fission
products,
heavy nuclei 20
6
6
COMPARISON
Weighting factors
WR (also termed
RBE or Q factor,
to avoid confusion
with tissue
weighting factors
Wf) used to
calculate
equivalent dose
according to ICRP
report 92

RBE Example
To achieve 50% survival fraction, 250 kV x-ray
needs 2 Gy, but the tested particle needs 0.66
Gy only. RBE ?
ANSWER:

BASIC RADIOBIOLOGY FOR RADIOTHERAPY

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