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3.
Applications of ionizing radiation
-
nuclear and radiation methods -
3.1. Nuclear and radiation methods
3.2. X-ray diagnostics
3.3. Radiation measurement of mechanical
properties of materials
3.4. Radiation analytical methods of
materials
3.5. Radioisotope tracking methods
3.6. Radiotherapy
3.7. Technological use of radiation
3.1. Nuclear
and radiation methods - general properties
In this chapter we will try to give a
brief overview of radioisotope measurement methods and
applications of ionizing radiation in various fields of science
and technology, health care, industry, ecology, etc. Before we
discuss specific radiation methods, we will mention some common
characteristics of these methods.
Note + apology:
The application methods of ionizing radiation are
discussed here from a physical point of view ,
without details of technical solutions, rather than from the
point of view of individual special fields of application; the
exceptions are methods of X-ray diagnostics, radiotherapy and
especially nuclear medicine (where reference is made to a
detailed and complete explanation - Chapter 4 " Radioisotope scintigraphy
"). Therefore, please othe leniency of experts
for specific methods, when they do not find a number of important
technical or medical aspects for practical use in their field; I
also apologize for any inaccuracies and excessive simplifications
in these aspects. I focus here mainly on the interpretation
of the physical nature .
Radioisotope and radiation methods have
some important advantages :
In addition to higher technical and cost demands, a certain disadvantage of radiation methods may be the risk of harmful effects of ionizing radiation on materials and human health; however, this risk can be eliminated or minimized by ensuring appropriate radiation protection - see Chapter 5 " Biological effects of radiation - radiation protection ".
Does the
material glow or not after the application of radiation?
This is a frequently discussed issue, especially in the general
public. It is argued that " During irradiation, a given
substance (including possibly the human body) absorbed radiant
energy, which should then be radiated! ". In the vast
majority of common applications of radiation, this seemingly
logical argument is flawed . Photon radiation,
X, gamma, passes through a substance at the speed of light
(corpuscular radiation only a little slower) and from the moment
it leaves the substance it no longer occurs in
it . Only physico-chemical (or later biological) effects of
radiation can persist :
¨ When
irradiated with X, g, b radiation with
energies less than about 10MeV, excitations and ionizations of
the atoms of the irradiated substance occur, accompanied by
secondary radiation and possibly. chemical radiation effects.
Thus, during exposure, the irradiated object emits secondary
radiation, the intensity of which represents a fraction of a
percentage of the intensity of the primary beam. After the end of
the radiation flow, deexcitation and recombination occur almost
immediately (within about 10 -8 sec.) And the substance does not radiate at all
. This radiation behaves like light to a certain extent: when we
stop the irradiation ("go out"), the radiation
immediately disappears (it is "dark"). Thus
, the patient does not shine
after X-ray examination or after normal radiotherapeutic
irradiation of gamma or X, does not shine objects after X-ray
fluorescence analysis or defectoscopy, does not shine materials
after radiation sterilization.
¨ A
more complex situation can occur with irradiation with neutron
radiation (even at low energies - slow neutrons) and in general
with high-energy radiation , the quantum of
which has an energy higher than about 10MeV. In this case, the
radiation can cause nuclear reactions , in which
radionuclides can be formed in originally
non-radioactive materials . Such a substance may "glow"
for some time after irradiation. Not because "accumulated
energy" is emitted, but because nuclear activation
has taken placematerial. Thus, the samples glow after neutron
activation analysis, targets irradiated in nuclear reactors and
accelerators glow strongly, weakly and for a short time also
patients after radiotherapy with radiation higher than 10MeV,
more significantly after hadron radiotherapy (see §3.6 " Radiotherapy ", part
" Hadron radiotherapy "). And, of course , patients shine
after the application of a radioactive substance in
nuclear medicine (the intensity of this radiation decreases
exponentially with the rate given by the half-life of the
radionuclide in question and the rate of its excretion from the
body).
Types
of radiation methods
For applications of ionizing radiation, closed emitters
- X-ray, radioisotope, particle accelerators, and open
emitters - radioactive liquids, gases or aerosols are
used. All applications of ionizing radiation can be divided into
two basic groups :
1.
Radiation measuring, analytical and detection methods
This large group of methods uses the properties of ionizing
radiation to measure certain physical and technical quantities,
to analyze the properties of substances and to study and detect
certain processes in natural and industrial systems or in living
organisms (see also section below). " Introskopy
") .
In terms of the nature of primary and
secondary radiation, as well as the relative position of the
radiation source, the analyzed object and the detector, these
methods can be further divided into three groups :
Fig.3.1.1. Geometric arrangement of the
radiation source, the analyzed or irradiated object and the
detector in various applications of ionizing radiation.
a) Transmission radiation measurements. b)
Scattering and fluorescence measurements. c)
Emission radiation measurement. d) Measurement
of radioactive samples. e) Radiation irradiation
of objects.
Intrascopy
Radiation measuring, analytical and detection methods belong to a
wider field, sometimes called introscopy (Latin i ntro = inside , Greek scopeo =
observation ; literally "looking inside") - non-destructive examination of the
internal structure of objects and the processes taking place in
them using physical methods : sound waves
(including ultrasound), electromagnetic field and electromagnetic
waves (light - eg classical endoscopy in medicine, radio
waves, UV, X and g-radiation), fluxes of elementary particles (accelerated
electrons, protons, neutrons, heavier ions). These methods are
used mainly in medicine (from classical stethoscope, through
optical endoscopy to ultrasound sonography, X-ray diagnostics and
gammagraphy), but also in a number of scientific and technical
and industrial applications (defectoscopy, activation analysis,
X-ray fluorescence analysis and more). All of these methods, when
using ionizing radiation or nuclear
physics methods , will be described in more detail
below.
2.
Radiation irradiation and technological methods
Here, the energy transferred to the substance
during irradiation is used here - Fig.3.1.1e, ionization of
substances and subsequent physical, chemical and biological
effects of ionizing radiation in the irradiated object. In the
field of medical applications, this includes radiotherapy
, industrial applications include some radiation-technological
processes in chemistry (such as polymerization),
sterilization of materials, production of radionuclides.
The following paragraphs (§3.2-§3.7) will describe individual specific methods of ionizing radiation application, some briefly (industrial applications), others in detail (X-ray diagnostics, radiotherapy; in a special reference to a separate chapter 4 " Radionuclide scintigraphy " then methods of nuclear medicine) .
Collimation
of ionizing radiation
In the vast majority of processes of ionizing radiation, this
radiation is emitted almost isotropically in all
directions *).
*) Exceptions are the interactions of high-energy
particles , where due to the relativistic laws of conservation of
momentum, the resulting particles and radiation are kinematically
directed (collimated) in the direction of motion
of primary high-energy particles.
However, we often need to direct
the radiation to a certain angle, or to concentrate
it in a certain place; Radiation in other directions can
be undesirable - disruptive or even harmful and dangerous. This
direction, or collimation of radiation, can be
performed in two basic ways :
¨ Electromagnetic
collimation of charged particles
In the case of corpuscular radiation of charged particles,
suitable direction - collimation - can be achieved by the action
of electric and magnetic fields, which exert a force on the
charged particles. This deflects the direction of movement of the
particles (powder), which can be directed to the
desired location.
¨ Mechanical absorption
collimation of radiation
However, a simpler way, which works both for charged
particles and for g and X radiation , is to use collimators. A
collimator is a mechanical and geometric arrangement of
materials absorbing a given type of radiation
that transmits only radiation from certain desired
directions (angles), while it absorbs and does not
transmit radiation from other directions *).
*) However, such absolutely sharp
collimations cannot always be achieved in practice. For
high-energy radiation penetrating grams occurring in peripheral
edges of the collimator partial radiography , in
which edge portions of the collimated beam produces a " penumbra
."
Collimators are used in virtually all
applications of ionizing radiation. Most of them are simple
collimators in the shape of various tubes or
orifices (as shown in a simplified way, for example, in
Fig.3.1.1). Intricately configured collimators then play a key
role especially in scintigraphy (imaging collimators with a large number of holes -
§4.2 "Scintillation cameras", part "Collimators "), in X-ray diagnostics(§3.2" X-ray diagnostics ")and in radiotherapy (eg multi-lamellar MLC collimators - §3.6"
Radiotherapy ", passage" Modulation of irradiation beams ").
Electronic radiation collimation
In some special detection and imaging systems, another method of
directional radiation selection, so-called electronic
collimation , is used without the use of a mechanical
collimator.It is based on the specific behavior of quantum
ionizing radiation in the detection system - propagation of pairs
(or more) of quantums in certain precisely given
directions ,their coincidence detection
system of a larger number of detectors and subsequent positional
and angular reconstruction of the direction of quantum
propagation. This analysis makes it possible to select for
further processing only those quantities of radiation that have
the desired direction - to perform electronic
collimation and display the distribution of radiation
in a given field. The electronic collimation method is used in positron
emission tomography PET (see §4.3 "Tomographic
cameras, part" PET cameras ")
and in some complex detection systems such as ring imaging
Cherenkov RICH detectors (see ....), trackers and
muon detection systems for accelerators (see §2.1, section
" Arrangement
and configuration of radiation detectors").
Radiation
imaging - radiography
The very concept of imaging is based on the
ability of our eyes to perceive light, its intensity, wavelength
and spatial distribution, from which we create basic ideas about
the shapes, size and placement of objects in space. If we want to
get an objective idea of ??an object, its structure, changes and
processes taking place in it, the most clear is to obtain the
relevant data in pictorial form . This applies
to an inanimate object, a living organism, the human body, or
perhaps a distant galaxy in space. This imaging is performed by visualizing
the physical fields with which the object under
investigation interacts or transmits. That is, using different
types of radiation
, which we irradiate the object,
or which the object itself emits. The transmitted, reflected,
scattered or emitted radiation is detected by suitable position-sensitive
detectors , which display the spatial distribution of
the radiation field (or its planar projections) and possibly also
its other properties (especially the energy of quantum radiation)
- see §2.1 " Methodology of ionizing radiation detection " .
Radiography is the
collective name for measuring quantity and displaying
distribution radiation from studied objects that emit
radiation either primarily or secondarily when they are
irradiated from external radiation sources. This imaging is
performed using photochemical manifestations in photographic
emulsions, fluorescence of luminescence of screens and especially
physical processes in electronic imaging detectors. This includes
a number of methods from the fields of X-ray diagnostics,
radiation defectoscopy, gammagraphy (scintigraphy) using
radiopharmaceuticals.
