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TOPIC 2
BASICS RADIOBIOLOGY FOR
RADIOTHERAPY
(2 hours)
122/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
2.1 Introduction
2.2 Radiation Chemistry
2.3 Volume Definition
2.3.1 Gross Tumour Volume (GTV)
2.3.2 Clinical Target Volume (CTV)
2.3.3 Planning Target Volume (PTV)
2.3.4 Treated Volume (TV)
2.3.5 Irradiated Volume (Iv)
2.3.6 Organs At Risk (Oar)
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2.4 5 Rs
2.4.1 Repair
2.4.2 Repopulation
2.4.3 Reoxygenation
2.4.4 Redistribution
2.4.5 Radiosensitivity
2.5 Biological Effect of Ionizing Radiation
2.5.1 Dose Response Curve
2.5.2 Cell Survival Curve
2.5.3 Systemic Effects
2.5.4 Oxygen Effect
2.5.5 LET
2.5.6 Relative Biological Effectiveness (RBE) 322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
2.1 Introduction
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INTERACTIONS
between Ionizing
radiation and
living systems
radiation
physics
+
biology
Radiation
oncology
2.1 Introduction
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ACTION Of
ionizing
radiation on
biological
tissues
radiation
physics
+
biology
Radiobiology
2.1 Introduction
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Radiobiology allows the
optimization of a radiotherapy
schedule for individual patients
in regards to:
Total dose and
number of fractions
Overall time of the
radiotherapy
course
Tumour control
probability (TCP) and
normal tissue
complication
probability (NTCP)
2.2 Radiation Chemistry
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2.2 Radiation Chemistry
Radiation may impact the DNA directly,
causing ionization of the atoms in the DNA
molecule (“direct hit”). It is a fairly uncommon
occurrence due to the small size of the target; the
diameter of the DNA helix =2 nm.
Dominant process in the
interaction of high LET
particles such as neutrons or
alpha particles with biological
material.
1) DIRECT ACTION
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2) INDIRECT ACTION
2.2 Radiation Chemistry
The radiation interacts
with non-critical target
atoms or molecules,
usually water.
This results in the
production of free
radicals, which are atoms
or molecules that have an
unpaired electron and
thus are highly reactive
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
• Indirect action: Electrons
produce free radicals which
break chemical bonds and
produce chemical changes
• Direct Action: Photon ejects
an electron which produce a
biological damage on the
DNA
2.2 Radiation Chemistry
2.2 Radiation Chemistry
2.2 Radiation Chemistry
2.3 Volume Definition
2.3.1 Gross Tumour Volume (GTV)
2.3.2 Clinical Target Volume (CTV)
2.3.3 Planning Target Volume (PTV)
2.3.4 Treated Volume (TV)
2.3.5 Irradiated Volume (Iv)
2.3.6 Organs At Risk (Oar)
1322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
•Volume definition is a prerequisite for meaningful 3-D treatment
planning and for accurate dose reporting.
•ICRU reports No. 50 and 62 define and describe several target and critical
structure volumes that aid in the treatment planning process and that
provide a basis for comparison of treatment outcomes.
•The following volumes have been defined as principal volumes related to
3-D treatment planning: gross tumour volume (GTV), clinical target
volume (CTV), internal target volume (ITV) and planning target volume
(PTV)
2.3 Volume Definition
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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
2.3 Volume Definition
The gross palpable, visible
and demonstrable extent and
location of the malignant
growth (ICRU Report No. 50)
2.3.1 Gross Tumour Volume (GTV)
•This is determined by physical examination by the oncologist and the
results of radiological investigations relevant to the site of the tumour.
•As the term suggests, tumours 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.
2.3.1 Gross Tumour Volume (GTV)
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 19
Gross Tumour Volume (GTV)
– Gross palpable or visible/demonstrable
extent and location of tumour
GTV
•“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)
2.3.2 Clinical Target Volume (CTV)
•Usually determined by the radiation oncologist, often after
other relevant specialists such as pathologists or radiologists
have been consulted.
•This volume may not be defined separately but considered when
defining the planning target volume (PTV) (e.g. CTV = GTV + 1
cm margin)
2.3.2 Clinical Target Volume (CTV)
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 22
Clinical Tumour Volume (CTV)
CTV Contains a GTV and/or sub-clinical
microscopic malignant disease, which has to
be eliminated CTV
•“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)
2.3.3 Planning Target Volume (PTV)
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• 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).
2.3.3 Planning Target Volume (PTV)
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• In practice, it is often the result of a compromise between
two contradictory issues: making sure that the CTV
will receive the prescribed dose while at the same time
ensuring that OARs will not receive an excessive dose.
2.3.3 Planning Target Volume (PTV)
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 26
Planning Target Volume (PTV)
• Contains a CTV and a margin to account for
variation is size, shape and position relative
to treatment beams
PTV
•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.
2.3.4 Treated Volume (TV)
•The TV should not be significantly larger than the PTV.
The use of 3D treatment planning and shaping the
radiation fields to the shape of the PTV using conformal
radiation delivery techniques ensures that the TV
encloses the PTV with as narrow a margin as possible.
This ensures minimal irradiation of surrounding OARs
while coverage of the PTV is assured.
2.3.4 Treated Volume (TV)
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 29
Treated volume
Treated volume – Volume enclosed by an isodose
surface selected as appropriate to achieve purpose
of treatment
Treated Volume
•The tissue volume receiving a radiation absorbed
dose that is considered significant in relation to
normal tissue tolerance.
•This concept is not often considered in practice
but may be useful when comparing one or more
competing treatment plans.
•Clearly, it would be preferable to accept the plan
with the smallest IV, all else being equal.
2.3.5 Irradiated Volume (Iv)
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 31
Irradiated volume
Irradiated volume – The volume that receives a
dose that is significant in relation to normal
tissue tolerance
Irradiated Volume
•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.
