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RADIATION THERAPY

Suplementary reading:
Introduction to Physics in Modern Medicine, Susan Amador Kane, 2003
Taylor & Francis, ISBN: 0-415-29963-2

Chapters:
7.3 – Origins of the biological effects of ionising radiation
7.4 – The two regimes of radiation damage: radiation sickness and cancer risk
7.5 – Radiation therapy: killing tumors with radiation
7.6 – New directions in radiation therapy

Main stages of ionising radiation interactions with biological systems:


1. Physical stage: absorption of photons and/or particles’ energy, which leads to:
• IONISATION
• EXCITATION
• FREE-RADICAL REACTIONS

2. Physico-Chemical and Chemical stage:


¾ radiochemical reactions initiated by radiation chemistry of water:

⎯→ H 2 O + + e − ⎯⎯→ H 2 O + + e aq
a) H 2 O ⎯⎯ -

H2 O + ⎯⎯→ ⋅OH + H+

⎯ H2 O ∗ ⎯⎯→ H ⋅ + ⋅ OH
b) H2 O ⎯⎯→

e aq - aqueous or solvated electron, ⋅OH - hydroxyl radical
H ⋅ - hydrogen radical
these species attack the bases in DNA and alter them
¾ inhibition of protein synthesis,

3. Biological stage: (cellular level)


¾ loss of some cellular functions
¾ temporary or permanent loss of ability for reproduction (sterilization),
¾ production of genetically new cells
¾ Tissue damage and disorder of physiological functions
All of cells, both normal and malignant, must reproduce in order to survive. In order to reproduce,
cells must have healthy genetic material – the DNA. The radiation that is given to a patient damages
the DNA in cancer cells. When cancer cells try to reproduce with their damaged DNA, they die.

Table 1

Stage of interaction Time scale

Physical
10-16 s
ionisation and excitation
Physico-chemical
10-13 – 10-11 s
arise of radicals
Chemical
10-3 s
reactions of radicals with biomolecules
Biological:
days, years
changes in biological properties

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I. INTERACTION OF ELECTROMAGNETIC RADIATION – INTRODUCTION
Electromagnetic radiation of high-energy photons is absorbed by a medium such as body tissue. The
absorption results in series of events shown in fig.1

RADIATION ENTERS BIOLOGICAL


SYSTEM IN THE FORM OF A BEAM
OF X-RAYS OR γ PHOTONS

PRIMARY INTERACTION
OCCURS WITH ELECTRON

Scattered radiation

High speed electron

Electron loses energy


along its track by

Ionisation Heat

Excitation
Breaking
molecular
bonds

Second interaction
with electron

Scattered radiation High speed electron

a few dozen of similar interactions are required to


completely absorb the energy of incident photon

Fig.1 Degradation of energy of photons of ionizig radiation during their interaction with matter.

Initially a photon collides with an electron in the body what may result in photoelectric absorption process
(photoelectric effect) or Compton effect. The photon may disappear as a result of the electron-positron pair
production too. Often all three processes take place simultaneously. Finally high-speed electrons are created
and some radiation is scattered. Some high-speed electrons because of their collisions with nuclei of the
medium and deceleration may produce bremsstrahlung (photons of energies from x-ray range).
Energy lost by photons on their way through a tissue is utilised for a) ionisation of irradiated tissue, b)
process of excitation of the medium molecules and in c) process of breaking of chemical bonds. Ultimately
this energy is converted into biological damage and useless heat producing of no biological effects.