Imaging methods using different types of
radiation are discussed below. About the X-ray image
in the following §3.2 " X-rays - X-ray diagnostics " (including the appendix
" X-ray telescopes ") . Autoradiography
-photographic representation of the distribution of the
beta-radioindicator in the examined preparations in close
contact of the photographic emulsion with the sample is
described in §2.2 " Photographic detection of ionizing
radiation ", passage " Autoradiography ". Gamma-ray
imaging is discussed in detail in Chapter 4 " Radionuclide Scintigraphy ", especially for applications in nuclear medicine
(however, there are also brief methods for g- imaging from
space - gamma-telescopes , " High-energy
gamma cameras ") .
In addition to the visual observing
and evaluating the thus obtained image is often also important mathematical
analysis of the images , either static
(filtering, comparing data from different locations of images or
between various images) or dynamic (evaluation and
quantification of temporal changes in different parts of the
image reflecting the dynamics of the respective processes in
displayed object); these aspects are discussed in detail for the
field of scintigraphy in §4.7 " Mathematical analysis and computer evaluation in
nuclear medicine ".
3.2.
X-radiation - X-ray diagnostics
The oldest, most widespread and still probably the most important
application of ionizing radiation is X-ray diagnostics
( X-ray diagnostics , often also
called radiodiagnostics , popularly called " rentgen
"). From a physical point of view, we
will here discuss the instrumentation and methods of X-ray
diagnostics :
Discovery of X-rays
In the last decades of the 19th century. A number of researchers
have studied high-voltage electric discharges in
dilute gases. The so-called cathode rays were discovered
, which were later found to be fast-moving electrons (see also
§1.1, section " Structure of atoms").
W.C.Röntgen did similar experiments with cathode ray tube
discharges in a laboratory in Württemberg in 1895. In the
darkroom, he observed the fluorescence caused by cathode rays on
luminescent screens. The illuminated tube glows, even when he
inserted a thick book between the tube and the screen, and only
when he placed a metal object between the tube and the screen did
a shadow appear on the screen, and when he placed his hand
between the cathode ray tube and the screen It was clear that unknown
penetrating rays emitted from the cathode ray tube -
" X- rays " (letter
Xas a symbol for something unknown - an unknown
variable in mathematics, an unknown person in a detective story) that can penetrate paper and fleshy tissue, but metal
objects and bones are "opaque" to this radiation.
Furthermore, Roentgen found that this radiation caused the
photographic plate to blacken.
Immediately after his discovery of
penetrating radiation emanating from the cathode ray tube in
1895, Roentgen himself took the historically first X-ray image on
a photographic plate, namely his wife's hand (Fig. 3.2.1 on the
right, with a ring). Both Roentgen and other physicians have been
aware from the beginning of the great importance of newly
discovered radiation for medicine.. Roentgen
thought that penetrating radiation originated in the diluted gas
of the cathode ray tube. In other experiments, it was shown that
the source of X-rays is not the discharge in the gas itself (it
only supplied electrons); on the contrary, the removal
(depletion) of gas and the use of a heated cathode will increase
the efficiency of X-rays - vacuum X-rays have
developed over the course of several decades (described in detail
below).
Note:
A brief reflection on the extent to which the
discovery of X-rays was the result of chance or methodological
procedure is given in §1.0 " Physics - fundamental
natural science ", passage " Significant
scientific discoveries - chance or method? ".
Fig.3.2.1. Left:
Basic principal scheme of X-ray imaging. Middle: X-ray
spectrum of the X-ray (filtered).
Right: The first X-ray taken by
Roentgen himself (his wife's hands).
Origin and properties
of the X-ray image
When using X-rays for imaging (especially in medicine), its basic
properties of penetrating even materials opaque
to light are used. The basic principal scheme of X-ray
transmission imaging is in the left part of Fig.3.2.1. The
penetrating electromagnetic X-rays with a photon energy of about
20 ¸ 150keV
(wavelengths of about 5 to 50 picometers) , generated in the X-ray tube , pass
through the examined object (organism tissue), while part of the
radiation is absorbed depending on the thickness
and density of the tissue . the remainder passes
through the tissue and is imaged either
photographically or on a luminescent screen, more recently using
electronic detectors. In the body, X-rays are most absorbed by
bones, less by soft tissues, least by body cavities and by air.
When exposed to X-rays, an X- ray image of the
examined tissue is created , which is a projection shadow
image of density , showing differences in density
tissues *). In other words, an X-ray image is created by
projecting X-rays from the focus of the anode, through tissue
structures within the organism with different absorption
coefficients and different thicknesses, onto a film or imaging
detector. Different absorptions of X-rays in different tissues
are assigned different intensities in grayscale in the image;
this assignment is realized either in an analog manner (film
blackening) or digitally (electronic imaging detectors +
computer, see below). This creates an image reflecting the size,
shapes and arrangement of tissues and organs in the body,
including any changes caused by pathological processes.
*) Differentiated
absorption X-rays are the basis of the X-ray image. This
absorption depends on the layer thickness, density and proton
number of the irradiated substance. Soft tissues have a lower
density and lower absorption of X-rays - more radiation is
transmitted through these places, we get a clearer image or
greater blackening of photographic material. The bones with
calcium content are denser and absorb more X-rays - less passes
through it, we get a less intense image or less blackening of the
photographic film in these places. In Fig.3.2.1 on the right is
an X-ray image on a photographic film.
X-rays interact with tissue atoms mainly through two
processes, discussed in more detail in §1.6, section " Interaction of gamma and X-rays ": photoeffect and Compton
scattering (formation of electron-positron
pairsdoes not occur here due to the low energy of photons
used in X-ray diagnostics; an insignificant exception may be
portal and tomo-therapeutic images on radiotherapy irradiators,
see §3.6 " Radiotherapy ") . Both of these processes are involved in the different
absorption of radiation in individual tissues (and also
in the different absorption in normal and pathological districts
within the same tissue), depending on the thickness, density of
the substance and the proton number of the atoms. X-ray
diagnostics is based on this different absorption of X-rays in
different tissues, as well as their physiological or pathological
conditions.
X-ray
image quality
Three parameters are important for high-quality X-ray imaging and
recognition of fine structures and anomalies :
¨ Sharpness
and resolution imaging
for visual projection image is important in small size
impinger foci from which the X-radiation is emitted (see below, " The design of the X-ray tube
") . For classical X-ray diagnostics,
the focus is about 0.5 ¸ 2 mm, but for X-ray microscopy, an almost point focus
with a diameter of the order of micrometers is required. Closely
related to sharpness is the spatial resolution of the
image *). Sharpness and resolution can also be affected by the
properties of the imaging medium - photographic film, amplifying
films, electronic imaging detectors. The resolution of the X-ray
image is around 0.5-2 mm, depending on the size of the focus(X-ray microscopy can be a thousand times better!) .
*) Resolution is defined
as the smallest distance between two "point" objects,
at which they still appear as two separate structures; or
equivalent to the half-width of the point object image profile.
At shorter distances, both objects appear as one, they are not
distinguished. As in photography, resolution is often measured in
the maximum number of lines per millimeter [lp / mm]
that can still be distinguished; in practice, the real resolution
is around 2-5 lp / mm. The quality of X-ray imaging in terms of
real resolution is sometimes quantified in detail using the
so-called modulation transfer function MTF
, indicating using Fourier harmonic analysis, what
details of the examined object can be displayed with the given
contrast. The issue of resolution, contrast and recognizability
of lesions on X-ray images is largely similar to scintigraphic
imaging - it is discussed in detail in §4.2, section " Scintigraphic
image quality and detectability of lesions ".
Significant deterioration in sharpness and resolution
occurs especially when the image is blurred
due to patient movement during exposure - motion blur
. With modern devices, this risk is minimized by shortening the
exposure time, while increasing the intensity of X-rays. Also,
the movements of certain structures inside the body - heart
beating or breathing movements - lead to image blur. This adverse
effect can be eliminated by gating (trigration) and
image synchronization in certain phases of cardiac pulsation or
respiration - ECG-gating , respiratory-gating .
¨ The contrast of
the image,
expressing the gradient of the display of differences in the
absorption of X-rays using the gray scale, is given by two
factors. First of all, it is the ratio of absorption coefficients
for different types of displayed tissue. It depends mainly on the
differences in the density of individual areas of
tissue; where this difference is negligible or non-existent, we
can sometimes increase it by applying contrast agents
(see below). The contrast in absorption further depends on the energy
of the X-rays. For thinner layers of soft tissue, soft
X-rays (approx. 20keV) are more suitable, which interact mainly
with a photoeffect with a steeper difference in absorption
depending on density (the greatest contrast
is achieved for X-rays close to the binding energy of electrons
on K or L shells ) . Harder X-radiation
(approx. 80 ¸ 100keV) is required to display thicker layers and denser
materials (eg skeletal structure ). Contrast is negatively
affected by Compton scattered radiation (see
"secondary diaphragms" below).
An important geometrical-anatomical factor,
significantly worsening the contrast of the X-ray image and the
overall recognizability of the lesions, is the irradiation and
superposition of X-rays from individual layers of tissues and
organs at different depths, generally with different densities.
This adverse effect is largely eliminated in CT imaging .
For digital
devices, the contrast can be additionally increased by computer
processing ( post-processing ) - a suitable brightness
modulation of the image. In such processing, the so-called bit
depth is important - the number of bits in which the
image is created in the process of analog-digital conversion.(ADC)
from an electronic X-ray detector to an image matrix in a
computer. When displayed, the bit depth indicates the maximum number
of shades of gray that we are able to display in the image -
the larger this number of shades of gray, the more depicted we
show particularly small differences in density and fine detail. A
higher number of bits in the image allows you to emphasize the
details in the image using suitable display windows for
brightness modulation - stretching a certain small range of
brightness values in the image to the full range.
The relationship
between the most commonly used bit depth and the maximum number
of shades of gray is as follows (given by the power of 2 b
):
2 bits = 2 shades (white and black only); 4 bits = 16 shades; 8
bits = 256 shades; 12 bits = 4096 shades; 14 bits = 16384 shades;
16 bits = 65536 shades; 24 bits = 16777216 shades.
Although a large number of shades (tens and hundreds of
thousands) are no longer directly distinguishable by the eye,
this allows the use of narrow display windows to emphasize
density gradients.