2.3.6 Organs At Risk (Oar)
•The following are examples of the most common OARs that must be
considered:
1. Brain: lens of eye, optic chiasm, brain stem
2. Head & neck: lens of eye, parotid glands
3. Thorax: spinal cord, lungs
4. Abdomen: spinal cord, large bowel, small bowel, kidneys
5. Pelvis: bladder, rectum, femoral heads, large bowel, small bowel
2.3.6 Organs At Risk (Oar)
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 34
Organs at Risk (OAR)
• Normal tissues whose radiation
sensitivity could significantly influence
treatment planning and/or the dose
prescription
OARs
• Lung
• Spinal cord
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2.4 Biological Factors (5 Rs)
2.4.1 Repair
2.4.2 Repopulation
2.4.3 Reoxygenation
2.4.4 Redistribution
2.4.5 Radiosensitivity
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Repair
Repopulation
Reoxygenation
Redistribution
Radiosensitivity
•The biological factors that
influence the response of
normal and neoplastic
tissues to fractionated
radiotherapy
2.4 Biological Factor (5 Rs)
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2.4.1 Repair
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•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
2.4.1 Repair
•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.
2.5.1 Repair
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2.4.2 Repopulation
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• In both tumours and normal tissues, proliferation of surviving cells may
occur during the course of fractionated treatment.
• Furthermore, as cellular damage and cell death occur during the course of
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
course of the treatment and reduce the overall response to irradiation)
2.4.2 Repopulation
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• This effect is most important in early-responding normal tissues (e.g.,
skin, gastrointestinal tract) or in tumours whose stem cells are capable of
rapid proliferation; it will be of little consequence in late-responding,
slowly proliferating tissues (e.g., kidney), which do not suffer much early
cell death and hence do not produce an early proliferative response to the
radiation treatment.
• Repopulation is likely to be more important toward the end of a course of
treatment, when sufficient damage has accumulated (and cell death
occurred) to induce a regenerative response.
2.4.2 Repopulation
•The repopulation time of tumour cells appears to vary during
radiotherapy - at the commencement it may be slow (e.g. due to
hypoxia), however a certain time after the first fraction of radiotherapy
(often termed the “kick-off time”, Tk) repopulation accelerates.
•Repopulation must be taken into account when protracting/prolong
radiation e.g. due to scheduled (or unscheduled) breaks such as
holidays.
2.4.2 Repopulation
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2.4.3 Reoxygenation
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•Oxygen is an important enhancement for radiation effects (“Oxygen
Enhancement Ratio” (OER)
•The tumor may be hypoxic (in particular in the center which may
not be well supplied with blood)
•One must allow the tumor to re-oxygenate, which typically happens
a couple of days after the first irradiation
2.4.3 Reoxygenation
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• The response of tumours to large single doses of radiation is dominated by the
presence of hypoxic cells within them, even if only a very small fraction of
the tumour stem cells are hypoxic.
• Immediately after a dose of radiation, the proportion of the surviving cells that
is hypoxic will be elevated. However, with time, some of the surviving
hypoxic cells may gain access to oxygen and hence become reoxygenated and
more sensitive to a subsequent radiation treatment.
• Reoxygenation can result in a substantial increase in the sensitivity of tumours
during fractionated treatment.
2.4.3 Reoxygenation
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2.4.4 Redistribution
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•Cells have different radiation sensitivities in different parts of
the cell cycle
•Highest radiation sensitivity is in early S and late G2/M phase of
the cell cycle
G1
G1
S (synthesis)
M (mitosis)G2
2.4.4 Redistribution
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• Variation in the radiosensitivity of cells in different phases of the cell cycle results
in the cells in the more resistant phases being more likely to survive a dose of
radiation.
• Two effects can make the cell population more sensitive to a subsequent dose of
radiation.
1. Some of the cells will be blocked in the G2 phase of the cycle, which is usually a
sensitive phase.
2. Some of the surviving cells will redistribute into more sensitive parts of the
cell cycle.
• Both effects will tend to make the whole population more sensitive to fractionated
treatment as compared with a single dose.
• .
•The distribution of cells in different phases of the cycle
is normally not something which can be influenced -
however, radiation itself introduces a block of cells in G2
phase which leads to a synchronization
•One must consider this when irradiating cells with
breaks of few hours.
2.4.4 Redistribution
2.4.5 Radiosensitivity
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•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 tumours are more radioresponsive than
others to a particular fractionation schedule, and this is
largely due to differences in radiosensitivity.
2.4.5 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 RSMedium RSHigh RS
2.4.5 Radiosensitivity
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2.5 Biological Effect of Ionizing Radiation
2.5.1 Dose Response Curve
2.5.1.1 Deterministic
2.5.1.2 Stochastic Effect
2.5.1.3 Sigmoid Curve
2.5.1.4 Cell Survival Curve
2.5.2 LET
2.5.3 OER
2.5.4 RBE 62Dr. Nik Noor Ashikin Bt Nik Ab Razak
2.5 Biological Effect of Ionizing Radiation
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2.5 Biological Effect of Ionizing Radiation
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2.5 Biological Effect of Ionizing Radiation
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2.5 Biological Effect of Ionizing Radiation
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2.5 Biological Effect of Ionizing Radiation
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2.5 Biological Effect of Ionizing Radiation
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2.5 Biological Effect of Ionizing Radiation
Module Medical IX. 70
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
2.5 Biological Effect of Ionizing Radiation
71
Dose to the tumor determines
probability of cure
Dose to normal structures determines
probability of side effects and
complications
Dose to patient, staff and visitors
determines risk of radiation
detriment to these groups
What matters in the end is
the biological effect!
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2.5 Biological Effect of Ionizing Radiation
2.5 Biological Effect
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Biological Effect
Stochastic Effects
(carcinogenic and genetic effects)
Deterministic Effects
(tissue reactions)
2.5.1 Dose Response Curve
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2.5.1.3 Sigmoid Curve (non-threshold)
DOSE
RESPONSE
CURVE
Line 3:
Non linear
dose response
Line 1:
No level of
radiation can be
considered safe.
