BASICS RADIOBIOLOGY FOR RADIOTHERAPY

TOPIC 2
BASICS RADIOBIOLOGY FOR
RADIOTHERAPY
(2 hours)
28/1/2018 Dr. Nik Noor Ashikin Bt Nik Ab Razak 1

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)

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)28/1/2018 Dr. Nik Noor Ashikin Bt Nik Ab Razak 3

2.1 Introduction

INTERACTIONS
between
Ionizing
radiation and
living systems
radiation
physics
+
biology
Radiation
oncology
2.1 Introduction
28/1/2018 5
ACTION Of
ionizing
radiation on
biological
tissues
radiation
physics
+
biology
Radiobiology

2.1 Introduction
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)

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.
Dominant process in the interaction of high LET
particles such as neutrons or alpha particles with
biological material.
1) DIRECT ACTION It is a fairly uncommon occurrence due to the
small size of the target; the diameter of the DNA
helix =2 nm.

2) INDIRECT ACTION
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

2) INDIRECT ACTION
If the water molecule is ionised
H2O = H2O+ + e-
(H2O is the water molecule ;
H2O+ is an ion radical )
Ion radicals have a short life,
usually no more than 10-10 s,
before they decay to form free
radicals
Free radicals are not charged,
but do have an unpaired
electron in the outer shell.
The water ion radical can, for
example, do the following:
H2O+ + H2O = H3O+ + OH*
(H2O+, H3O+ are the ion radicals
H2O is a water molecule)
OH* is a highly reactive hydroxyl
radical, with 9 electrons,
therefore one is unpaired.
Hydroxyl radicals (OH*), are
highly reactive and can go on to
react with DNA. It is estimated
that 2/3 of the x-ray damage to
mammalian DNA is by hydroxyl
radicals

• 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

•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)

GTV – Gross Tumour Volume
CTV – Clinical Target Volume
PTV – Planning Target Volume
OAR – Organ at Risk
TV – Treated Volume
IV – Irradiated Volume

The gross palpable, visible
and demonstrable extent
and location of the
malignant growth (ICRU
Report No. 50)

•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.

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)

•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)

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)

• 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).

• 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.

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.

•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.

Treated volume
Part VIII.3.7 Operational Considerations – Planning of physical
treatment
Slide 32
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.

treatment
Slide 34
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.

•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

treatment
Slide 37
OARs
• Lung
• Spinal cord

2.4 Biological Factors (5 Rs)
2.4.1 Repair
2.4.2 Repopulation
2.4.3 Reoxygenation

RADIATION DAMAGE CLASSIFICATION
•Radiation damage to mammalian cells are divided into three
categories:
• 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.
2.4 Biological Factor (5 Rs)

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.

What DO You Think?
Single dose
vs
Fractionation Dose

Repair
Repopulation
Reoxygenation
Redistribution
Radiosensitivity
•The biological factors
that influence the
response of normal and
neoplastic tissues to
fractionated radiotherapy

2.4.1 Repair

•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

2.4.2 Repopulation

• In both tumours and normal tissues, proliferation of surviving cells
may occur during the course of fractionated treatment.
• 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

• 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

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
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

• 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
2.4.2 Repopulation

2.4.3 Reoxygenation

•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

Reoxygenation
•Phenomenon by which
hypoxic cells become
oxygenated after a
dose of radiation is
termed reoxygenation.
2.4.3 Reoxygenation

• When a tumour outgrows its blood
supply, the cells in the centre of the
tumour do not get enough oxygen.
• As the tumour shrinks during radiation
treatment, the hypoxic cancer cells in
the centre of the tumour come closer
to the blood supply.
• They then become oxygenated and
more sensitive to the next dose of
radiation.
Oxygen Effect2.4.3 Reoxygenation

Reoxygenation
• Cells at the center of tumor are
hypoxic and are resistant to low
LET radiation.
• Hypoxic cells get reoxygenated
occurs during a fractionated
course of treatment, making them
more radiosensitive to subsequent
doses of radiation.
2.4.3 Reoxygenation

• 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

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
2.4.3 Reoxygenation

• 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
• With multiple doses, cells progress through to a
new phase of the cell cycle (sensitive)
• “Sensitization due to re-assortment” causes
therapeutic gain.
G1
G1
S (synthesis)
M (mitosis)G2

Reassortment / Redistribution
• Increase in survival during 1st 2hrs in split dose experiment results from repair of
SLD
• If interval between doses is 6hrs then resistant cells move to sensitive phases
• If interval is more than 6hrs then cells will repopulate & results in increase of
surviving fraction.
• Hence dose fractionation enable normal tissue to recover between fractions
reducing damage to normal tissue
• Ability of normal tissue to repair radiation damage better than tumor forms basis of
fractionation.