¨ Number of photons in the image -
statistical noise
To obtain a quality well-exposed image, a certain optimal
number of X-ray photons is needed . In
films and luminescent screens, this number of photons is mainly
determined by sensitivity the material used so
that the image is not underexposed or overexposed. With digital
imaging detectors, we can additionally adjust the brightness of
the image, but the image quality is still determined by the
following factor: X-ray emission, its interaction and imaging
detection is subject to stochastic quantum laws ,
leading to quantum statistical fluctuations in
photon flux. With insufficient X-ray photons, the image is
"noisy," composed of disturbing artificial brighter and
darker spots and clusters of dots where fine structures and
details can disappear. If we have the registered number of N
photons of X-rays in a given element (pixel) of the image , then
the local statistical fluctuations - scattering, relative error -
are SD = 1/ÖN. To obtain a well-drawn image with statistical
fluctuations of less than 3%, more than 1000 photons must be
recorded in each element of the image, for 1% of the fluctuation
there must be more than 10,000 pulses / element. For digital
imaging detectors - flat panels (described below) - the
quality of the X-ray image in terms of noise depends on the
sensitivity of the sensor: this is given by the detection
quantum efficiency DQE ( Detection Quantum
Efficiency ), which is the percentage of photons X-rays
incident on the detector. is actually recorded by the detector
and used to create the image (the rest is
uselessly absorbed by the input window or detector material
without scintillation or electrical response). For digital X-ray images, especially CT, the
statistical noise of the image is expressed in Hounsfield
units HU (introduced below in the
section " X-ray tomography -CT ", passage " Origin of the density
image ") ; in a good picture,
the SD noise should not exceed about 20-30 HU. The total number
of photons for the exposure of a given image is set by the
product of the X-ray current and the exposure time (see below " X-raytube ", section " Braking X-rays
") - " milliampere-seconds
" [mAs]; it can also be electronically controlled using automatic
exposure - see below " Setting X-ray parameters "," .
¨ Artifacts
on an X-ray image
Under certain circumstances, some structures that do not
originate in the displayed object may appear on X-ray images -
they are false artifacts . flat-panel, unwanted
objects (eg metal) in the X-ray beam.In CT imaging, so-called structural
artifacts may arise, arising during the reconstruction of
transverse sections in places with sharp differences in density,
especially at the transition of bone and soft tissue.
X-ray
tube
Source of X-rays for X-imaging is a special vacuum tube called X-ray
tube , X-ray tube or tubes (Eng. X-ray tube
). From an electronic point of view, the X-ray machine is simply
a classic diode connected in a circuit with a
high voltage of approx. 20-200 kV. The heated cathode
emits electrons which are attracted to the anode
*) with a high positive voltage, while they are accelerated
by a strong electric field to the kinetic energy E = Ue,
given by the high voltage U between the cathode and the
anode (ie E = approx. 20 ¸ 200keV). Just before the impact on the anode, it obtains
an electron with charge e and mass me
a very high velocity v = Ö (2.eU/m e ) (for voltage U = 60kV, the electrons will have a kinetic
energy of 60keV and an impact velocity of approximately
150000km / s, which is half the speed of light) . Upon impact with the anode, the electrons brake rapidly
, converting some of their kinetic energy to hard electromagnetic
radiation - X-rays of two types: bremsstrahlung
and characteristic radiation (the
origin and properties of these two types of radiation are
discussed below) . This X-ray leaves the
anode and flies out of the tube (Fig.3.2.1 left).
*) The anode, the electrode located
opposite the cathode, was formerly also calledanticathode
, especially in cathode ray tubes. Anode it
is made of a heavy material (most often tungsten), which has a
high electron density, so the incident electrons are sharply
braked by a large repulsive force, which, according to the laws
of electrodynamics, changes part of their kinetic energy into
braking electromagnetic radiation - X-ray photons. However, the
efficiency of this process is relatively small - only about 1% of
the total kinetic energy of electrons is transformed into X-ray
photons, the rest is converted into heat. The reason is that only
about 1% of electrons penetrate deep enough inside the atoms of
the anode material, up to the L or K shell, where large Coulomb
electric forces act only causing a sharp change in the speed of
the electrons and thus effective excitation of hard
bremsstrahlung. The other electrons transfer their kinetic energy
to the electrons and atoms of the crystal lattice, which results
in heat. Note: The
X-ray can be considered the simplest particle accelerator
(§1.5 "Elementary particles", part " Charged particle accelerators ") - it is a linear electrostatic accelerator of
electrons, the source of which is a hot cathode, the (inner)
target is the anode. + characteristic) X-rays.
Braking X-rays
Braking radiation is a consequence of the laws of Maxwell's
electrodynamics, according to which every uneven
("accelerated") movement of an electric charge emits
electromagnetic waves - see §1.5 " Electromagnetic
field. Maxwell's equations.
", Larmor's formula (1.61 '), monograph " Gravity,
black holes and space-time physics
" . Therefore, even when the braking of the electron after the
impact on the anode, the more intense and harder the
electromagnetic radiation, the sharper the braking (the greater the deceleration and
in the mentioned formula) - see also §1.6, passage " Braking
radiation " .
The
effective cross section for the production of
bremsstrahlung is generally given by the highly complicated Bethe-Heitler
formula (derived from quantum
radiation theory, corrected by the Sauter and Elwert
factors of the Coulomb shielding of the electron shell) . For a not very wide range of kinetic energies E e of incident
electromains (tens to hundreds of keV) and proton numbers Z target material (medium to heavy
materials), the overall efficiency of brake radiation
production h can be approximated by a simplified formula :
h = E e [kev] . Z . 10 -6 [photons
/ electron].
By converting the number of electrons n e to the current I = n e .q e / ta by substituting the value of the charge of the
electron q e = 1,6.10 -19 C (= 1,6.10 -16 mAs) from this relation the resulting flux of
photons I X [number of photons / s.] braking radiation depending on
X-ray current I [mA]and anode voltage U [kV] :
I
X = U. I.
(Z / 1.6). 10 10 [photons / s],
which will be used below in the section " Setting X-ray parameters
". Only a relatively small part (only about
1%) of the original kinetic energy of the incident particle
changes to braking radiation when braked in the fabric. Most of
the energy, with multiple Coulomb scattering, is eventually
transferred to the kinetic energy of the atoms of the anode
substance - it is converted into heat .
Total energy spectrum of X-rays
(braking + characteristic), emitted from the anode of the X-ray tube, is drawn
below in Fig. 3.2.5 at the top right. The graphic form of the
energy spectrum I (E) of continuous braking X-rays
is approximately approximated by the so-called Kramers
formula :
I
(E) = K. I. Z . (E max - E),
where I (E) is the relative intensity of energy photons E
, K is a constant, Z is the proton (atomic) number
of the anode material, E max is the maximum energy of X-ray photons, given by the
kinetic energy of incident electrons. It is clear that I (E max ) = 0 and the
formula is valid only for E <E max .
It is logical that the efficiency of brake radiation
production is higher for high Z - large electric Coulomb forces
act around such nuclei, causing abrupt changes in the velocity
vector of the incident electrons that get close to the nucleus.
The efficiency of bremsstrahlung [number of photons / electron]
increases with energy E eincident electrons. Low-energy electrons are usually
scattered on the outer shells of the atoms of the anode material
and emit soft radiation, which often does not even reach the
X-ray energy range. The higher the energy of the incident
electrons, the more likely they are to penetrate deeper into the
anode atoms, close to the nucleus, where the greatest electrical
forces act, significantly changing the electron velocity vector,
leading to higher energy and efficiency of brake X-ray
production. However, the overall energy efficiency - the ratio of
the total energy of the emitted photons to the energy of the
incident electrons - is lower for higher energies (due to the
higher percentage of low-energy photons). And the heat losses in
the target (anode) are higher.
The stopping X-rays produced by the X-ray tube have a continuous
spectrum from energies close to zero to the maximum
energy given almost by the value of the anode voltage - Fig.3.2.1
in the middle (here is the spectrum after
partial filtering of the softest component - see below) . The energy of the braking radiation depends on the
speed (acceleration) at which the electrons are braked on impact
with the anode surface. The individual electrons penetrate at
different depths into the atoms of the anode material, thus
emitting different wavelengths or energies of photons. Those
electrons, which "softly" brake with repeated multiple
scattering on the outer electron shells of the anode atoms, emit
a series of photons of braking (and
characteristic) low-energy radiation; some
of them fall into the area of ??soft X-rays, others into the area
of ??UV and visible light(The resulting
low-energy photons are often absorbed in the anode material and
do not fly out) . The deeper the electrons
penetrate into the interior of the anode atoms, the closer to the
nucleus, the faster the intense Coulomb forces change their
velocity vector and the harder the braking X-rays are produced.
The shortest wavelengths arise for electrons that have penetrated
to the level of the K shell and closer to the nucleus, where they
can be braked almost once. Depending on the impact factor of
individual electrons relative to the anode atoms, which is random
, all possibilities are continuously realized - such a different
degree of electron braking causes a mixture of radiation of
different wavelengths or photon energies - the result is a continuous
spectrumbraking radiation. Low-energy X-ray photons are
the most represented in this continuous spectrum, only a very
small percentage at the end of the spectrum corresponds to high
energies, close to the energy of incident electrons, given the
high voltage between the cathode and the anode of the X-ray (see Fig. 3.2.5 below) ) .
The
wavelength and energy of X-rays
The nature of X-radiation of electromagnetic waves of short
wavelength of about 10 -9 ¸ 10 -11 m but which
radiates as quanta - photons - the energy of
about 5keV ¸ 200keV ( " The particle-wave duality ") . Earlier (until the 1960s) it was customary to
characterize X-rays with a wavelength of l and in the older
literature was given the so-called Duan-Hunt relation lmin [nm]
= hc / eU @ 1.234 / U [kV] between the voltage U [in
kilovolts] at X-ray and the minimum wavelength l min [in
nanometers] of the resulting braking X-rays *). A Kramer's
formula for the spectrum was given in the form I ( l ) = KZI [( l / l min ) - 1] / l 2 (in this form it was compiled by HAKramers
in 1923; at that time X-rays were described only by wavelength) .
This method was considerably disadvantageous
and misleading, especially in relation to the mechanism of this
radiation, where the values ??of the accelerating voltage in [kV]
occur. Now abandoned long ago , the X-ray
spectrum is expressed mainly by the photon energy
E X [keV],
which in X-rays is derived directly from the voltage U
(maximum energy E Xmax @ U, mean energy
<E X
> » U
/ 3] and The Duan-Hunt relation has lost its importance.
*) It is actually a differently written
relation E X = h / l between the energy of the photon E X in [keV] and the wavelength l in [nm] for the situation
when all the kinetic energy E = Ue of the electron of charge e
, accelerated by the voltage U , is converted into a
photon X-rays (corresponds to the energy E Xmax and
the wavelength l min ).
Characteristic
X-rays
In addition to braking X-rays with a continuous spectrum, a
certain smaller amount of characteristic X-rays
with a line spectrum (characteristic pair of peaks K a , K b ) is emitted , the
energy of which does not depend on the anode voltage but is given
by the anode material; for the most commonly
used tungsten, these are the 59.3 + 67.2keV peaks (and also the L
peak around 10keV), which appear as "bumps" on the
continuous curve of the spectrum (Fig. 3.2.1 in the middle).