Diagnostic
Imaging
Line 2:
Threshold is
assumed, response
expected at lower
doses.
(Radiotherapy)
Stochastic
Effect
2.5.1.1 Deterministic Effect
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2.5.1.1 Deterministic Effect
DETERMINISTIC
EFFECTS/
(High Dose)
erythema
skin breakdown
cataracts
death
Have a dose
threshold
Due to cell killing
(high dose given
over short period)
Severity of harm is
dose dependent
Specific to
particular tissues
Acute effect/
short term effect/
early effect
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2.5.1.1 Deterministic Effect
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Acute radiation syndrome
(ARS)
 ARS is 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)
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2.5.1.2 Stochastic Effect
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2.5.1.2 Stochastic Effect
STOCHASTIC
EFFECT
(low dose)
Eg:
-cancer induction
(Somatic effect)
-hereditary effects
Severity (example
cancer) independent of
the dose
Due to cell changes and
proliferation towards a
malignant disease
No dose threshold -
applicable also to very
small doses
Probability of effect
increases with dose
Late effect / Chronic
effect)
2.5 Biological Effect2.5.1.2 Stochastic Effect
Phases of cancer induction
and manifestation
Initia tion Muta te d Cells
Elimia tion Re pa ra tion
Progre ssion
Pre-c a nce r
Norma l Cells
Promotion
Minima l Ca nc er
Clinic a l Ca ncer
Spre a ding
2.5.1.3 Sigmoid Curve (non-threshold)
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Dose
Repairing cell
structures is still
possible
No repairing: a low dose
means a great damage
Practically all the cells are
dead
dose
2.5.1.3 Sigmoid Curve (non-threshold)
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2.5.1.3 Sigmoid Curve (non-threshold)
LD 50/60
amount of radiation
that will cause 50% of
exposed individuals to
die within 60 days
2.5.1.4 Cell Survival Curve
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Biological Effects At Cellular Level
Possible mechanisms of cell death:
• Physical death
• Functional death
• Death during interphase
• Mitotic delay
• Reproductive failure
Cellular effects of ionizing radiation are
studied by cell survival curves
%survivalcells(semilogarithmic)
Dose
n = targets
Dq
D0
(threshold)
(radiosensitivity)
2.5.1.4 Cell Survival Curve
• Do = 37% dose slope
- Dose required to reduce the number of clonogenic cells to
37% of their former value
• Dq = Quasi threshold dose
- Dose at which straight portion extrapolated backward cuts
the dose axis
• n = extrapolation number
- Extrapolating the straight portion of the survival curve
until it cuts the “surviving fraction” axis
 Radiosensitive cells are characterized by curves with steep
slope D0 and/or small shoulder (low n)
Loge n = Dq / D0
%survivalcells(semilogarithmic)
Dose
n = targets
Dq
D0
(threshold)
(radiosensitivity)
2.5.1.4 Cell Survival Curve
2.5.2 LET
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2.5.2 LET
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LET
the linear rate of energy
absorption by absorbing
medium as charged particle
traverses the medium
(dE/dl, KeV/mm)
defining the quality
of an ionizing
radiation beam
Photon
Proton
Helium
Carbon
Oxygen
Neon
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
http://dmco.ucla.edu/McBride_Lab
WMcB2008
• 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
http://dmco.ucla.edu/McBride_Lab
WMcB2008
Repairable Sublethal Damage
X- or -radiation is sparsely ionizing; most damage can be
repaired
4 nm
2 nm
http://dmco.ucla.edu/McBride_Lab
WMcB2008
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
http://dmco.ucla.edu/McBride_Lab
WMcB2008
At high dose, intertrack
repairable Sublethal Damage may
Accumulate forming
unrepairable, lethal MDS
Also known as  - type killing
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2.5.2 LET
2.5.3 Oxygen Enhancement Ratio
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2.5.3 Oxygen Enhancement Ratio
106
1
• Oxygen is a powerful oxidizing agent and therefore acts as a
radiosensitizer if it is present at the time of irradiation (within msecs).
• Its effects are measured as the oxygen enhancement ratio (O.E.R.)
2
• 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
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2.5.3 Oxygen Enhancement Ratio
107
3
• The effect is quite dramatic for low LET (sparsely ionizing) radiations,
while for high LET (densely ionizing) radiations it is much less
pronounced
4
• 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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2.5.3 Oxygen Enhancement Ratio
2.5.3 Oxygen Enhancement Ratio
109
5
• For densely ionizing radiation, such as low-energy α-particles,
the survival curve does not have an initial shoulder
6
• 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
22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
http://dmco.ucla.edu/McBride_Lab
WMcB2008
Oxygen Enhancement Ratio (OER)
Dose required to produce a specific biological effect in the absence of oxygen
Dose required for the same effect in its presence=
OER varies with level of effect but can be 2.5 - 3 fold
1) Culture Cells
(
3) Count cells in hemocytometer
4) irradiate under oxic or hypoxic conditions
0 Gy 2Gy 4Gy 6Gy
5) Plate cells and
grow for about 12 days
. . .
.
.
.. .
6) Count colonies
Dose (Gy)
S.F.
0 2 4 6 8 10
1.0
0.1
0.01
oxic
hypoxic
Physical Dose = Biological Dose
2) Suspend Cells
trysinization)
http://dmco.ucla.edu/McBride_Lab
WMcB2008
• Hypoxic areas occur almost solely in tumors and are more
radioresistant than oxic areas.
