APPLICATION

OF
RADIOBIOLOGY
IN
RADIOTHERAPY

NILESH KUMAR
PG RADIATION PHYSICS
DEAPARTMENT OF RADIATION PHYSICS
 The role of radiotherapy in cancer control

 Radiotherapy can be used alone, or as an effective neoadjuvant and

adjuvant treatment in combination with other treatment modalities such as
surgery, chemotherapy and hormonal therapy.

 Neoadjuvant therapies are delivered before the main treatment, to help

reduce the size of a tumor or kill cancer cells that have spread.

 Adjuvant therapy, also known as, add-on therapy, is therapy that is given in
addition to the primary or initial therapy to maximize its effectiveness. It is
delivered after the primary treatment, to destroy remaining cancer cells
 The aim of radiotherapy may be cure, control, and palliation, offering
benefits in terms of:

 organ preservation
 
 quality of life  

 survival outcomes  

 effective palliation of symptoms

 The treating team considers a
range of factors when deciding on
a course of radiotherapy.

 Tumour related factors include:

 the site of the cancer 

 an histologically-proven cell type

 the grade and stage of the tumour

 the radiosensitivity of the tumour.

 Key concepts of radiobiology

• Radiotherapy aims to treat

cancer through delivering
sufficient doses of ionizing
radiation to a specific area of the
body to damage target DNA that
eventually results in cell death.

• Ionizing radiation causes cell

death either directly or
indirectly. 
DIRECT EFFECT:

• If radiation interacts with the atoms of the DNA

molecule, or some other cellular component
critical to the survival of the cell, it is referred to
as a direct effect.

• The direct ionization of atoms in DNA molecules

is the result of energy absorption via the
photoelectric effect and Compton interactions.

• If this absorbed energy is sufficient to remove

electrons from the molecule then bonds are
broken, which can break one or both DNA
strand.

• A single broken strand can usually be repaired

by the cell, while two broken strands commonly
result in cell death.
Single strand and double strand DNA break
INDIRECT EFFECT:
• If a cell is exposed to radiation, the probability of the radiation interacting
directly with the DNA molecule is very small.

• The indirect effect of radiation on molecules includes the formation of

free radicals by energy transfer from radiation, and the resulting molecular
damage caused by the interactions of these free radicals with DNA.

• This phenomenon is most probably due to the interaction of radiation

with water molecules, since the human body is approximately 80% water.

• Free radicals are electrically neutral atoms that contain “free” (i.e.,
unbound) electrons. They are highly electrophilic and reactive.
 The basic principles of radiobiology are:

 Reoxygenation: occurs when radiation is delivered in multiple fractions to cells

that may be relatively resistant due to hypoxia; cells may become
reoxygenated and therefore more radiosensitive.

 Redistribution: is defined by cells that survive a dose of radiation due to

synchronisation in resistant phases of the division cycle and redistributing into
more sensitive phases of the cell cycle during subsequent doses of radiation.

 Repopulation: describes cells responding to lethal injury by repopulating or

regenerating themselves.

 Repair: occurs following sub lethal cellular injury which represents damage to
the strands of the DNA and which can be repaired by enzymatic processes.
• The four Rs of radiation biology, the tumouricidal dose, and the tolerance
of surrounding critical tissues determine the prescription for a site specific
tumour with a particular histology and pathology.

• To quantify the amount or dose of absorbed radiation within a recipient,

the unit of Gray (Gy) is used. 

• 1 Gray (Gy) = 1Joule of energy absorbed per kg of mass = 1J/kg. 

• This absorbed dose is an indicator of the level of biological effects that

may occur in the different tissues of the body due to ionizing radiation.
• Based on the principles of radiobiology, the total dose of radiation prescribed
to treat a particular tumour is divided into a number of daily doses or
fractions.

• This aims to protect normal surrounding tissue while maximizing the radiation
effect on the tumour.

• Different tissues have varying tolerance levels to radiation exposure which, if

exceeded, results in high morbidity of the treatment.
Application Of Radiobiology In Radiotherapy
 Categorization Of Application Of Radiobiology In Radiotherapy Is-:

1. Fractionation

2. Tissue Tolerance

3. Toxicity
 FRACTIONATION

 Fractionation effects are utilised in the treatment of cancer with radiation

therapy.

 When the total dose of radiation is divided into several, smaller doses over a
period of several days, there are fewer toxic effects on healthy cells.

 This maximizes the effect of radiation on cancer and minimizes the negative
side effects.
 A typical fractionation scheme divides the dose into 30 units delivered every
weekday over six weeks.