The
characteristic X-rays are caused by two processes :
¨ Direct process of the impact photoeffect
at the internal energy levels of the electron shell in the atoms
of the anode material - fast electrons penetrate into the atoms
and eject bound electrons from the K and L shells. shell K
(K-series), or from the shell M to L (L-series) the difference of
energies is then radiated in the form of photons of
electromagnetic radiation - characteristic X-radiation (cf. also
with Fig.1.1.3 in §1.1).
¨ Indirect process of photoelectric absorption of
braking radiation- braking X-rays, generated by the
above-mentioned mechanism during the braking of accelerated
electrons, interact with other atoms inside the anode substance,
among others by a photon photoeffect (described in §1.6, part " Interaction
of gamma and X-rays ",
Fig.1.6.3 left) , emitting
electrons from the inner shells, followed
by an electron jump and the emission of characteristic X-rays,
similar to the previous case.
The impact electron photoeffect and
the emission of photons also occur when electrons jump in the
outer shells, but the energy of these photons is low and this
radiation is covered by continuous bremsstrahlung at the
beginning of the spectrum.
A certain minimum (threshold) anode
voltage is required for the formation of characteristic X-rays,
higher than the binding energy of electrons on the K-shell of
atoms of the anode material (for tungsten
it is about 70keV, for molybdenum 20keV) .
If the anode voltage is lower, only continuous bremsstrahlung is
generated in the X-ray, and when the threshold voltage is
exceeded, the spectrum contains both brakes and peaks of
characteristic X-rays.
The proportion of characteristic X-rays in
the total spectrum of the X-ray tube depends on the anode
material and the anode voltage. For a tungsten anode, it is
approximately 30% at a voltage of 100 kV and only about 3% at a
voltage of 200 kV.
X-ray tube design
Unlike conventional tubes used in low-current electronics, X-rays
tubes have a relatively robust design (they
resemble screens or transmitter tubes in size), given two
circumstances. On the one hand, it is a very high
voltage, reaching hundreds of kilovolts. The second
circumstance is thermal heating : electrons
incident at high speed on the anode convert only a small part of
their energy into X-rays, the vast majority of their kinetic
energy is converted into heat - the anode of the
X-ray tube is heated strongly . To dissipate
this heat, the anode must have a relatively massive construction;
in addition, anode rotation or cooling is used (described below).
One of the technical parameters is maximum power of the
X-ray machine [kW] - peak electrical power input of the X-ray
machine, which the X-ray machine can still "withstand"
without overheating and thermally damaging.
The most commonly used material
for the anode of an X-ray machine is tungsten
(tungsten), a heavy and heat-resistant metal. To improve the
thermal properties of the anode, especially the heat capacity,
rhenium-alloyed tungsten (10%) is often used, or the anode is
composed of several layers - alloyed tungsten, molybdenum,
graphite. For X-ray tubes for X-rays around 20keV for
mammography, the anode is made of molybdenum.
X-rays tubes can be
divided into two main groups, which govern their design (+ the third group of special constructions listed
below) :
¨
X-rays tubes for industrial irradiation and radiotherapeutic use
,
which do not require focusing of electrons to an almost point
focus and which have a fixed (non-rotating) anode. High energy
and X-ray intensity are common requirements here; the anode is
actively cooled by the flow of cooling medium through its
interior.
¨ X-rays
tubes for X-ray diagnostics
with focusing of the electron beam into the focus and mostly with
a rotating anode (to prevent local overheating of the focus).
Below we will deal mainly with these X-rays tubes for
radiodiagnostics. The anode target material
is mostly tungsten, for
low X-ray energies (around 20-40keV) molybdenum is used as the
anode target material; the X - ray machine is additionally
equipped with a beryllium exit window - see below " X -
ray mammography".
¨ Special
types of X-ray tubes
In addition to the cathode and anode, in some types of
X-rays we can meet a third electrode - a wire grid
, located between the cathode and the anode, in close proximity
to the cathode. electrons (ie. the anode current) and thus the
intensity of X-rays. by applying higher negative voltage on the
grid can be quickly interrupted anode current and the emission of
X-rays (used sometimes for a quick X-ray film). Mikroohniskové
ray tube (microfocus X-ray Tube) have an extremely small
impact focus of electrons on the anode, of the order of mm. This is achieved
by placing a special set of electrodes (electron optics -
"objective") between the hot cathode and the anode,
focusing electrons from the cathode into a very narrow beam
incident almost point on the target-anode. They provide very high
sharpness and resolution of the image, but only limited power
(intensity, fluctuation) of X-rays. They are used for X-ray
microscopy and CT defectoscopy (see below §3.3, section " Radiation
defectoscopy ").
For special purposes (especially spectrometric and
micro -X-rays) X- rays tubes with a frontal transmission
anode ( Target Transmission X-ray Tube ) are
constructed.), where the beam of accelerated electrons impinges
on the thin front-located anode, the resulting X-rays passing
through the material of the thin anode to the outside of the tube
where it is used. It can also be designed as the above-mentioned microfocus
.
In addition to the usual tightly closed (sealed)
evacuated X-ray tubes, so-called open X-ray lamps
are sometimes constructed . They have a metal casing that the
user can open, replace the cathode filament and anode material
(tungsten, copper, molybdenum, etc.) as needed, and close the
tube again and evacuate.
Fig.3.2.2. Special microfocus X-ray tube with transmission anode
for X-ray microscopy
Historical
development of X-ray tubes
X-ray tubes originally evolved from discharge lamps
, which are gas-filled glass tubes with electrodes to which a
voltage of the order of hundreds of volts is applied. The next
stage was Crookes cathode ray tubes - discharge
lamps with very dilute gas, on the electrodes of which a high
voltage of the unit of up to tens of kilovolts is applied. The
classic radiant discharge practically no longer occurs here, but
the ionization of the atoms of the diluted gas releases electrons
, accelerated by a high voltage towards the anode - cathode
radiation . In addition to the fluorescence of the flask
or inserted objects, there is also a secondary penetrating photon
radiation - X-rays (discovered by X-rays and
independently by other researchers),
braking and characteristic. Cathode ray tubes also played an
important role in atomic physics, with their help J.J. Thomson
discovered electrons, which allowed them to penetrate the
structure of atoms.
The first " cold cathode "
X-rays were actually Crookes cathode ray tubes with specially
modified electrodes. An important milestone was the creation of a
vacuum X-ray tube with a hot cathode , designed
by WDCoolidge in 1913 (shown in Fig. 3.2.1 on the left). Later,
with increasing performance, the anode rotation as
well as other technical improvements and special designs were
added to X-ray imaging diagnostics (see below). Experiments with X-ray
laser sources are currently being performed- whether the
excitation of characteristic X-rays in a high-temperature plasma
generated by a laser beam or braking X-rays on the impact of
accelerated electrons on a target. On the sidelines, we can note
that the most complicated special "X-rays" (sources of
X-rays) can be considered wigglers and undulators of
electron synchrotrons (see §1.5, section " Charged
particle accelerators ").
Electron focusing, focus
In order to achieve good sharpness and
resolution of the projection shadow transmission image in X-ray
diagnostics, it is necessary that the X-ray beam comes from an
almost point source . In X-ray machines for
X-ray diagnostics, the filament - a tungsten
spiral - is embedded in a recess or focusing slit of the
cathode , which has a negative polarity, so that its
repellent effect clusters electrons into a narrow strip *). After
acceleration by high voltage, the electrons then fall into a
relatively sharply localized place of the anode - the impact
focus , which has a rectangular shape due to the
elongated shape of the filament. Real, optical focus the
resulting X-ray is a geometric projection of the radiating
surface on the anode, i.e. the impact focus, into a plane
perpendicular to the beam of radiation used for imaging. The
originally rectangular impact focus is reduced in the
longitudinal direction due to the inclined, tilted surface of the
anode; its projection in the direction of the display has an
almost square shape, usually 0.5-2 mm in size.
*) These X-rays tubes usually have two
cathode fibers - shorter and longer. By switching the heating
current, one or the other fiber can be heated and thus the size
of the impact focus on the anode can be changed.
Some new X-rays tubes, instead of the classic
incandescent fiber, have an incandescent cathode solved by the
so-called flat emitter technology (ftat
emitter). It consists of a rectangle of hot thin sheet metal,
masked by several holes. By adjusting the negative voltage
between the cathode gap and the emitter, a very sharply localized
impact focus can be achieved more precisely.
Asymmetry of the X-ray
beam from the focus, heel effect
In the first approximation, the X-ray is emitted from the impact
focus isotropically , with the same intensity in
all directions. However, some of the incident electrons penetrate
below the surface of the anode and the X-rays generated there are
partially absorbed and attenuated as they pass through the anode
material. This leads to a change in the shape of the radiation
pattern from the target at the anode, to a certain angular
asymmetry
X-ray beam emanating from the chamfered anode: for an angle of
about 30 ° in the direction of the cathode, the radiation
intensity is about 5% higher than in the center (0 °), in the
opposite direction (to the anode disk) about 15% lower. This
shaping of the radiation characteristics are sometimes referred
to as anode heel effect, some "heel
effect", "skew". This phenomenon may manifest
itself in some minor inhomogeneity of the X -
ray image, especially during exposures of large imaging fields,
or during X-ray mammography. This inhomogeneity is smooth and
gradual, so it does not interfere with visual evaluation;
however, digital evaluation is sometimes computer-corrected.
Anode cooling and
rotation
Local overheating of a single anode site ( focus), where
the electrons fall, is often prevented by rotating the
anode *) : the cathode is eccentrically placed in the
X-ray tube, the anode in the shape of a conical disk (about 5-10
cm in diameter) rotates around the
longitudinal axis, so that the electron beam always falls to a
different place the circumference of the anode, making the
heating and heat dissipation more uniform (Fig.3.2.2 left).
Although X-rays emanate from the same place - the focus, which is
against the stationary cathode, this place is due to the rotation
of the anode constantly formed by another physical part of the
anode disk; the heat is thus better dissipated in the anode
material. X-rays tubes for very high performances (eg in
industrial use) then have an anode actively cooled
- inside the anode there is a cavity through which the cooling
liquid flows.
*) Anode
rotation
Because the anode is located inside a high vacuum tube, its
rotation cannot be ensured by a mechanical transmission from the
outside. No bearing is so tight that no air enters the tube over
time - the vacuum would be broken. Rotation of the anode is
driven electromagnetically : within the anode
neck x-ray tube is on bearings fixed to the metal roller shaft
connection with the anode which serves as a rotor
, outside the X-ray tubes are disposed coils supplied with
alternating current - those forming the stator ,
giving the rotating magnetic field which, by
electromagnetic induction ( eddy currents are induced in the
rotor) rotates by a roller and an anode inside the tube
(Fig.3.2.2 left). From an electromechanical point of view, such
an X-ray tube is actually a small asynchronous electric motor.