• Hypoxia contributes to treatment failure
• Reoxygenation occurs between radiation dose fractions giving a
rationale for dose fractionation
• The oxygen effect is greater for low LET than high LET radiation
Giacca and Brown
Pimonizadole (oxygen mimetic)
staining colorectal carcinoma
The effects of hypoxia were first
discovered in 1909 by Schwarz who
showed that strapping a radium source on
the arm gave less of a skin reaction than
just placing it there. This was used to give
higher doses to deep seated tumors.
Clinical Relevance of Hypoxia
2.5.4 Relative Biological Effectiveness (RBE)
11222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
2.5.4 RBE
113
1
• Equal doses of different LET radiation DO
NOT produce equal biological effects
2
•A term relating the ability of radiations with
different LETs to produce a specific biologic
response is relative biological effectiveness (RBE)
2.5.4 RBE
114
3
• 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
4
•250 kV x-rays or 1.17/1.33 MeV 60Co as the
standard radiation
RBE is end-point dependent
Fractionated doses of dense vs. sparse ionizing beam:
The RBE of high LET beam becomes larger when the fraction number is increasing.
2.5.4 RBE
The ICRP 1991 standard values for
relative effectiveness
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
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
2.5.4 RBE
http://dmco.ucla.edu/McBride_Lab
WMcB2008
ACUTE RESPONDING TISSUES
(responses seen during standard therapy)
Gut
Skin
Bone Marrow
Mucosa
LATE RESPONDING TISSUES
(responses seen after end of therapy)
Brain
Spinal Cord
Kidney
Lung
Bladder
Tissue Type Matters
Dose (Gy)
Surviving
Fraction
2016128400
.01
.1
1
Late Responding
Tissues
Acute Responding
Tissues and
Many Tumors
Physical Dose = Biological Dose
Example
• To achieve 50% survival fraction, 250 kV x-ray needs 2
Gy, but the tested particle needs 0.66 Gy only
RBE = D250/Dt 2 = 2 / 0.66 = 3
RBE at survival fraction of 0.5 for the tested particle is 3.
2.5.4 RBE
2.5.4 RBE
http://dmco.ucla.edu/McBride_Lab
WMcB2008
Questions on
Interaction of Radiation with Biological Matter:
what is biological dose?
Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu
http://dmco.ucla.edu/McBride_Lab
WMcB2008
1.The lifetime of radicals in target molecules is
about
– 10-3 secs
– 10-6 secs
– 10-9 secs
– 10-12 secs
#2 – free radicals are highly unstable and reactive
http://dmco.ucla.edu/McBride_Lab
WMcB2008
2.Electromagnetic radiation is considered ionizing
if it has a photon energy greater than
– 1.24 eV
– 12.4 eV
– 124 eV
– 1.24 keV
#3 – this is sufficient to break bonds in biological
molecules
http://dmco.ucla.edu/McBride_Lab
WMcB2008
3.The S.I. unit of absorbed dose is
– Becquerel
– Sievert
– Gray
– Roentgen
#3 The International System (IS) unit is the Gray, named
after the radiobiologist Louis “Hal” Gray who was based
in London
http://dmco.ucla.edu/McBride_Lab
WMcB2008
4.Which of the following are not charged
particles?
– Electrons
– Neutrons
– Protons
– Heavy ions
– Alpha particles
#2 – which is why they are called NEUTRons
http://dmco.ucla.edu/McBride_Lab
WMcB2008
5. Which of the following is NOT a characteristic of the
indirect action of ionizing radiation
– Production of diffusible free radicals
– Production of reactive oxygen species
– Involvement of anti-oxidant defenses
– Causes a change in redox within a cell favoring
reduction of constituents
#4 the free radicals produced makes ionizing
radiation an oxidative stress overall
http://dmco.ucla.edu/McBride_Lab
WMcB2008
6. Which of the following is true about the oxygen
enhancement ratio
– Is the same at all levels of cell survival
– Can be measured by the dog-leg in a cell survival
curve after single high dose irradiation of tumors
– Is the ratio of doses needed for an isoeffect in the
absence to the presence of oxygen
– Is low for cells in S cell cycle phase compared to
cells in G2/M phase
#3 responses should be compared by the doses
needed for a particular isoeffect. The OER varies with
the level of effect eg survival
http://dmco.ucla.edu/McBride_Lab
WMcB2008
7. Which of the following is true about Linear Energy
Transfer
– It is a measure of the biological effectiveness of
ionizing radiation
– Shows an inverse correlation with the oxygen
enhancement ratio
– Is maximal at a relative biological effectiveness of
150 keV/micrometer
– Is measured in keV/micrometer
#4 LET is an average value imparted per unit path length.
Because the radiations vary in energy, the LET is not
biologically very useful
http://dmco.ucla.edu/McBride_Lab
WMcB2008
8.The Relative Biological Effectiveness of a
radiation is
– Assessed by the dose required for to
produce the same effect as 250kVp X-rays
– Is the ratio of the dose required of 250 kVp
X-rays to that of the test radiation for a given
isoeffect
– Is directly related to Linear Energy Transfer
– Is about 3 for alpha particle radiation
#2 - again, measured by isoeffective doses – classically
relative to 250kVp x-rays, but often more recently 60Co
has been used
http://dmco.ucla.edu/McBride_Lab
WMcB2008
9. Which of the following radiobiological
phenomena occurring between dose
fractions has little or no effect on normal
tissue radiation responses?
