Radiotherapy

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.

2.

Physical stage: absorption of photons and/or particles’ energy, which leads to: • IONISATION • EXCITATION • FREE-RADICAL REACTIONS Physico-Chemical and Chemical stage: ¾

radiochemical reactions initiated by radiation chemistry of water: hν a) H 2 O ⎯⎯ ⎯→ H 2 O + + e − ⎯⎯→ H 2 O + + e aq

H2 O + ⎯⎯→ ⋅OH + H+ hν ⎯ H2 O ∗ ⎯⎯→ H ⋅ + ⋅ OH b) H2 O ⎯⎯→ − e aq

¾

3.

aqueous or solvated electron, ⋅OH - hydroxyl radical

H ⋅ - hydrogen radical these species attack the bases in DNA and alter them inhibition of protein synthesis,

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 ionisation and excitation Physico-chemical arise of radicals Chemical reactions of radicals with biomolecules Biological: changes in biological properties

10-16 s

1

10-13 – 10-11 s 10-3 s days, years

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 ⎞ ~ 2 ⎟⎟ ™ type of radiation ⎜⎜ LET = v ⎠ Δl ⎝ ™ 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 quantitative 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:

E [D ] = J = Gy (Grey) m kg 1 Gy = 100 rad D=

(1)

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 ⎟ . Thus absorption of 5J of energy increases the tem− specific heat of water - cw = kgK m ΔT ⎟⎠ ⎝ 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 considered. There are many additional and also very important factors that can modify the biological results in the irradiated tissue. These are: a) b) c) d)

presence of oxygen that is saturation of a tissue with the oxygen (see fig. 5) type of radiation via its LET (linear energy transfer) also is meaningful (fig.6) the kind of tissue and the type of cell culture dose rate – (the speed of irradiation) the same dose may be delivered to the tissue over a long period 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 irradiation (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 0 e − D0

or

− N = 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 N0

⎛ N 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

N = 0,37 N 0

or

Now you can say that the mean lethal dose D0 is the dose that is required to reduce the population of entities 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 practice 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 explains 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 having 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

b

a 1.0

0

Diploid cells

10

Diploid cells 0.8

10-1

Haploid cells

0.6

10-2 0.4

0.0

Haploid cells

10-3

0.2

0

3

6

9

12

15

10-4

0

3

6

9

Dose, Gy

12

15

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 N = 1 − 1 − e −D / D0 N0 when n is interpreted as the number of targets. For large doses (D >> D0 ) the equation 4 reduces to:

(

)

(4)

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

dose D = 0 the surviving fraction

N 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 OYaxis. Also, it can be calculated form the formula: Dq= D0· ln n.

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FRACTION SURVIVING n=10

10

D0 =1.3 Gy

n=1

1 1/e

0,1 2

0,01

D37=3,9Gy D37=D0=1.3Gy

0,001 0,0001

1

tg α = 1/D0

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): The required dose must reduce population to

1 = 10 −10 of its initial number of cells (1010-times): 10 10 D − 1 1 Gy = e 10 10

D

− 1 1 Gy e = 10 10

− 10 ⋅ ln 10 = −

D 1 Gy

ln

⇒ ⇒

ln

D 1 =− 10 10 1 Gy

D = 10 ⋅ ln 10

[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) varln(N/N0) ies with type of radiation and with the Small oxygen concentration biological system. Attempts have been made to utilD (no O2 ) ize the oxygen effect in radiotherapy OER = D (normal concentration of O2 ) either by having the patient to breathe the pure oxygen during irradiation D(no O2) – the dose which generates the same treatment or carrying out the treatbiological effect in the absence of O2 as the dose ment with the patient in a sale chamD applied in normal concentration of O2 ber containing oxygen at 3 atm. It is For mammals OER = 2÷3 noteworthy that most of oxygen effect occurs at low oxygen concentrations. Tumour cells have a reduced concenDose 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 particles such as electrons, protons or neutrons. The term LET tells us how effectively the particle transfers its energy to the irradiated tissue.

Energy deposited (dE ) q LET = ∝ 2 distance travelled (dx ) v

ln(N/N0)

small LET

[J/m]

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).

Dose rate =

Absorbed dose time

ln(N/N0)

[Gy / s]

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 patient 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 recover 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). 10

1

10

0

10

1

Surviving fraction N/N0

25 Gy in 10 fractions 2,5 Gy each

10

-1

10

-2

10

10

25 Gy in 5 fractions 5 Gy each

-3

0

10

-1

10

-2

10

-3

10

-4

25 Gy in one fraction 10

-4

-5

-5

10 Dose, Gy 0 5 10 15 20 25 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. 10

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 ¾

the dose per treatment

D 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

High Relatively high Medium Relatively small Small

Organ

Lymphatic organ, bone marrow, intestine, ovaries Skin and organs of epithelial lining (cornea, mouth, oesophagus, rectum, vagina, cervix, urinary bladder, eye lens, stomach Capillaries, cartilage and bone tissue in the period of growth Mature cartilages and bones, salivary glands, respiratory organ, kidneys, liver, pancreas, adrenal gland, pituitary gland Muscles, brain, spinal cord

VII. Some conclusions. o

Radiation therapy is the treatment of disease using penetrating beams of high-energy photons 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 energy depends on its velocity). Xand 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 significant bearing on the treatment of patients. The protons of very high velocity interact weaker with the matter than the protons of high or medium velocity. Thus, the maximal LET and absorbed dose is observed at some specific depth of tissue at which these protons stop. The depth of treatment in the tissue 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 Xand 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 penetrate 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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