The rotation speed of the anode is usually 50 rpm (3000 rpm),
10-12,000 rpm is also used for high power X-rays. A certain
problem is the wear of the bearings on which the
anode rotor is anchored. These bearings are highly mechanically
and thermally stressed, they are outside the evacuation area
outside the possibility of maintenance and lubrication (only
"dry" lubrication with silver or lead metal powder is
used) - their wear is usually the main limiting factor of X-ray
tube life.
In modern X-ray machines , hydrodynamic lubrication
of bearings with a thin layer of suitable molten
metal is sometimes used (a kind of
"aqua-planing" of the shaft in liquid metal, with
minimal friction). One suitable metal is gallium, which
has a low melting point of about 130 ° C and a sufficiently high
boiling point of 2204 ° C, so that even at relatively high
temperatures of several hundred ° C, the vacuum does not
contaminate its vapor. Furthermore, such a lubricating contact
surface in the bearing efficiently dissipates heat from the
anode. Before the actual operation, after switching on the
device, the bearing is first heated and only after the melting of
the lubricating metal does the rotation of the anode begin, which
is then maintained continuously even outside the exposure, until
the device is switched off. The bearing is heated and the
required temperature is maintained by the effect of eddy currents
induced in the rotor (these are the same eddy currents which, by
their interaction with the rotating magnetic field of the stator,
drive the rotation of the anode). Special so-called eutectic
alloys are also used to lubricate the anode bearing metals
which are liquid even at normal temperatures (eg gallium, indium
and tin in an alloy of suitable ratio, with a melting point of
-10 ° C).
From a mechanical point of
view, the rapidly rotating massive anode behaves like a flywheel
, preserving its vector of rotational momentum. If we try to tilt
the X-ray machine with a rotating anode (change the direction of
its axis), due to the gyroscopic effect , the
rotating anode puts up resistance and its bearings are
stressed by considerable forces. This is especially the
case with CT tomography devices, where the X-ray machine orbits
around the examined object relatively quickly. Therefore, X-rays
with double-sided anchoring of the anode axis
are sometimes used here. The shaft of the rotating anode, passing
through the whole X-ray tube, is mounted in bearings at both
ends. The cathode portion of the X-ray tube then has two
protrusions: one on the side for mounting and feeding the
eccentrically located cathode, the other in the middle for
mounting the second anode bearing. When the rotary anode shaft is
anchored on both sides, the gyroscopic forces are distributed and
the bearings are significantly less stressed.
Fig.3.2.3. Design of X-ray tubes used in radiodiagnostics.
Left: Classic X-ray lamp with rotating anode. Right:
STRATON type X-ray tube, rotating as a whole, with the front
anode in direct contact with the oil cooling bath and with the
magnetic deflection of the electrons from the cathode.
Although the rotation of the
anode prevents local overheating of the impact focus on the
anode, during longer operation the anode heats up strongly as a
whole and this heat is only slowly transferred by
infrared radiation through a vacuum out of the X-ray lamp to the
cooling medium. It is therefore necessary to observe certain time
delays between individual exposures in order for the anode to
cool down. Another disadvantage of the rotating anode is the wear
of the bearing inside the vacuum flask, which cannot be
lubricated or otherwise maintained from the outside. In addition,
when the bearing wears, unwanted fumes are released into the
vacuum space of the X-ray tube.
Rotating X-ray machine
as a whole
A new Straton X-ray tube design has therefore
been developed for higher performance, where the beam of
accelerated electrons from the axially positioned cathode,
deflected by the magnetic field of the deflection coils (located
outside the tube) *) impinges peripherally on the opposite front
anode, which is in direct contact with the
cooling oil bath from which the X-ray tube is immersed -
Fig.3.2.2 on the right. The X-ray tube rotates as a whole
around its longitudinal axis connecting the cathode to the center
of the anode, the X-rays emanating in the lateral direction
(similar to a conventional Coolidge-type tube). The glow and
anode voltage is applied to the X-ray tube by means of collecting
rings, on which electric brushes slide ( slip-ring
technology , similar to that of electric motors for direct
current). The main advantage of this design
is the substantially better cooling of the anode
, which is in direct contact with the cooling medium, while there
are no mechanically moving parts inside the vacuum space. The
bearings on which the entire X-ray tube is mounted are easily
accessible and can be effectively lubricated. This leads to the
possibility of achieving higher performance and significantly extending
the life of the X-ray tube .
*) The current through the deflection coils
must be precisely set depending on the accelerating anode
voltage: the higher the voltage [kV] at X-ray is set, the higher
the current must flow through the deflection coils so that the
electron beam is properly bent and hits the desired location at
the anode edge. The desired current can be set by electronic
current control in the deflection coilsthe position of
the impact focus of the electrons on the anode. By
controlling the deflection current, it is possible to define several
foci that can operate simultaneously in multiplex
operation.
Furthermore, the Straton X-ray
machine is significantly smaller and lighter at
the same power than conventional X-ray machines with a rotating
anode. This is very advantageous in new technologies of high
- speed multi-slice CT devices, where the
rotational mechanics are strongly stressed by centrifugal,
gravitational and gyroscopic forces.
Power
supply of the X-ray machine
The X-ray tube, as an electronic
source of radiation, requires an appropriate power supply
, supplying electrical energy generating X-rays and providing
other functions necessary for the correct operation of the
device. The X-ray machine has three basic power supplies:
¨ The heating current source
for the X-ray tube cathode. It is a glow transformer ,
they supply a low voltage of usually 6-12V and a current in the
range of approx. 0.5-10A on their secondary winding, with the
possibility of continuous regulation (see below "Setting the
X-radiation parameters").
Fig.3.2.4. X-ray Power Supply
Above: High anode voltage source. Middle: AC voltage for anode
rotation. Bottom: Cathode glow voltage.
Note: I present this
arrangement of an X-ray under high voltage, with a hot cathode, a
rotating anode and X-ray emission on a "work table" as
an experimental demonstration.
¨ High
voltage source
- anode voltage for accelerating electrons in
X-ray. This is a voltage in the range of mostly about 20kV-150kV;
it can also be lower for special X-ray machines for spectrometric
use, and up to 400 kV in industrial applications. The basis of
this source (also called a generator ) is a high-voltage
transformer , which transforms the
mains voltage (220V / 380V) upwards - either directly from the
mains voltage to the required value, or more recently via an
electronic oscillating circuit. The high-voltage transformer has
a high gear ratio (given by the ratio of the number of
turns on the primary and secondary windings) of the order of 1000
or more.
Newer devices use high-frequency sources high
voltage. The mains voltage is first rectified and smoothed. This
DC voltage is supplied to the high-frequency oscillator
(inverter), which uses thyristors to generate an AC voltage of
about 10kHz with sharp edges. This is then converted into a high
AC voltage in the high-voltage transformer, which is further
rectified and smoothed (see below). The advantage of this
solution is that the high-frequency transformer can have
significantly smaller dimensions and weight at the same power
than a conventional transformer with a frequency of 50Hz.
The value of the anode voltage can be regulated
either continuously or stepwise in suitable steps. This is
achieved using an autotransformer which is preceded by a
high voltage transformer. The autotransformer regulates the mains
voltage in the range of approx. 20-220V, which is then multiplied
by the high-voltage unit by a constant ratio (approx. 1: 1000).
In the case of electronic high-frequency sources, the
high-voltage regulation is carried out by means of frequency
control .
The AC high voltage is rectified *)
by vacuum or semiconductor diodes. The simplest rectification is one-way
(" single- pulse") by means of one diode
connected in series (or without
rectification, rectified by X-ray - note below) , when the emission of radiation occurs only in the
positive half-period of alternating current. Two-way
rectification is more perfect ("two-pulse") using 4
diodes in a bridge Graetz connection, or 2 diodes in a double
secondary winding, where there is always a positive (pulsating)
voltage at the anode and the X-ray machine operates in both
half-periods of AC voltage. Sometimes a three-phase
mains supply of a three-phase high-voltage transformer
is used and 6 diodes in a bridge connection are used for
rectification - only a slightly pulsating DC voltage is generated
(which never drops to zero, but only by about 15% of the peak
voltage), the pulsations have a frequency of 300Hz; it is
sometimes referred to as six-pulse smoothing. A
three-phase high-voltage transformer can have two triple
secondary coils, phase-shifted by 60 °; after rectification by
means of 12 diodes in a bridge circuit, only a slightly pulsating
DC voltage is obtained (with a frequency of 600Hz it fluctuates
only by about 4% - "12-pulse smoothing "),
close to the right smoothed DC voltage. In the case of
high-frequency high-voltage sources, smoothing by means of
capacitors can be carried out very well after
rectification , so that a minimally pulsating DC voltage with a
high frequency of small pulses is obtained.
*) In fact, the X-ray machine itself is
basically a diode that can take care of the rectification itself.
For older and simpler devices, therefore, the X-ray machine was
supplied with alternating voltage, while the emission of
X-rays occurs only in half-periods when there is a positive
voltage at the anode. The disadvantage of this solution is the
increased proportion of the soft component of radiation (arising
at the beginning and end of the half-period, when the
instantaneous voltage is significantly lower) and at higher
powers also the possibility of reverse current (" backfire
") - in the final half-period the secondary electrons
emitted from heated foci of anode, towards the cathode, which are
bombarded by high kinetic energy and can damage it.
The value of high X-ray voltage is
expressed in thousands of volts - kilovolts [kV]
. If a pulsating voltage is applied between the anode
and the cathode of the X-ray tube , the maximum energy of the
emitted X-rays is given by the maximum positive value of the
anode voltage, which is expressed as [kVp] -
"number of kilovolts in the peak".
¨ Power
supply for anode rotation ,
which is an alternating voltage
(usually 220 / 380V mains), applied to the stator coils
, creating a rotating magnetic field for X-ray anode
rotation. At a mains voltage frequency of 50Hz, the fundamental
frequency of rotation of the anode is 3000rpm; by segmenting the
stator coils, lower speeds of 1500, 1000, 750, 600 rpm can be
achieved. To achieve higher speeds, the X-ray stator must be
powered by an electronic oscillator , providing a
frequency higher than 50Hz. A higher starting voltage is
first applied to the stator, which is reduced to about 1/3 after
spinning to maintain synchronous speed. The speed of the anode
(rotor) can be electronically monitored on the basis of the
current flowing at a given voltage through the stator coils when
the rotating magnetic field is excited (after reaching the
synchronous speed this current decreases significantly). Only
after the anode has been rotated to the required speed can the
high anode voltage start and the exposure begin. In order to
prevent the X-ray anode from rotating unnecessarily for a long
time, the opposite phase of alternating voltage is connected to
the respective stator coils for a while after the exposure,
whereby the rotating magnetic field reverses its direction and
the rotation of the anode is electromagnetically braked.(For
some types, a separate winding is installed in the stator for
braking, a DC supply for magnetic braking of the rotor is also
used). Exceptions are anodes with molten metal (gallium)
lubricated bearings, which rotate continuously, even between
exposures, as described above.