– Repair
– Redistribution of cells in the cell cycle
– Repopulation
– Reoxygenation
#4 – Normal tissues are generally considered to be well
oxygenated

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BASICS RADIOBIOLOGY FOR RADIOTHERAPY

  • 1. TOPIC 2 BASICS RADIOBIOLOGY FOR RADIOTHERAPY (2 hours) 122/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 2. 2.1 Introduction 2.2 Radiation Chemistry 2.3 Volume Definition 2.3.1 Gross Tumour Volume (GTV) 2.3.2 Clinical Target Volume (CTV) 2.3.3 Planning Target Volume (PTV) 2.3.4 Treated Volume (TV) 2.3.5 Irradiated Volume (Iv) 2.3.6 Organs At Risk (Oar) 222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 3. 2.4 5 Rs 2.4.1 Repair 2.4.2 Repopulation 2.4.3 Reoxygenation 2.4.4 Redistribution 2.4.5 Radiosensitivity 2.5 Biological Effect of Ionizing Radiation 2.5.1 Dose Response Curve 2.5.2 Cell Survival Curve 2.5.3 Systemic Effects 2.5.4 Oxygen Effect 2.5.5 LET 2.5.6 Relative Biological Effectiveness (RBE) 322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 4. 2.1 Introduction 422/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 5. INTERACTIONS between Ionizing radiation and living systems radiation physics + biology Radiation oncology 2.1 Introduction 522/3/2017 ACTION Of ionizing radiation on biological tissues radiation physics + biology Radiobiology
  • 6. 2.1 Introduction 622/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak Radiobiology allows the optimization of a radiotherapy schedule for individual patients in regards to: Total dose and number of fractions Overall time of the radiotherapy course Tumour control probability (TCP) and normal tissue complication probability (NTCP)
  • 7. 2.2 Radiation Chemistry 722/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 8. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 8 2.2 Radiation Chemistry Radiation may impact the DNA directly, causing ionization of the atoms in the DNA molecule (“direct hit”). It is a fairly uncommon occurrence due to the small size of the target; the diameter of the DNA helix =2 nm. Dominant process in the interaction of high LET particles such as neutrons or alpha particles with biological material. 1) DIRECT ACTION
  • 9. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 9 2) INDIRECT ACTION 2.2 Radiation Chemistry The radiation interacts with non-critical target atoms or molecules, usually water. This results in the production of free radicals, which are atoms or molecules that have an unpaired electron and thus are highly reactive 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
  • 10. • Indirect action: Electrons produce free radicals which break chemical bonds and produce chemical changes • Direct Action: Photon ejects an electron which produce a biological damage on the DNA 2.2 Radiation Chemistry
  • 13. 2.3 Volume Definition 2.3.1 Gross Tumour Volume (GTV) 2.3.2 Clinical Target Volume (CTV) 2.3.3 Planning Target Volume (PTV) 2.3.4 Treated Volume (TV) 2.3.5 Irradiated Volume (Iv) 2.3.6 Organs At Risk (Oar) 1322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 14. •Volume definition is a prerequisite for meaningful 3-D treatment planning and for accurate dose reporting. •ICRU reports No. 50 and 62 define and describe several target and critical structure volumes that aid in the treatment planning process and that provide a basis for comparison of treatment outcomes. •The following volumes have been defined as principal volumes related to 3-D treatment planning: gross tumour volume (GTV), clinical target volume (CTV), internal target volume (ITV) and planning target volume (PTV) 2.3 Volume Definition
  • 15. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 15
  • 16. GTV – Gross Tumour Volume CTV – Clinical Target Volume PTV – Planning Target Volume OAR – Organ at Risk TV – Treated Volume IV – Irradiated Volume 2.3 Volume Definition
  • 17. The gross palpable, visible and demonstrable extent and location of the malignant growth (ICRU Report No. 50) 2.3.1 Gross Tumour Volume (GTV)
  • 18. •This is determined by physical examination by the oncologist and the results of radiological investigations relevant to the site of the tumour. •As the term suggests, tumours 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. 2.3.1 Gross Tumour Volume (GTV)
  • 19. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 19 Gross Tumour Volume (GTV) – Gross palpable or visible/demonstrable extent and location of tumour GTV
  • 20. •“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) 2.3.2 Clinical Target Volume (CTV)
  • 21. •Usually determined by the radiation oncologist, often after other relevant specialists such as pathologists or radiologists have been consulted. •This volume may not be defined separately but considered when defining the planning target volume (PTV) (e.g. CTV = GTV + 1 cm margin) 2.3.2 Clinical Target Volume (CTV)
  • 22. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 22 Clinical Tumour Volume (CTV) CTV Contains a GTV and/or sub-clinical microscopic malignant disease, which has to be eliminated CTV
  • 23. •“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) 2.3.3 Planning Target Volume (PTV)
  • 24. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 24 • 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). 2.3.3 Planning Target Volume (PTV)
  • 25. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 25 • In practice, it is often the result of a compromise between two contradictory issues: making sure that the CTV will receive the prescribed dose while at the same time ensuring that OARs will not receive an excessive dose. 2.3.3 Planning Target Volume (PTV)
  • 26. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 26 Planning Target Volume (PTV) • Contains a CTV and a margin to account for variation is size, shape and position relative to treatment beams PTV
  • 27. •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. 2.3.4 Treated Volume (TV)
  • 28. •The TV should not be significantly larger than the PTV. The use of 3D treatment planning and shaping the radiation fields to the shape of the PTV using conformal radiation delivery techniques ensures that the TV encloses the PTV with as narrow a margin as possible. This ensures minimal irradiation of surrounding OARs while coverage of the PTV is assured. 2.3.4 Treated Volume (TV)
  • 29. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 29 Treated volume Treated volume – Volume enclosed by an isodose surface selected as appropriate to achieve purpose of treatment Treated Volume
  • 30. •The tissue volume receiving a radiation absorbed dose that is considered significant in relation to normal tissue tolerance. •This concept is not often considered in practice but may be useful when comparing one or more competing treatment plans. •Clearly, it would be preferable to accept the plan with the smallest IV, all else being equal. 2.3.5 Irradiated Volume (Iv)