•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 .

•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.

•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.

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

Summary
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.

6th R???
• Remote cellular effects or bystander effects occur when non-irradiated cells
that are located nearby irradiated cells undergo cellular damage similar to the
irradiated cells. This experimental observation contradicts the formerly
accepted theory of radiation-induced targeted cell kill. While targeted cells
can be killed by radiation, according to the bystander theory, non-targeted
cells can also present signs of radiation damage that eventually kills the cell.
This happens as a consequence of cellular communication when radiation-hit
cells direct damage signals through gap junctions to the neighbouring non-
targeted cells, which then act as being hit by radiation.
Remote bystander effects

2.5.1.1 Deterministic
2.5.1.2 Stochastic Effect
2.5.2 LET
2.5.3 OER
2.5.4 RBE Dr. Nik Noor Ashikin Bt Nik Ab Razak 76

Module Medical IX. 78
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

28/1/2018
Dr. Nik Noor Ashikin Bt Nik Ab Razak
79

Tumor, Benign, Malignant

*A tumor is an abnormal lump or growth of cells.
*When the cells in the tumor are normal, it is benign.
*Something just went wrong, and they overgrew and produced a lump.
*When the cells are abnormal and can grow uncontrollably, they are
cancerous cells, and the tumor is malignant.
*To determine whether a tumor is benign or cancerous, a doctor can
take a sample of the cells with a biopsy procedure.
*Then the biopsy is analyzed under a microscope by a pathologist, a
doctor specializing in laboratory science.
•TUMOR

*If the cells are not cancerous, the tumor is benign.
*It won't invade nearby tissues or spread to other areas of the body
(metastasize).
*A benign tumor is less worrisome unless it is pressing on nearby tissues,
nerves, or blood vessels and causing damage.
*Fibroids in the uterus or lipomas are examples of benign tumors.
*Benign tumors may need to be removed by surgery.
*Some types of benign tumors such as intestinal polyps are considered
precancerous and are removed to prevent them becoming malignant.
*Benign tumors usually don't recur once removed, but if they do it is usually in
the same place.
BENIGN TUMORS: NONCANCEROUS

*Malignant means that the tumor is made of cancer cells and it can invade
nearby tissues.
*Some cancer cells can move into the bloodstream or lymph nodes, where they
can spread to other tissues within the body this is alled metastasis.
*Cancer can occur anywhere in the body including the breast, intestines, lungs,
reproductive organs, blood, and skin.
*For example, breast cancer begins in the breast tissue and may spread to
lymph nodes in the armpit if it's not caught early enough and treated. Once
breast cancer has spread to the lymph nodes, the cancer cells can travel to
other areas of the body, like the liver or bones.
Malignant Tumors: Cancerous

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!

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.
Stochastic
Effect

2.5.1.1 Deterministic Effect

DETERMINISTIC
EFFECTS/
(High Dose)
+Erythema
+Skin Breakdown
+Cataracts
+Death
Have a dose threshold
(above 500–1000 mSv)
high dose
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

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)

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
(below several tens or 100–
200 mSv).
Probability of effect
increases with dose
Late effect / Chronic
effect)

Low doses are considered by
observations in epidemiology, cellular
radiation biology and microdosimetry.

Stochastic Effect VS Deterministic Effect

Comparison between deterministic and stochastic
effects

Somatic effects
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)

2.5.2 LET

2.5.2 LET
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
– 4 MeV protons
•14 protons which give 300
• The biological effectiveness of
these different radiations vary!
-ray
’-ray
excitation
ionization
 particle
excitation and ionization

WMcB2008
Repairable Sublethal Damage
X- or -radiation is sparsely ionizing; most damage can be
repaired
4 nm
2 nm

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

WMcB2008
At high dose, intertrack
repairable Sublethal Damage may
Accumulate forming
unrepairable, lethal MDS
Also known as  - type killing

2.5.2 LET

Thought of the day……
Why difference in the energy of electron
beam having difference LET values?

2.5.3 Oxygen Enhancement Ratio

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

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)

28/1/2018 126

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

2.5.4 Relative Biological Effectiveness (RBE)

2.5.4 RBE
129
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
130
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

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

Pre-TASK 2
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