Newer X-ray devices also use other
voltages to supply electric motors for sliding and rotating
movements, X-ray cooling, as well as control and regulation
electronics, including detection and evaluation circuits.
X-ray
tube cover
During actual operation in X-ray machines, the X-ray tube is
encapsulated in a special metal cover (made of
aluminum alloys) of cylindrical shape *). The cover is shielded
from the inside lead sheet approx. 3 mm before unwanted
penetration of X-rays into the surroundings. At the ends of the
housing there are bushings through which voltage is
applied between the anode and the cathode by means of
well-insulated high-voltage cables , and a low glow
voltage is then applied at the cathode end. In the middle part *)
of the cover there is an exit window (of course
unshielded, to which the X-ray machine must be turned with its
impact focus) made of a light material, mostly acrylic glass,
through which the X-ray beam comes out for the respective use. In
power X-rays tubes, the space between the X-ray lamp and the
walls of the package is filled with a cooling medium -
transformer oil . The oil environment also increases the electrical
strengthcircuits - prevents high voltage electric shocks. To
eliminate the mechanical stress on the cover due to the thermal
expansion of the cooling oil, a rubber expansion
membrane is built in a suitable place on the wall of the
X-ray cover (prevents, for example, the
cover from bursting when the X-ray tube overheats) .
*) For Straton X-rays,
the housing has a double cone shape and the exit window is near
the end where the anode is. The appropriate location of the
impact focus on the anode opposite the output window in the
housing is ensured by deflection coils (incl. The angle of their
rotation), located from the outside in the narrowed part of the
housing - Fig.3.2.2 on the right.
Smaller, low-power
X-ray machines sometimes use a compact design: a
high-voltage transformer (for the anode) with a winding current
winding for the cathode is built into the common housing together
with the X-ray tube. Only such a 220V mains supply is then
supplied to such a compact system.
Collimation
and localization system
The following is a collimation system ,
consisting of a tubus with adjustable orifices defining the
geometric shape of the X-ray beam. The apertures are adjusted so
that the X-ray beam covers only the displayed area and other
parts of the body are not unnecessarily irradiated. A light
localization system is installed in the X-ray tube
collimation system for visual focus and
adjustment of the displayed field - the light from the filament
lamp is guided by optical projection through the collimation
system so as to achieve a match between the visible light field
and the X-ray field. Before the examination, it is possible to
adjust the position of the displayed field on the film cassette
or display panel, as well as on the surface of the patient's
body.
Mechanical design of
X-ray devices
The cover with X-ray tube and collimation system, together with
the opposite film cassette or imaging panel, are mounted on
special stands of several types and
constructions, according to the required X-ray imaging
methodology - Fig.3.2.5. For skiagraphic imaging
, the X-ray is most often mounted on top of a vertical
stand (column tripod mounted
on the floor or ceiling mount) with the possibility of easy
mechanical movement. The film cassette or display panel is
mounted at the bottom of the stand, again with the possibility of
sliding. Between them is a sliding bed with the patient for
examination while lying down. For standing (or sitting) imaging,
the X-ray machine with the collimation system is rotated
horizontally, the opposite cassette or flat-panel is on a
separate vertical stand (so-called vertigraph ). The
horizontal movement (travel) of the X-ray machine can be realized
by means of rails mounted on the ceiling or
floor of the examination room. Displacements of individual parts
of the X-ray system can be manual or motorized
, using electronically controlled electric motors. For new
systems, the so-called autotracking - automatic
synchronous coupling of display panel and X-ray displacements
(equipped with a collimation system). Some systems for both
sciagraphy and sciascopy have the option of rotating or tilting
the X-ray stand, display panel, or tilt to
various angles , from horizontal to vertical - such a
system is called an X - ray tilting wall
and has a wide range of uses.
For flexible sciascopic
imaging , the X-ray tube and the opposite
imaging detection system are often mounted on a special stand in
the shape of the letter "C" - the so-called C-arm
( C-arm ) - Fig.3.2.3b., Or the so-called U-arm
- Fig.3.2 .3c. These arms can be rotated using
electric motors to different angles around the patient, allowing
flexible display in different projections. These systems (which
are sometimes mobile) are used in a wide range of applications,
such as digital subtraction angiography (see below DSA - Fig.3.2.3), X-ray navigation of
interventional procedures, afterloading in radiotherapy
(see §3.6, section " Brachyradiotherapy " - Fig.3.6.7) and others.
A separate category of X-ray device design solutions
is transmission X-ray tomography CT , where the
X- ray machine and the opposite electronic detection system are
mounted on a portal rotary stand - gantry
- described in more detail below.X-ray
tomography - CT ", Fig.3.2.4. This
includes special constructions of X-ray imaging devices,
installed directly on IGRT radiotherapeutic
irradiators (see §3.6, section" Isocentric
radiotherapy ", Fig.3.6.1c) or tomotherapy
(§3.6, part " Modulation
of irradiation beams ",
Fig.3.6.4a)
Further technical details of the construction of
X-ray devices and their accessories are already outside the scope
of this physically focused discussion.
Setting of X-ray parameters
To optimize X-ray diagnostics, it is necessary to set suitable
X-ray parameters. In the electrical circuit of the X-ray tube, two basic electrical
parameters are regulated and set as needed (the third is only time, the fourth is realized by
mechanical arrangement) :
¨ Anode
voltage U [kV] ,
which is a high voltage supplied between cathode and anode the
energy of the photons of the resulting X-rays, its
"hardness". The maximum energy of X-rays in [keV] is
numerically practically equal to the anode voltage U in
[kV], the mean energy is slightly higher than 1/3 of the max.
energy. With increasing anode voltage, the whole spectrum of
X-rays shifts towards higher energies (shorter
wavelengths) and the relative proportion of
higher energies (harder shortwave
components) increases .
In practice, the anode voltage ranges in a wide range
from about 20kV to 200kV (depending on the type of displayed
structures), in the industrial use of X-rays then higher.
Note: The energy - hardness - of
X-rays emitted is often referred to in X-ray jargon as the "
quality " of X-rays.
¨ The anode current I
[mA]
flowing through the X-ray tube, determines the intensity
(fluence) of X-radiation emitted by the X-ray tube I X . It is most easily
regulated by changing the heating of the cathode
- the heating current - and thus the temperature of the
cathode fiber. The glow current can be regulated simply by means
of a rheostat in the glow circuit (in
the glow transformer circuit), more
recently with special electronic circuits equipped with
transistors and thyristors. At higher heating of the cathode
fiber, more electrons are emitted, a larger stream of electrons
flows through the X-ray and a higher intensity of X-rays is
emitted. The average X-ray current is in the range of mA units to
about 200mA, the peak current can be significantly higher (in
pulse mode). E.g. an X-ray machine with a tungsten anode (Z = 74)
supplied with an anode voltage U = 120 kV at a X-ray current of 1
mA emits X-rays with an intensity I X of approximately 6.10 13 photons /s (follows from the
approximate relationship for braking radiation production
efficiency given in " X-ray tube ", passage " Braking X-rays
") .
¨ Exposure
is the total amount of X-rays of photons, which determines the
quality of X-rays images and also the radiation exposure of the
patient. It is given by the product of radiation intensity I X (photon fluence / s)
and exposure time T - it is therefore proportional to the product
of anode current by X-ray tube [mA] and exposure
time [s]: "milliampere-seconds" mA.s
= Q , which is the total charge
Q electrons or the electrical amount that passes
through the X-ray lamp during exposure (the
coefficient of proportionality h is given above in the
section "Braking X-rays") . At Q
= 1mAs, approx. 10 13 is radiated from the anodeof photons, of which only a
small part is used for X-ray imaging - of most photons flying in
different directions, only a relatively narrow conical beam is
selected by collimation, low energy photons are further removed
by filtration (see below).
Note: The energy
of X-rays does not depend on the magnitude of current, time or
electrical quantity.
For the acquisition of common skiagraphic
images of soft tissues, the exposure to X-rays of about 2 ¸ 6 mAs is used,
for the skeleton about 20 ¸ 80 mAs, for CT also 200 mAs. In modern X-ray devices
capable of operating in a pulsed mode with high instantaneous
power, a high current value [mA] at a short exposure time [s] is
preferred to achieve the desired exposure [mAs] - thus reducing
the risk of blurring the image with patient movement.
Based on
empirical experience, the recommended value of anode voltage [kV]
and exposure [mAs] is determined for each type of X-ray
examination, providing a quality image of the required structures
at a relatively low radiation exposure. Some devices also use automatic
exposure , which electronically switches off the anode
voltage in the generator - and thus the exposure - after reaching
a certain preset "amount" of X-rays. For the purposes
of automatic exposure, the flux of transmitted X-rays is
monitored by means of ionization chambersplaced behind
the film cassette or behind the flat panel. For digital imaging
detectors, presetting the total number of pulses stored in the
digital image can also be used to interrupt the exposure.
Similarly, exposure optimization works for CT instruments, where
according to the signal level from the detectors in the
pre-planning radiographic display of SPR (topogram), the optimal
current values ??[mA] can be automatically adjusted during
self-diagnostic scanning - ATCM ( Automatic
Tube Current Modulation ), see below " CT ".
The already generated X-rays are subsequently treated by
filtration:
¨ Filtration, collimation
The soft X-rays of longer wavelengths and the low energy of
photons at the beginning of the continuous spectrum of X-ray
radiation are of no significance for diagnosis, they are usually
absorbed in the skin and shallow layers of tissue - causing only
unwanted radiation exposure. Therefore, it is removed by filtration
- an aluminum or copper plate about 1.5-4 mm thick is inserted
into the radiation path, which absorbs the soft component of
X-rays to a large extent, while transmitting the harder component
- see the shape of the spectra in Figure 3.2.5. The initial
partial filtration of the generated X-rays is already created by
passing through the material of the anode, the glass flask of the
X-ray tube, the cooling oil, the material of the cover and the
outlet window.(thus the X-ray tube glass
flask itself acts inherently as a partial filter, equivalent to
about 0.5 mm Al; similarly the cooling oil and the X-ray tube
cover window) .
In some
special cases when we need sharper and more selective filtering
of certain areas of the energy so used filtration K-edge
( K-edge filter ). It is based on significantly
increased (" resonant ") absorption of photon
radiation at energy equal to or slightly higher than the binding
energy of electrons on the K-shell of atoms of the material used
(see §1.6, section " Interaction of
gamma and X-rays ", Fig.1.64). By
combining a standard filter (Al, Cu) and a filter made of a
suitable heavier material using the K-edge effect, we
obtain a bandpass filter , selecting a certain section
of energies from a continuous spectrum of X-rays. This is
especially true for mammography , where a molybdenum or
rhodium filter cuts off photons of higher energies than about
20-23keV to achieve better contrast (see "X-ray
mammography" below). Also for DEXA methods -
analysis of absorption using two X-ray energies (see below "
CT
with 2 X-rays - DSCT: Dual Source and Dual Energy CT ").