  • 31. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 31 Irradiated volume Irradiated volume – The volume that receives a dose that is significant in relation to normal tissue tolerance Irradiated Volume
  • 32. •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. 2.3.6 Organs At Risk (Oar)
  • 33. •The following are examples of the most common OARs that must be considered: 1. Brain: lens of eye, optic chiasm, brain stem 2. Head & neck: lens of eye, parotid glands 3. Thorax: spinal cord, lungs 4. Abdomen: spinal cord, large bowel, small bowel, kidneys 5. Pelvis: bladder, rectum, femoral heads, large bowel, small bowel 2.3.6 Organs At Risk (Oar)
  • 34. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 34 Organs at Risk (OAR) • Normal tissues whose radiation sensitivity could significantly influence treatment planning and/or the dose prescription OARs • Lung • Spinal cord
  • 35. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 35
  • 36. 2.4 Biological Factors (5 Rs) 2.4.1 Repair 2.4.2 Repopulation 2.4.3 Reoxygenation 2.4.4 Redistribution 2.4.5 Radiosensitivity 3622/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 37. Repair Repopulation Reoxygenation Redistribution Radiosensitivity •The biological factors that influence the response of normal and neoplastic tissues to fractionated radiotherapy 2.4 Biological Factor (5 Rs)
  • 38. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 38
  • 39. 2.4.1 Repair 3922/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 40. •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 2.4.1 Repair
  • 41. •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. 2.5.1 Repair
  • 42. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 42
  • 43. 2.4.2 Repopulation 4322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 44. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 44 • In both tumours and normal tissues, proliferation of surviving cells may occur during the course of fractionated treatment. • Furthermore, as cellular damage and cell death occur during the course of 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 course of the treatment and reduce the overall response to irradiation) 2.4.2 Repopulation
  • 45. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 45 • This effect is most important in early-responding normal tissues (e.g., skin, gastrointestinal tract) or in tumours whose stem cells are capable of rapid proliferation; it will be of little consequence in late-responding, slowly proliferating tissues (e.g., kidney), which do not suffer much early cell death and hence do not produce an early proliferative response to the radiation treatment. • Repopulation is likely to be more important toward the end of a course of treatment, when sufficient damage has accumulated (and cell death occurred) to induce a regenerative response. 2.4.2 Repopulation
  • 46. •The repopulation time of tumour cells appears to vary during radiotherapy - at the commencement it may be slow (e.g. due to hypoxia), however a certain time after the first fraction of radiotherapy (often termed the “kick-off time”, Tk) repopulation accelerates. •Repopulation must be taken into account when protracting/prolong radiation e.g. due to scheduled (or unscheduled) breaks such as holidays. 2.4.2 Repopulation
  • 47. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 47
  • 48. 2.4.3 Reoxygenation 4822/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 49. •Oxygen is an important enhancement for radiation effects (“Oxygen Enhancement Ratio” (OER) •The tumor may be hypoxic (in particular in the center which may not be well supplied with blood) •One must allow the tumor to re-oxygenate, which typically happens a couple of days after the first irradiation 2.4.3 Reoxygenation
  • 50. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 50 • The response of tumours to large single doses of radiation is dominated by the presence of hypoxic cells within them, even if only a very small fraction of the tumour stem cells are hypoxic. • Immediately after a dose of radiation, the proportion of the surviving cells that is hypoxic will be elevated. However, with time, some of the surviving hypoxic cells may gain access to oxygen and hence become reoxygenated and more sensitive to a subsequent radiation treatment. • Reoxygenation can result in a substantial increase in the sensitivity of tumours during fractionated treatment. 2.4.3 Reoxygenation
  • 51. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 51
  • 52. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 52
  • 53. 2.4.4 Redistribution 5322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 54. •Cells have different radiation sensitivities in different parts of the cell cycle •Highest radiation sensitivity is in early S and late G2/M phase of the cell cycle G1 G1 S (synthesis) M (mitosis)G2 2.4.4 Redistribution
  • 55. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 55 • Variation in the radiosensitivity of cells in different phases of the cell cycle results in the cells in the more resistant phases being more likely to survive a dose of radiation. • Two effects can make the cell population more sensitive to a subsequent dose of radiation. 1. Some of the cells will be blocked in the G2 phase of the cycle, which is usually a sensitive phase. 2. Some of the surviving cells will redistribute into more sensitive parts of the cell cycle. • Both effects will tend to make the whole population more sensitive to fractionated treatment as compared with a single dose. • .
  • 56. •The distribution of cells in different phases of the cycle is normally not something which can be influenced - however, radiation itself introduces a block of cells in G2 phase which leads to a synchronization •One must consider this when irradiating cells with breaks of few hours. 2.4.4 Redistribution
  • 57. 2.4.5 Radiosensitivity 5722/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 58. •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 tumours are more radioresponsive than others to a particular fractionation schedule, and this is largely due to differences in radiosensitivity. 2.4.5 Radiosensitivity
  • 59. Muscle Bones Nervous system Skin Liver Heart Lungs Bone Marrow Spleen Thymus Lymphatic nodes Gonads Eye lens Lymphocytes (exception to the RS laws) Low RSMedium RSHigh RS 2.4.5 Radiosensitivity
  • 60. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 60
  • 61. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 61