 Fractionation is classified into -:

 Conventional-fractionation

 Hypo-fractionation

 Hyper-fractionation

 Accelerated-fractionation
 Radiation biology have found that as the absorbed dose of radiation
increases, the number of cells which survive decreases.

 They have also found that if the radiation is fractionated into smaller doses,
with one or more rest periods in between, fewer cells die.

 This is because of self-repair mechanisms which repair the damage to DNA

and other biomolecules such as proteins.
 Need of Fractionation in Radiotherapy

 The 5’Rs of radiotherapy is the basis for Fractionation.

 The total dose cannot be directly in one time, since it is divided into
fractions because dose rate at one time can give rise to-:

 Adverse reaction.

 Exceed NTT.

 Chances of Recurrence.
 Therefore, it is necessary to divide the
total dose in fractions.

 Normal cell can protect themselves

from radiation through Repair and
Repopulation during the inter-fraction
period.

 Tumor cells are sensitized to radiation

through Reoxygenation and
Redistribution.
 Radiotherapy is usually fractionated given in a series of daily doses spread
over no; of weeks.

 The 4- factors that may be influence the effect of such fractionated

treatment -:

 Repair of subleathal damage.

 Repopulation by surviving cell.

 Redistribution of cell throughout the division cycle.

 Reoxygenation of hypoxic cells

Cell cycle
• G0 = Cell rests (it’s not dividing) and
does its normal work in the body.

• G1 = RNA and proteins are made for

dividing.

• S = Synthesis (DNA is made for new

cells).

• G2 = Apparatus for mitosis is built.

• M = Mitosis (the cell divides into 2

cells)
RADIATION TOLERANCES
OF ORGAN AT RISK:
 TISSUE TOLERANCE
 CLASSIFICATION OF ORGAN AT RISK:

 Serial organ -:

 whole organ is continuous unit and damage of the organ ( spinal cord,
digestive system). So point dose is significant.

 Parallel organ -:

 organ consist of several functional units and if one part is damaged, the
rest of the organ makes up for all the loss (lung or bladder). Dose
delivered to a given volume or average/mean dose is considered.

 Serial-parallel : kidney , heart .

Serial Organ is looked
for Maximum dose.

Parallel Organ is looked

for Mean dose
 TOXICITY

 The degree to which a substance (a toxin or poison) can harm humans or

animals.

 Chronic toxicity is the ability of a substance or mixture of substances to

cause harmful effects over an extended period, usually upon repeated or
continuous exposure, sometimes lasting for the entire life of the exposed
organism.

 Toxicity of Radiation

 Radiation toxicity involves exposure to ionizing radiation, most commonly in

the alpha, beta, gamma, delta, and theta wavelengths, which causes
damage at the chromosomal and cellular levels.
Overview
LET and RBE
 DEPOSITION OF RADIANT ENERGY

• If the radiation is absorbed in the biological material

– the events (ionisation) tends to localise along the tracks of individual

particles and that depends on the type of ionising radiation

– Electromagnetic or particulate
 DIRECTLY IONISING INDIRECTLY IONISING

•  
protons, - particles, x-rays ,
Electrons, neutrons gamma rays

Densely ionising Sparsely ionising

radiations radiations
 LINEAR ENERGY TRANSFER (LET)

• Is defined as “ energy transferred per

unit length
of the track “
• Or “energy deposited per unit track “
• Unit used is keV/μm
(kiloelectron volt per
micrometer)
LINEAR ENERGY TRANSFER (LET)

•• LET
  (L) of charged particles in a medium is the quotient
of dE/dl

dE- average energy locally imparted to the

medium by a charged particle of specified energy
in traversing a distance of dl

L=
• LET is an average quantity because at the
microscopic level, the energy per unit length of
track varies over such a wide range.
• Average is calculated by Track average and
Energy average

• Track average
It is obtained by dividing the track into equal
lengths, calculating the energy deposited in
each
length and finding the mean.
• Energy average
It is obtained by dividing the track into equal
energy increments and averaging the lengths of
track over which these energy increments are
deposited.

• X-rays or monoenergetic charged particles – two methods

of averaging yield similar results
• In 14-MeV neutrons
– track average LET - 12 keV/μm
– energy average LET - 100 keV/μm
•• High
  LET radiations:
It is a type of ionising radiation that deposits large
amount of energy in a small distance(densely
ionising )
Eg: particles, neutrons

• Low LET radiations :

It is a type of ionising radiation that deposits less
amount of energy along the track or have
infrequent or widely spaced ionising
events(sparsely ionisong)
Eg: x- rays, gamma rays
Interacts- 4 cells
Irregular path
1 hit in same
number of cells

Interacts – 2 cells
Straight path
2 hits in nuclei of
2 different cells
•  LET VALUES :

• Low LET radiations : 0.3 - 3.0 keV/m

• High LET radiations: 30 - 300 keV/m
• Intermediate LET : 5 – 20 keV/m (neutrons)
 RELATIVE BIOLOGIC EFFECTIVENESS (RBE)
• For comparing various radiations, x-rays is used as the standard.