The geometric
delimitation of the X-ray beam is performed by collimation
(mentioned above) .
Giant. 3.2.5. Basic scheme of X-ray examination.
Left: Arrangement of X-ray tube, filter,
DAP-meter, primary and secondary diaphragm, film or detector. Right:
Energy spectra of X-rays from X-ray tube, after filtration and
after passing through the patient.
Scattered
X-rays
When X-rays interact with matter, Compton scattering of
photons on free or weakly bound electrons occurs, among
other things . These scattered photons fly out of the tissue with
lower energy and in different directions . The
proportion of scattered radiation is greater the larger the
patient (and is also higher for harder X-rays from X-rays -
higher voltage [kV]). Scattered radiation degrades the
quality of the X-ray image - it reduces its contrast.
The possibility of suppressing scattered radiation is mentioned
in the following paragraph. This Compton-scattered X-rays further
cause some less radiation exposure even outside
the X-ray beam itself from the X-ray machine. This radiation
exposure is not high, scattering albedo of the human
body for X-rays is less than 1% ( albedo
was discussed in §1.6, section " Interaction
of radiation passing through matter
") . At a distance of 1 m, the
radiation dose is about 0.1 m
Gy / 1 mAs, in 2 meters only about 0.005 m Gy / 1 mAs.
Nevertheless, during X-ray examinations, radiation workers should
not stay in the examination room during the exposure, unless
necessary, but in a shielded control room - the exception is, for
example, interventional radiological procedures.
Filters
and screens for X-ray imaging
In the practical diagnostic application of X-rays, it is
important to use filters and collimating screens - Fig.3.2.5.
Suitable primary apertures ensure the geometric
delimitation of the X-ray beam, reaching only the
necessary examined area (a sharp image with high spatial
resolution is ensured by the fact that the radiation comes from
an almost point focus on the anode by X-ray tube, as described
above). Immediately behind the X-ray tube is a filter
, most often made of aluminum sheet, which absorbs low-energy
photons (from the beginning of the continuous X-ray spectrum),
which are not usable for imaging (they would penetrate only into
the subcutaneous tissue) but would increase the patient's
radiation exposure (mentioned above). ) . This is followed by a tube with
adjustable orifices for the geometric
delimitation of the X-ray beam (size of the penetrating field). A
thin plane-parallel ionization chamber is
usually mounted on the outlet window of the tube for monitoring
the exposure to X-rays, the so-called DAP meter (see below " Radiation load during TRG examination ") , allowing to determine
the radiation dose of the patient during X-ray examination -
Fig.3.2.5 top left.
A secondary screen is then placed between the
patient and the film (or screen or imaging detection system, flat
panel) . It is a lattice formed by parallel or
diverging absorption lamellae (lead strips)
which, through their gaps, transmit only primary X-rays passed in
the direction of the original beam, while secondary
Compton-scattered photons (moving in other directions) are
absorbed in the partitions. It is therefore a collimator , which
attenuates the radiation only minimally in the primary direction,
while the attenuation of the obliquely transmitted scattered
radiation is considerable. The quality of the secondary screen is
determined by the grid density (number of lamellae per
centimeter) and the grid ratio (the ratio between the
distance of the absorbent strips and their height). Suppression
of secondary scattered radiation significantly improves
the contrast of the X-ray image. On the other hand, the
secondary aperture also absorbs some of the useful X-rays (eg with a Bucky aperture, the attenuation is about 1.8
times) , so it is necessary to increase the
exposure. Three types of secondary screens (grids) are used :
- Converging focused Bucky-Potter screen
(approx. 10 slats / cm). Bucky The
screen has relatively thick partitions (approx. 1 mm), which
would be projected into an X-ray image and have a disturbing
effect. This disturbing raster is eliminated by moving the
aperture during exposure, blurring its image and disappearing
into the overall background.
- Parallel fine Lysholm screen (40-60
slats / cm).
- Ultrafine Smith screen (density> 100
lamellae / cm). Due to too high absorption,
it is not used in practice.
Terminological note: In radiodiagnostics, it is
often customary to use the not very precise generic name " aperture
". More precisely, however, these are collimators
and filters .
Visualization and recording of X-ray images
X-rays, carrying density information after
passing through the displayed tissue, is invisible
to us , so it is necessary to " make it visible
" or register it using suitable material
and electronic methods. There are basically three ways to display
this X-ray :
- Visual observation
of the image on a luminescent screen
A luminescent screen is a plate or
foil on which a suitable material (such as
zinc sulphide, .......) is applied , in
which the interaction fluorescence is produced
with ionizing X-rays
. Thus, we can see a projection density image on the luminescent
screen via X-rays. The advantage of this simplest method was the
possibility of continuous dynamic observation - sciascopy
. However, the main disadvantage is the low sensitivity
and high radiation exposure of both the patient
and the radiologist. .......
- Imaging on
photographic film
Ionizing X-rays cause a photochemical reaction
in suitable photographic materials, mostly containing silver
bromide This photographic emulsion, applied on the surface of a
plastic film, forms a photographic film in which
the incident X-rays form a latent photographic image - is
described in more detail in §2.2 " Photographic detection
of ionizing radiation". After
development, we receive a negative density photographic
image in X-rays.
- Scanning with an
electronic imaging detector,
which registers incident X-rays, converts it into electrical
impulses and, after adjustment by complex electronic circuits,
creates digital density images in computer
memory - described in more detail below " Electronic imaging X-ray detectors ." .........
Amplifiers
and digital X-ray image sensor, indirect and direct digitization
Direct X-ray photographic film for
display belongs to the past, and is gradually replaced by more
sophisticated technologies. to increase the sensitivity
of the scanning X-ray suitable image enhancement
methods are used in the image, more recently
methods of electronic image capture. This makes it possible to
significantly reduce the required intensity of X-rays and thus
the radiation dose for the patient, as well as to reduce the
undesired exposure for radiation workers.
- Amplifying foils
During photographic skiagraphy, amplifying
luminescent foils are attached to the film
, the task of which is to convert X-rays into light, which is
exposed by the photographic film. It consists of a layer of
phosphor dispersed in an emulsion of gelatin or nitrocellulose.
Use calcium tungstenate (emits blue light), lanthanoxid
bromide (blue light), gadolinium-carryover (green
light), barium chloride (blue light) ... The movie has
to be sensitized to the color of the light from the
phosphor. It is already abandoned.
- Xeroradiography ,
where a positively charged semiconductor (selenium) plate is used
instead of film. The incident photons of X-rays there evoke a
photoeffect, in which the photoelectrons locally compensate for
the original positive charge - a latent electrostatic
image is created ; in the copier, powder particles of
dye are then attracted to differently charged places of the
plate, which are finally printed on paper where a visible image
is created. It is also abandoned.
- Memory foils
replace the film in the X-ray cassette and
retain a latent electron image after radiation exposure. The
sensitive layer usually contains europium atoms (BaFCl:
Eu 2+ , instead of Cl it can be
iodine or bromine). The impact of X-rays photons
excites in the sensitive layer of the film, electrons are
released from the europium atoms, which are trapped in the halide
metastable levels of so-called " electron traps
" - a latent electron image is formed .
This latent image is made visible after exposure by photostimulation
using a laser infrared beam: a "trapped" electron is
released into the conduction band, after which the electron is
captured on the excited surface in the luminescent center.,
followed by deexcitation to baseline, accompanied by photon
emission of light. This light is registered by a sensitive
photomultiplier, the generated electrical pulses are sampled and
converted by an analog-to-digital converter into digital image
information. The device that reads and digitizes the latent image
is called a digitizer - it is an indirect
digitization of an X-ray image.
- Image intensifiers
During sciascopy, the image on the fluorescent screen ( "shield"
) is amplified by a special image tube - image
intensifier. The light image created by the impact of
X-rays photons on the fluorescent screen of the inlet window of
the tube causes a photoelectric effect on the enclosed
photocathode by its emitted photons of visible light. The emitted
photoelectrons are accelerated by a voltage between the
photocathode and the anode (approx. 10-20kV) and directed by
electron optics to a luminescent screen, where they create a
reduced inverted image, but its brightness is more than 1000
times greater than the original image. This image is then
optically captured by a video camera and displayed on a TV screen
or computer monitor. It is still used for older devices, new
devices are already supplied with digital flat-panels
.
- Electronic imaging
detectors - flat panels
All of the above image amplifiers or television sensors are only
a temporary technical solution. New systems are equipped with an
electronic digital image sensor on a flat
called. Flat panel , consisting of a scintillator
(e.g. cesium iodide CsI: Tl or based on gadolinium Gd 2 O 2 S: Tb - GOS; see
§2.4 of scintillators, the " scintillators and their properties ") and semiconductor optoelectronic amorphous
silicon ( a -Si). The detection panel
consists of a large number of elements - cells, pixels
, assembled into an image matrix of about 2000 ´2000 elements, and
more. The most perfect imaging detectors are semiconductor
pixel detectors (SPD), see §2.5 " Semiconductor detectors ". The pulses from the individual elements of the
detector are stored in multiplex mode with the help of an
analog-to-digital converter (ADC) directly into the computer's
memory - they create a digital X-ray image .
Only this technology of so-called direct digitization
belongs to the future ... - it was described in more detail below
in the section " Electronic X-ray
imaging detectors ".
Note: The terminology for " direct
" and " indirect " digitization is temporary
and will be abandoned soon: all X-ray imeges will be
automatically primarily digital (a technology now called "direct digitization
") .
Electronic X-ray imaging detectors
The earlier imaging using photographic film or a luminescent
screen is now being replaced by electronic imaging
detectors - Fig.3.2.6. The advantage is significantly
higher detection sensitivity and wide possibilities of electronic
and computer image processing (digitization). All these imaging
detectors are based on modern technologies called quantum
optoelectronics ( photonics ), which use an
internal or external photo effect to convert photons into
electrical signals.
¨ Image
intensifier
Electronic imaging with image intensifier was
widely used in the 1960s and 1980s - fig.3.2.6a. The image
intensifier is a special vacuum tube with two windows - input and
output. On the inside of the inlet window is a layer of
scintillator (mostly cesium iodide) and below it a thin metal
layer of photocathode. The incident X-rays cause flashes of light
in the input scintillation layer, which electrons eject electrons
from the photocathode. The electrons thus generated are then
attracted by annular accelerating and focusing electrodes, to
which a high positive voltage is connected (gradually increasing
up to about 30 kV at the anode at the output scintillator). This
electro-optical system, acting as a continuous "electric
lens", throws electrons onto an output scintillator (mostly
ZnS: Ag), where the accelerated electrons produce intense
flashes. The resulting reduced, inverted but very clear
("amplified", intense) image is then captured by an
optical TV camcorder and (analog) displayed on the TV screen.