  • 62. 2.5 Biological Effect of Ionizing Radiation 2.5.1 Dose Response Curve 2.5.1.1 Deterministic 2.5.1.2 Stochastic Effect 2.5.1.3 Sigmoid Curve 2.5.1.4 Cell Survival Curve 2.5.2 LET 2.5.3 OER 2.5.4 RBE 62Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 63. 2.5 Biological Effect of Ionizing Radiation 6322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 64. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 64 2.5 Biological Effect of Ionizing Radiation
  • 65. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 65 2.5 Biological Effect of Ionizing Radiation
  • 66. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 66 2.5 Biological Effect of Ionizing Radiation
  • 67. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 67 2.5 Biological Effect of Ionizing Radiation
  • 68. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 68 2.5 Biological Effect of Ionizing Radiation
  • 69. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 69 2.5 Biological Effect of Ionizing Radiation
  • 70. Module Medical IX. 70 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
  • 71. 2.5 Biological Effect of Ionizing Radiation 71 Dose to the tumor determines probability of cure Dose to normal structures determines probability of side effects and complications Dose to patient, staff and visitors determines risk of radiation detriment to these groups What matters in the end is the biological effect! 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 2.5 Biological Effect of Ionizing Radiation
  • 72. 2.5 Biological Effect 7222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak Biological Effect Stochastic Effects (carcinogenic and genetic effects) Deterministic Effects (tissue reactions)
  • 73. 2.5.1 Dose Response Curve 7322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 74. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 74 2.5.1.3 Sigmoid Curve (non-threshold) DOSE RESPONSE CURVE Line 3: Non linear dose response Line 1: No level of radiation can be considered safe. Diagnostic Imaging Line 2: Threshold is assumed, response expected at lower doses. (Radiotherapy) Stochastic Effect
  • 75. 2.5.1.1 Deterministic Effect 7522/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 76. 2.5.1.1 Deterministic Effect DETERMINISTIC EFFECTS/ (High Dose) erythema skin breakdown cataracts death Have a dose threshold Due to cell killing (high dose given over short period) Severity of harm is dose dependent Specific to particular tissues Acute effect/ short term effect/ early effect
  • 77. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 77
  • 78. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 78
  • 79. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 79 2.5.1.1 Deterministic Effect
  • 80. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 80
  • 81. Acute radiation syndrome (ARS)  ARS is 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)
  • 82. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 82
  • 83. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 83
  • 84. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 84
  • 85. 2.5.1.2 Stochastic Effect 8522/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 86. 2.5.1.2 Stochastic Effect STOCHASTIC EFFECT (low dose) Eg: -cancer induction (Somatic effect) -hereditary effects Severity (example cancer) independent of the dose Due to cell changes and proliferation towards a malignant disease No dose threshold - applicable also to very small doses Probability of effect increases with dose Late effect / Chronic effect)
  • 87. 2.5 Biological Effect2.5.1.2 Stochastic Effect
  • 88. Phases of cancer induction and manifestation Initia tion Muta te d Cells Elimia tion Re pa ra tion Progre ssion Pre-c a nce r Norma l Cells Promotion Minima l Ca nc er Clinic a l Ca ncer Spre a ding
  • 89.
  • 90. 2.5.1.3 Sigmoid Curve (non-threshold) 9022/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 91. Dose Repairing cell structures is still possible No repairing: a low dose means a great damage Practically all the cells are dead dose 2.5.1.3 Sigmoid Curve (non-threshold)
  • 92. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 92 2.5.1.3 Sigmoid Curve (non-threshold) LD 50/60 amount of radiation that will cause 50% of exposed individuals to die within 60 days
  • 93. 2.5.1.4 Cell Survival Curve 9322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 94. Biological Effects At Cellular Level Possible mechanisms of cell death: • Physical death • Functional death • Death during interphase • Mitotic delay • Reproductive failure Cellular effects of ionizing radiation are studied by cell survival curves %survivalcells(semilogarithmic) Dose n = targets Dq D0 (threshold) (radiosensitivity) 2.5.1.4 Cell Survival Curve
  • 95. • Do = 37% dose slope - Dose required to reduce the number of clonogenic cells to 37% of their former value • Dq = Quasi threshold dose - Dose at which straight portion extrapolated backward cuts the dose axis • n = extrapolation number - Extrapolating the straight portion of the survival curve until it cuts the “surviving fraction” axis  Radiosensitive cells are characterized by curves with steep slope D0 and/or small shoulder (low n) Loge n = Dq / D0 %survivalcells(semilogarithmic) Dose n = targets Dq D0 (threshold) (radiosensitivity) 2.5.1.4 Cell Survival Curve
  • 96. 2.5.2 LET 9622/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 97. 2.5.2 LET 9722/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak LET the linear rate of energy absorption by absorbing medium as charged particle traverses the medium (dE/dl, KeV/mm) defining the quality of an ionizing radiation beam
  • 99. 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
  • 100. http://dmco.ucla.edu/McBride_Lab WMcB2008 • 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
  • 101. http://dmco.ucla.edu/McBride_Lab WMcB2008 Repairable Sublethal Damage X- or -radiation is sparsely ionizing; most damage can be repaired 4 nm 2 nm
  • 102. http://dmco.ucla.edu/McBride_Lab WMcB2008 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
  • 103. http://dmco.ucla.edu/McBride_Lab WMcB2008 At high dose, intertrack repairable Sublethal Damage may Accumulate forming unrepairable, lethal MDS Also known as  - type killing
  • 104. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 104 2.5.2 LET
  • 105. 2.5.3 Oxygen Enhancement Ratio 10522/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 106. 2.5.3 Oxygen Enhancement Ratio 106 1 • Oxygen is a powerful oxidizing agent and therefore acts as a radiosensitizer if it is present at the time of irradiation (within msecs). • Its effects are measured as the oxygen enhancement ratio (O.E.R.) 2 • 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 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 107. 2.5.3 Oxygen Enhancement Ratio 107 3 • The effect is quite dramatic for low LET (sparsely ionizing) radiations, while for high LET (densely ionizing) radiations it is much less pronounced 4 • 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) 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 108. 22/3/2017 108 2.5.3 Oxygen Enhancement Ratio