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II. Factors determining biological effects of radiation

™ radiation dose
™ how the radiation is applied
⎛ ΔE q 2 ⎞
™ type of radiation ⎜⎜ LET = ~ 2 ⎟⎟
⎝ Δl v ⎠
™ tissue radiosensitivity dependent on
¾ typ of cell population (table 2)
¾ specialization of tissue functions
¾ cell cycle
™ ability to damage repair !!!
™ presence of oxygen

The response of a living organism on irradiation (does not matter harming or curing) depends on many
factors. It seems to be obvious that the amount of the deposited energy plays the crucial role. For quantita-
tive description of the absorbed energy the term dose (or absorbed dose) is used and defined as follows:
The absorbed dose D with unit Grey (Gy) is the amount of radiation energy E (in Jules)
absorbed per unit mass m (in kilograms) of material:

D=
E
[D ] = J = Gy (Grey)
m kg (1)
1 Gy = 100 rad
This is not the thermal energy associated with absorption of radiation which causes the biological effects.
It is known that about 5 Gy dose is lethal for mammals in case of total body irradiation. What does it mean in
term of body temperature rise?
4190 joules is the energy required to raise temperature of 1 kg of water by 1 Kelvin
⎛ J Q ⎞
⎜⎜ 4190 − specific heat of water - cw = ⎟ . Thus absorption of 5J of energy increases the tem-
⎝ kgK mΔT ⎟⎠
perature of 1kg of water by approximately 0.001K
It is obvious that such small rise of body temperature is not responsible for acute biological effects.

The amount of the absorbed energy is not the only important factor as far as biological effects are con-
sidered. There are many additional and also very important factors that can modify the biological results in
the irradiated tissue. These are:

a) presence of oxygen that is saturation of a tissue with the oxygen (see fig. 5)
b) type of radiation via its LET (linear energy transfer) also is meaningful (fig.6)
c) the kind of tissue and the type of cell culture
d) dose rate – (the speed of irradiation) the same dose may be delivered to the tissue over a long pe-
riod of time having usually less effect than this same dose applied during a short period.(see fig.7).
Radiologists take advantage of this fact to protect healthy tissues against harming effects of irradia-
tion (see further in the text – dose fractionation problem).
e) depth of penetration of radiation into the tissue depends on photon energy – the greater the photon’s
energy the deeper the penetration.

Knowledge concerned with the mentioned problems enables radiologists to utilise the powerful tool in
their fight against cancer.

The questions listed below constitute main problems of radiation therapy and this text attempts to answer
them in very short.

- How to predict and asses the influence of ionising radiation on living organisms?
- How to choose the dose of radiation to obtain a desired curing effect?
- How to protect the healthy tissue during treatment of the ill one?
- How to deliver the radiation – that is – in what fractions and in what time intervals?
- How to establish the spatial conditions of irradiation of the cancer?

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III THE SURVIVAL CURVES - How to predict the effect of radiation.
The effect of radiation is usually studied throughout analysis of ability to maintain the vital functions that is
to survive. The most sensitive function affected by radiation is the ability of a tissue cells for reproduction.
The percentage change of cells survival as the effect of the increased absorbed dose is given by so-called
survival curves.

a) Survival curves for the model: ‘Single target – single hit’


Suppose that a biological object (for instance cell colony, a tissue, or an organism) contains total number
N0 of cells or any biological entities (cells, DNA molecules, tumour cells, viruses).
Let as make one assumption:
1° - One hit is enough to inactivate the cell. It means 1 target in the cell has to be hit in order to inactivate it.
The theory developed on this base is called “single hit – single target response”
Let us note that the “target theory” explains shape of survival curves without considering detailed
mechanism for cellular destruction.

The following formula represents the relation between the number of surviving cells and the absorbed dose
in this model:
D D
N −
N = N 0 e − D0 or = e D0
N0
where: - N0 is the initial number of cells,
- N is the number of living cells after application of the dose D,
- D0 is called the mean lethal dose – parameter which describes the specific cell population
- N / N0 – is the surviving fraction.
- D is the absorbed dose
The above equation yields well-known exponential form:

N
⎛ N ⎞
N0 ln ⎜⎜ ⎟⎟
⎝ N 0 ⎠
1 (100%) 1 (100%)

1
e

D0 dose dose

Fig.2a Regular co-ordinate system. Fig.2b semi-logarithmic co-ordinate system.

If we will apply the dose D=D0 we obtain in equation (3):

N = N 0 e −1 or N = 0,37 N 0

Now you can say that the mean lethal dose D0 is the dose that is required to reduce the population of en-
tities to 37% or 1/e of its initial value N0 – in the result 63% of the population becomes inactivated.