• RBE of a radiation (r) compared with x-rays is defined by the ratio D250 /Dr ,
where , D250  dose in Gy of 250 keV x-rays
Dr  dose of test radiation
required for same biologic effect.
 RBE

• Amount or quantity of radiation is

expressed in terms of the absorbed dose,
measured with the unit of gray (Gy).
• Absorbed dose is a measure of the energy
absorbed per unit mass of tissue.
• Equal doses of different types of
radiation do not produce equal biologic
effects.
RBE as a function of LET
• RBE depends on radiation quality includes
– type of radiation and its energy
– whether electromagnetic or particulate
– whether charged or uncharged.
 RBE as a function of LET
• As
  LET increases -
RBE increases

• Maximum at
100keV/.

• Beyond this value

for LET , RBE again
falls
 THE OPTIMAL LET
• LET of about 100 keV/μm is optimal for producing a biologic effect.

• At this density of ionization, the

– average separation between ionizing events

– coincides with the diameter of the DNA double helix (20 Å or 2 nm).

• Radiation with this density of ionization has the highest probability of

causing a double-strand break (DSB) by the passage of a single charged
particle.
• For a cell to be killed
– enough energy must be deposited in the DNA to
produce a sufficient number of DSBs.

• Sparsely ionizing- low-LET radiation is

inefficient
– because more than one particle may have to pass
through the cell to produce enough DNA DSBs
• Densely ionizing- very high-LET radiation is also inefficient

– because it deposits more energy per cell, and hence produces more
DNA DSBs than are actually needed to kill the cell. These cells are
‘overkilled’
– Per gray there is less likelihood that other cells will be killed, leading to
a reduced biological effect.

• Radiation of optimal LET deposits the right amount of energy per cell,
which produces just enough DNA double-strand breaks to kill the cell.
CONCLUSION
 OXYGEN EFFECT

• The Oxygen Enhancement

Ratio (OER) or oxygen
enhancement effect in
radiobiology refers to the
enhancement of therapeutic or
detrimental effect of ionizing
radiation due to the presence of
oxygen.

• This so-called oxygen effect is

most notable when cells are
exposed to an ionizing radiation
dose.
• The OER is traditionally defined as the ratio of radiation doses during lack of
oxygen compared to no lack of oxygen for the same biological effect.

• This may give varying numerical values depending on the chosen biological
effect.

• Additionally, OER may be presented in terms of hyperoxic environments

and/or with altered oxygen baseline, complicating the significance of this
value
• The maximum OER depends mainly on the ionizing density or LET of the
radiation.

• Radiation with higher LET and higher relative biological effectiveness (RBE)
have a lower OER in mammalian cell tissues .

• The value of the maximum OER varies from about 1–4.

• The maximum OER ranges from about 2-4 for low-LET radiations such as X-
rays, beta particles and gamma rays, whereas the OER is unity for high-LET
radiations such as low energy alpha particles.
 Working of oxygen effect

• The oxygen effect refers to

the increased killing of
cells the occurs in the
presence of oxic
conditions, particularly
with low-LET radiation
such as photons or
electrons.

• The OER is dependent on

the dose, radiation quality,
cell cycle stage and cell
type.
HYPERBARIC OXYGEN
• Oxygen is known to increase the
radiosensitivity of cells.

• The simplest approach to enhance the

radiosensitivity of hypoxic tumor cells
would be to increase the oxygen tension
in the tumor.

• By keeping the patient in a high-

pressure oxygen tank just before tumor
irradiation.

• This study showed an increase in the 5-

year survival of patients with cancers of
uterine cervix and head and neck.
 Therapeutic window.

• The objective of radiation therapy is to control tumors without causing

excessive normal tissue toxicity.

• Predictive models may be used to compute,-

 Tumor control probabilities (TCP) as well as

 Normal tissue complication probability (NTCP).

• Increasing the dose or volume of radiation tends to increase both values.

• The difference between TCP and NTCP is called the therapeutic window.
•
THANK YOU

REFERENCES-:

• Biological Effects of Radiation Report

• Hall, Eric J.; Giaccia, Amato Radiobiology for the Radiologist

• Physics of radiobiology.

• Physics and Radiobiology of Nuclear Medicine by: Gopal B. Saha, Ph.D.

• Radiation Oncology Physics: By E.B. Podgorsak