  • 109. 2.5.3 Oxygen Enhancement Ratio 109 5 • For densely ionizing radiation, such as low-energy α-particles, the survival curve does not have an initial shoulder 6 • 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 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 110. http://dmco.ucla.edu/McBride_Lab WMcB2008 Oxygen Enhancement Ratio (OER) Dose required to produce a specific biological effect in the absence of oxygen Dose required for the same effect in its presence= OER varies with level of effect but can be 2.5 - 3 fold 1) Culture Cells ( 3) Count cells in hemocytometer 4) irradiate under oxic or hypoxic conditions 0 Gy 2Gy 4Gy 6Gy 5) Plate cells and grow for about 12 days . . . . . .. . 6) Count colonies Dose (Gy) S.F. 0 2 4 6 8 10 1.0 0.1 0.01 oxic hypoxic Physical Dose = Biological Dose 2) Suspend Cells trysinization)
  • 111. http://dmco.ucla.edu/McBride_Lab WMcB2008 • Hypoxic areas occur almost solely in tumors and are more radioresistant than oxic areas. • Hypoxia contributes to treatment failure • Reoxygenation occurs between radiation dose fractions giving a rationale for dose fractionation • The oxygen effect is greater for low LET than high LET radiation Giacca and Brown Pimonizadole (oxygen mimetic) staining colorectal carcinoma The effects of hypoxia were first discovered in 1909 by Schwarz who showed that strapping a radium source on the arm gave less of a skin reaction than just placing it there. This was used to give higher doses to deep seated tumors. Clinical Relevance of Hypoxia
  • 112. 2.5.4 Relative Biological Effectiveness (RBE) 11222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  • 113. 2.5.4 RBE 113 1 • Equal doses of different LET radiation DO NOT produce equal biological effects 2 •A term relating the ability of radiations with different LETs to produce a specific biologic response is relative biological effectiveness (RBE)
  • 114. 2.5.4 RBE 114 3 • 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 4 •250 kV x-rays or 1.17/1.33 MeV 60Co as the standard radiation
  • 115. RBE is end-point dependent Fractionated doses of dense vs. sparse ionizing beam: The RBE of high LET beam becomes larger when the fraction number is increasing. 2.5.4 RBE
  • 116. The ICRP 1991 standard values for relative effectiveness 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 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 2.5.4 RBE
  • 117. http://dmco.ucla.edu/McBride_Lab WMcB2008 ACUTE RESPONDING TISSUES (responses seen during standard therapy) Gut Skin Bone Marrow Mucosa LATE RESPONDING TISSUES (responses seen after end of therapy) Brain Spinal Cord Kidney Lung Bladder Tissue Type Matters Dose (Gy) Surviving Fraction 2016128400 .01 .1 1 Late Responding Tissues Acute Responding Tissues and Many Tumors Physical Dose = Biological Dose
  • 118. Example • To achieve 50% survival fraction, 250 kV x-ray needs 2 Gy, but the tested particle needs 0.66 Gy only RBE = D250/Dt 2 = 2 / 0.66 = 3 RBE at survival fraction of 0.5 for the tested particle is 3. 2.5.4 RBE
  • 120. http://dmco.ucla.edu/McBride_Lab WMcB2008 Questions on Interaction of Radiation with Biological Matter: what is biological dose? Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. wmcbride@mednet.ucla.edu
  • 121. http://dmco.ucla.edu/McBride_Lab WMcB2008 1.The lifetime of radicals in target molecules is about – 10-3 secs – 10-6 secs – 10-9 secs – 10-12 secs #2 – free radicals are highly unstable and reactive
  • 122. http://dmco.ucla.edu/McBride_Lab WMcB2008 2.Electromagnetic radiation is considered ionizing if it has a photon energy greater than – 1.24 eV – 12.4 eV – 124 eV – 1.24 keV #3 – this is sufficient to break bonds in biological molecules
  • 123. http://dmco.ucla.edu/McBride_Lab WMcB2008 3.The S.I. unit of absorbed dose is – Becquerel – Sievert – Gray – Roentgen #3 The International System (IS) unit is the Gray, named after the radiobiologist Louis “Hal” Gray who was based in London
  • 124. http://dmco.ucla.edu/McBride_Lab WMcB2008 4.Which of the following are not charged particles? – Electrons – Neutrons – Protons – Heavy ions – Alpha particles #2 – which is why they are called NEUTRons
  • 125. http://dmco.ucla.edu/McBride_Lab WMcB2008 5. Which of the following is NOT a characteristic of the indirect action of ionizing radiation – Production of diffusible free radicals – Production of reactive oxygen species – Involvement of anti-oxidant defenses – Causes a change in redox within a cell favoring reduction of constituents #4 the free radicals produced makes ionizing radiation an oxidative stress overall
  • 126. http://dmco.ucla.edu/McBride_Lab WMcB2008 6. Which of the following is true about the oxygen enhancement ratio – Is the same at all levels of cell survival – Can be measured by the dog-leg in a cell survival curve after single high dose irradiation of tumors – Is the ratio of doses needed for an isoeffect in the absence to the presence of oxygen – Is low for cells in S cell cycle phase compared to cells in G2/M phase #3 responses should be compared by the doses needed for a particular isoeffect. The OER varies with the level of effect eg survival
  • 127. http://dmco.ucla.edu/McBride_Lab WMcB2008 7. Which of the following is true about Linear Energy Transfer – It is a measure of the biological effectiveness of ionizing radiation – Shows an inverse correlation with the oxygen enhancement ratio – Is maximal at a relative biological effectiveness of 150 keV/micrometer – Is measured in keV/micrometer #4 LET is an average value imparted per unit path length. Because the radiations vary in energy, the LET is not biologically very useful
  • 128. http://dmco.ucla.edu/McBride_Lab WMcB2008 8.The Relative Biological Effectiveness of a radiation is – Assessed by the dose required for to produce the same effect as 250kVp X-rays – Is the ratio of the dose required of 250 kVp X-rays to that of the test radiation for a given isoeffect – Is directly related to Linear Energy Transfer – Is about 3 for alpha particle radiation #2 - again, measured by isoeffective doses – classically relative to 250kVp x-rays, but often more recently 60Co has been used
  • 129. http://dmco.ucla.edu/McBride_Lab WMcB2008 9. Which of the following radiobiological phenomena occurring between dose fractions has little or no effect on normal tissue radiation responses? – Repair – Redistribution of cells in the cell cycle – Repopulation – Reoxygenation #4 – Normal tissues are generally considered to be well oxygenated