In other words we can say that the mean lethal dose is the dose that is required to hit each target in the
tissue exactly 1 time. Due to the random nature of the these energy deposition, some targets are hit in prac-
tice more that 1 time and some targets are hit 0-times and these ones avoid the destruction. So that instead
of destroying all the cells, the mean lethal dose D0 destroys only 63% of them.
The statements presented above form the base for so called “single target – single hit theory”, which ex-
plains shape of observed relation between the number N of unaffected entities (targets) in an irradiated
sample if the dose D applied.
This model is true for haploid cells and for few diploid cells.

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b) Survival curves for the model: “Multi-target - single hit”

It may bye more than one sensitive target in a cell that must be hit to inactivate it. All the targets in the cell
have to be hit in this model in order to inactivate the cell. This relation was found for diploid cells (that is hav-
ing the basic chromosome number doubled). The curve surviving fraction vs dose has a kind of a “shoulder”
for small doses and exponential decay for large doses (fig.3).

N/N0 N/N0
101
a b
1.0 0
10 Diploid cells
Diploid cells
0.8
10-1
0.6 Haploid cells
10-2
0.4

0.2
10-3 Haploid cells

0.0 10-4
0 3 6 9 12 15 0 3 6 9 12 15
Dose, Gy Dose, Gy

Fig.3 Comparison of survival curves obtained for haploid and diploid (multi-target) cells in (a) regular
and (b) semi-logarithmic coordinate system.

The shape of survival curve can be described in this case by the expression:
N
N0
(
= 1 − 1 − e −D / D0
n
) (4)

when n is interpreted as the number of targets.


For large doses (D >> D0 ) the equation 4 reduces to:
N
= n ⋅ e −D / D0 (5)
N0
If the straight-line portion is extended back to zero dose - an intercept on the vertical axis is obtained. For
N
dose D = 0 the surviving fraction becomes equal to n and can be read off from the graph (see fig.4.) as
N0
the number of targets.
D0 – can be read of from the graph as the inverse tangent of straight-line part of the Surviving Curve (tg α =
1 / D0).

The term Dq - stands for the quasithreshold dose because the doses smaller than Dq slightly influence the
tissue and the doses higher than Dq influence the tissue significantly. This dose can be read of from the
graph as the interception point of the straight line passed to the Surviving Curve and the value “1” on the OY-
axis. Also, it can be calculated form the formula: Dq= D0· ln n.

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FRACTION SURVIVING

n=10
10
n=1 D0 =1.3 Gy
1
1/e
0,1

0,01 2
D37=3,9Gy
D37=D0=1.3Gy 1 tg α = 1/D0
0,001

0,0001
Dq= 3 Gy

0,00001
0 2 4 6 8 10
Dose, Gy

Fig.4 Two lines: curve 1 - straight line, represents ‘single target-single hit’ population (n = 1) ,
curve 2 – ‘multi-target-single hit’ cell population (n=10). The symbol D37 is used to specify the
dose required to reduce the surviving population to 37% of the original number. If the survival
curve is exactly exponential (graph 2a or curve for haploid cells in the fig. 3a) the dose D37
exactly equals D0. However if the curve is not exponential the dose D37 is grater than D0.
Dq – is the Quasithreshold Dose.

c) How to choose the dose of radiation to obtain desired curing effect?


– Example of calculation
Example of usage of “target theory” in prediction of possible results of irradiation:
Assume that a particular tumour contains 1010 cells. What is the dose required to destroy all cells except one.
Assume mean lethal dose D0 = 1Gy and number of targets n=1 (the exponential survival):
1
The required dose must reduce population to = 10 −10 of its initial number of cells (1010-times):
10 10
D
1 −
= e 1 Gy

10 10
D
1 − 1 D
10
= e 1 Gy
ln ⇒ ln 10
=−
10 10 1 Gy
D
− 10 ⋅ ln 10 = − ⇒ D = 10 ⋅ ln 10 [Gy ]
1 Gy

Finally, because ln 10 ≅ 2.303 we obtain the required dose D = 23.03 Gy


Let us compare the result (the surviving fraction) in case of population described by multi-target system with
n = 5 after 23.03 Gy irradiation:
N
= 1 − (1 − e −23.03Gy / 1Gy ) 5 = 1 − (1 − e −23.03 ) 5 = 1 − (1 − 10 −10 ) 5 = 5 ⋅ 10 −10
N0
In this case the surviving fraction is 5-time as big as in the case of single target population.

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IV. What can modify the shape of survival curves?

1. The oxygen effect - the presence of molecular oxygen at the time of irradiation acts as sensitising agent
– the biological effects of the irradiation are greater in the presence of oxygen than in its absence.
OER (oxygen enhancement ratio) var-
ies with type of radiation and with the ln(N/N0)
Small oxygen concentration
biological system.
Attempts have been made to util-
ize the oxygen effect in radiotherapy D (no O2 )
OER =
either by having the patient to breathe D (normal concentration of O2 )
the pure oxygen during irradiation
treatment or carrying out the treat- D(no O2) – the dose which generates the same
biological effect in the absence of O2 as the dose
ment with the patient in a sale cham- D applied in normal concentration of O2
ber containing oxygen at 3 atm. It is
noteworthy that most of oxygen effect For mammals OER = 2÷3
occurs at low oxygen concentrations.
Tumour cells have a reduced concen-
Dose
tration of oxygen because of poorer
oxygen supply to the tumour. Fig.5 The oxygen effect: the same radiation dose produces more
defects in a tissue in the presence of oxygen than in its depletion.

2. Type of radiation by its LET (Linear Energy Transfer)

Radiation can be delivered in form of a beam of charged par- ln(N/N0)


ticles such as electrons, protons or neutrons. The term LET
tells us how effectively the particle transfers its energy to the
irradiated tissue. small LET
Energy deposited (dE ) q
LET = ∝ 2 [J/m]
distance travelled (dx ) v
The grater the charge q and the smaller the velocity v the
greater the LET
Small LET - γ, neutrons (no charge)
2+ - + +
Large LET - α , β , β , p (charged particles)
Dose
Fig.6 The same dose of greater the LET
the smaller the fraction surviving after
irradiation with the same dose.

3. The dose rate


The same dose D spread out over a longer period of time usually has less effect (fig.7).

ln(N/N0)
Dose rate =
Absorbed dose
[Gy / s]
time Small dose rate

Big dose rate

Dose
Fig. 7 The dose rate influences surviving fraction.

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V. How to protect the healthy tissue during the treatment of the ill one?
In order to protect normal cells the doses of radiation are carefully planed, limited and the treatment is
spread out over time. Normal tissues are shielded as much as possible during process of irradiation of the
cancer.

a) Irradiation from different direction


If the tumour is not on the surface, irradiating the pa-
tient from several directions can increase the ratio of
tumour dose to normal tissue dose (fig.8).

b) Time fractionation!
Assumption: different tissues have different recovery rates. In general, normal cells re-
cover faster than tumour cells.
After each treatment both the tumour and normal cells recover, but if the normal cells recover more than
the tumour cells, a differential is achieved and eventually the dose and the dose rate can be found at which
the normal cells recover but the tumour cells cannot.
Normal cells are able to repair DNA damage far better after small doses of radiation than after large doses.
As a rule, it is better to minimize side effects by dividing a large total dose of radiation into many smaller daily
doses delivered over several weeks rather than giving a few massive doses in several days (fig.9).
1 1
10 10
25 Gy in 10 fractions 2,5 Gy each
0 0
10 10
Surviving fraction N/N0

-1 -1
10 10

-2
25 Gy in 5 fractions -2
10 5 Gy each 10

-3 -3
10 10
25 Gy in one fraction
-4 -4
10 10

-5 -5
10 10
0 5 10 15 20 25 Dose, Gy
Fig.9 The same dose 25 Gy is delivered in three distinct manners. The least harming effect is
observed if the dose in fractionating into 10 portions by 2.5 Gy each. The greatest population
of normal cells survives – the least side effects.
Between each of daily doses, the normal cells are repairing their damaged DNA. This results in fewer side
effects.

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It is essential for the radiotherapist to specify:
¾ the total tumour dose D
¾ the number of fractions f
¾ the total time in days N
D
¾ the dose per treatment
f
Radiation therapy usually is given 5 days a week for 6 or 7 weeks. Typical fractioning is 1.8-2.8 Gy per day.
When radiation is used for palliative care, the course of irradiation lasts for 2 to 3 weeks

***

VI. Radiosensitivity for the specific kinds of tissues

The Bergonie - Tribondeau law:


The highest the:
mitotic activity
and
number of cells in the phase of functional differentiating
the greater tissues radiosensitivity

Table 2 Radiosensitivity spends on organ or tissue type:


Relative
radiosensitivity Organ

High Lymphatic organ, bone marrow, intestine, ovaries


Skin and organs of epithelial lining (cornea, mouth, oesopha-
Relatively high gus, rectum, vagina, cervix, urinary bladder, eye lens, stom-
ach
Medium Capillaries, cartilage and bone tissue in the period of growth
Mature cartilages and bones, salivary glands, respiratory or-
Relatively small
gan, kidneys, liver, pancreas, adrenal gland, pituitary gland
Small Muscles, brain, spinal cord

VII. Some conclusions.


o Radiation therapy is the treatment of disease using penetrating beams of high-energy pho-
tons of electromagnetic radiation or streams of ionising particles.

o The radiation used for irradiation comes from variety of sources:


- x-ray machines,
- an electron beams from linear accelerators (liniacs),
- gamma rays from cobalt-60 (Co) sources
- generators of heavy particles.

o The type of radiation to be used depends on the cellular type of cancer and how deep in the
body it is located.

o How does radiation therapy work?


High doses of radiation can kill cells or keep them from growing and dividing. Radiation therapy is a
useful tool for treating cancer because:
¾ cancer cells grow and divide more rapidly than many of normal cells around them
¾ most normal cells appear to recover faster and more fully from the effects of radiation than
do cancer cells.
o There are alternative ways of radiation delivery. The radiation is delivered by:
- a beam of ionising radiation form external sources (teletherapy)
- sealed radioactive sources placed in proximity with the tumor (brachytherapy)

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- injection or swallowing of radionuclides (unseald sources)
VIII. The future of radiotherapy

The differences between protons (charged, heavy particles) and


X- and gamma rays radiation therapy.
Protons are large particles with a
positive charge that penetrate
matter to a finite depth based on
the energy of the beam (the en-
ergy depends on its velocity). X-
and γ-rays are electromagnetic
waves that have no mass or
charge and are able to penetrate
completely through tissue while
losing a few energy (the energy
depends on its frequency). These
physical properties have a signifi-
cant bearing on the treatment of
patients.
The protons of very high velocity
interact weaker with the matter
than the protons of high or me-
dium velocity. Thus, the maximal
LET and absorbed dose is ob-
served at some specific depth of
tissue at which these protons
stop.
The depth of treatment in the tis-
sue for protons (and other heavy
particles) is related to a quantity
known as the Bragg Peak.
The idea of clinical application of
the Bragg peak is presented in
the figure 10.

Fig. 10

Fig. 11 presents us how the depth of penetration in tissue


depends on types of ionising radiation. In the case of X-
and γ-rays the absorbed (delivered) dose take its maximum
at the beginning of the beam path in the tissue, affecting all
organs that lay along it. The entrance dose is very high and
highly affects superficial organs.
Electrons as charged but very light particles do not pene-
trate a tissue deep and may not be used for teletherapy
(beam therapy) of deep located tumours.
In the case of protons’ beam the entrance dose is relatively
small (!) whereas the peak of energy deposition can be
placed exactly at the tumour target and there is no tissue
affected beyond the Bragg peak (!).

Fig. 11

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