More recently, digital CCD camera imaging with computer image
recording was used. Image intensifiers or TV sensors were just
temporary technical solution, the future belongs to
fully digital X-ray image transmitters - flat panels .
Fig.3.2.6 Electronic imaging detectors in X-ray diagnostics.
Left: X-ray acquisition using an image
intensifier. Middle: Flat-panel with indirect
(scintillation) and direct (semiconductor) conversion of X-rays
into electrical signals. Right: Ring-arranged CT
detectors with fast ceramic scintillators and photodiodes.
¨ Flat - panels
Modern and more advanced electronic X-ray imaging detectors are
so-called flat panels ( flat
- they have the surface shape of a thin plate), which provide signals for direct digital X-ray image.
The detection panel consists of a large number of elements -
cells, pixels , assembled into an image
matrix of about 2000 ´
2000 image elements, and more. The level of
the electrical signal from each pixel is proportional to the
intensity, resp. the number of X-rays of photons incident on a
given location of the flat-panel. From electronic multiplex
registration circuits ( multiple
read-out ) the image signal via the
ADC is fed to the image matrix of the computer, in the individual
elements ( pixels ) of which information about the
intensity of X-rays from the corresponding location of the
irradiated object is stored. In terms of how to convert X-rays
into an electrical signal is constructed by flat-panel of two
kinds :
- Indirect
(scintillation) conversion ,
when photons of X-rays impinge first on the layer of scintillator
material (most commonly used cesium iodide CsI: Tl) *) in which
they evoke flashes of visible light (scintillators
and their use for the detection and spectrometry of ionizing
radiation is discussed in detail in §2.4 " Scintillation detection and gamma-ray
spectrometry "). This scintillation light then enters the semiconductor
photodiodes (mostly silicon - a-Si - amorphous silicon
is used as the semiconductor material ), in which an electric
charge is released by the internal photo effect (electrons and
"holes") and the light is thus converted into an
electrical signal - fig. .3.2.6b. This flat panel design is
currently the most widely used.
*) Scintillation crystals of
some flat panels have a "fibrous" design. They are
composed of densely spaced thin vertical needles. This design
reduces the lateral scattering of light scintillations, leading
to a sharper image.
ISS technology
Some new types of flat panels with scintillation conversion have
a somewhat curious design with "opposite orientation"
with respect to Fig.3.2.6b: the displayed X-rays are coming
on the side of the layer of photodiodes and reading TFT
transistors, a scintillation crystal passes through this layer
and impinges on the CsI. Scintillation interactions then usually
occur in a layer near the photodiodes, thereby reducing lateral
scattering by scintillation and improving resolution. This
solution, referred to as ISS ( Irradiated Side Sampling
) technology , is made possible by the electronic miniaturization
of the photodiode and reading circuit layer, which is thin
and has virtually no effect on the transmitted X-rays.
- Direct conversion ,
where photons of X-rays fall directly into semiconductor
detectors (suitable material is selenium or CdZnTe - CZT ), where by their interaction they release electric
charges and are thus directly converted into an electrical signal(The general principle of semiconductor detectors is
given in §2.5 " Semiconductor
detectors ") - Fig.3.2.6c. Flat panels with direct conversion are
still very rarely used, but they probably have a future. They are
also constructed in smaller dimensions (in
the order of centimeters - MEDIPIX ) with a very high density of miniature image elements
(high image resolution) and are used in special laboratory
methods such as X-ray microscopy (mentioned above).
Terminological note:
Please do not confuse indirect and direct X-ray
conversion in flat panels with indirect and direct digitization
of X-ray images! It has nothing to do with it, it is always a direct
digitization , only with a different physical-technological design. In both
cases, the electrical signal from the photodiodes or
semiconductor detectors is sensed by a special matrix of TFT ( Thin Film Transistors ) transistors implanted in thin-film integrated circuit technologies
on a glass support. Scanning, so-called read-out , takes
place in multiplex mode in the X and Y directions - it provides coordinate
pulses about the position of the X-ray photon detection
location in the flat panel. These coordinate pulses are converted
to digital form by an analog-to-digital converter (ADC) and
stored in the corresponding memory addresses in the image matrix
of the computer - a digital X-ray image is
created. The transfer of image data to the acquisition computer
from modern flat panels is solved wirelessly
using modems ( WiFi ).
Electronic imaging flat-panels are also
used in verification and dosimetric systems of so-called image-
guided radiotherapy with modulated beams - in isocentric
irradiators with a linear accelerator and in cybernetic gamma
knives (§3.6, part " Isocentric
radiotherapy " and " Stereotactic
radiotherapy SBRT ") ; they are sometimes
abbreviated EPID ( Electronic Portal Image Device ).
¨ X-ray detectors for
CT
The current CT X-ray detectors
work on a similar principle as flat-panels with indirect
conversion. They consist of a large number of semicircular
elements, each of which is a small scintillation crystal
(scintillators based on rare earth-doped silicon oxides, such as
lutetium and yttrium - LYSO, or gadolinium oxisulphide, with a
very short flash duration) are now used. with photodiode; see
below " X-ray tomography - CT ", section " X-ray detectors for CT
".
Properties of
electronic X-ray detectors
An important characteristic of electronic imaging detectors is
their resolution, which is the smallest distance
of two "point" objects at which they still appear as
two separate structures; or equivalent to the half-width of the
point object image profile. At shorter distances, both objects
appear as one, they are not distinguished. The resolution is
given mainly by the size of the individual pixel of the detector
(this limits the smallest possible point that can be displayed),
it is also affected by the scattering of X-rays and light in the
detector and the processes of converting X-rays into electrical
signals. As in photography, resolution is often measured at the
maximum number of lines per millimeter[lp / mm], which
can still be distinguished. Modern flat-panels theoretically
reach up to 10 lp / mm, which corresponds to a resolution of 0.1
mm; in practice, however, the real resolution is around 2-5 lp /
mm. The quality of X-ray images in terms of real resolution is
sometimes quantified in detail using the so-called modulation
transfer function MTF , which indicates
using Fourier harmonic analysis , which details of the
object can be displayed with a given contrast.
Another important parameter of electronic
X-ray detectors is the sensitivity of the sensor
. It is reported numerically using the detective quantum
efficiency DQE ( Detection Quantum Efficiency),
which is the percentage of X-ray photons incident on the detector
that is actually recorded by the detector and used to create the
image (the rest is uselessly absorbed by the input window or
detector material without a scintillation or electrical response)
. Electronic
imaging detectors enable more detailed analysis of fine
structures using enlarged image sections -
so-called " zoom " or " magnification
". In the case of image intensifiers, this is an analog
zoom (achieved by changing the voltage), in which a smaller
part of the input area is "stretched" over the entire
image at the output. The flat panel is a digital zoom -
additional software zoom of the selected part of the image,
without changing the resolution. If we want to maintain a high
image quality on the magnified image (maintain the same
signal-to-noise ratio as in the basic image), it is necessary to
increase the number of incident photons, which will increase the
dose. Digital X-ray systems, especially CT, are equipped with
software providing a number of other options for computer image
editing - post-processing .
X-ray
planar imaging - skiagraphy, sciascopy
X-ray
projection
The human body is a complex 3D system of a large number of
differently arranged tissues, organs, bones, body cavities, etc.
During X-ray radiation, these individual structures can
"shadow" and overlap each other - this
can prevent their good display and recognition of possible
anomalies. This interference and the overlap of the displayed
structures substantially depends on the angle of the
transmission beam. As a rule, it is possible to find the
projection angle for which the lesion is best shown,
without disturbing the surrounding structures. Based on the
long-term experience of radiologists, certain projections
are prescribed for planar X-ray examinations of each
organ or area, that provide the best imaging - eg anterior-posterior
AP projections, anterior-posterior PA, left LL (
latero-lateral, also SIN-sinister) or right RL (right-lateral,
also DX-dextrum) side projections, oblique projections left LAO
(left anterior oblique), LPO (left posterior oblique), or right
RPO, RAO and other projections and special
positions. The problem of overlapping structures is largely
eliminated in CT X-ray tomography - see " X-ray
tomography - CT " below, which
provides images from different angles and projections.
In terms of X-ray
imaging and processing, planar X-ray diagnostics are divided into
two groups :
¨ Skiagraphy
In simple X-rays, called skiagraphy, incident
X-rays passed through the examined tissue on photographic
film containing silver halides (silver bromide), in
which photochemical reaction leads to the
release of silver from the bond in the compound - formed latent
image , which is in inducing in the
developer visualized with the density of grains of colloid
silver; the remaining silver bromide is dissolved in the
stabilizer. The blackening density of the film is proportional to
the amount of X-rays passed. The resulting X-ray
photographic image represents a negative imaging
of tissue density: sites with low density (soft tissues)
have lower absorption and therefore high blackening, sites with
high density (eg bones) absorb X-rays more and are therefore
shown light (low blackening) on the film.
For X-ray imaging, special films are
used, the emulsion of which is thicker and contains an increased
content of silver halides compared to conventional photographic
materials *). Films are produced in various sizes - the smallest
fields of approx. 2x2cm are used for dental X-ray diagnostics,
the largest formats of approx. 43x43cm for lung imaging, or
96x20cm on the spine. When shooting, movies are stored in a
special light-tight cassette, provided with
metal marks and letters at the edge, which are projected onto the
film during exposure, are visible after development and ensure
the geometric orientation and identification of the image. In the
dark chamber, they are then removed from the cassettes, special
concentrated developers are used to develop them, providing high
contrast and saturation of the blackening of the film;
the process of developing, setting and drying is carried out in
developing machines. Overall, however, the use of films and the
"wet process" is in decline, the future belongs to electronic
scanning and digitization of X-ray
images (see below). In connection with this, in the case of
modern digital devices, the difference between skiagraphy and
sciascopy is largely blurred - in a computer system it is
possible to choose whether the recording of a digital image will
be static or dynamic.
*) The photochemical sensitivity of films
is relatively low for X-rays. To increase the sensitivity (and
thus reduce the required amount of X-rays, reduce the radiation
exposure of the patient), amplifying luminescent foils
are attached to the film , see below.
¨ Skiascopy
As skiascopy or fluoroscopy
becomes continuous visual observation image of
the transmitted X-rays, originally on the fluorescent screen
( "shield"). Direct sciascopy was used
very often in the past, but due to the high radiation exposure of
the examining radiologist (and also the patient), it has already
been abandoned. Indirect sciascopy is performed
on devices equipped with an image intensifier and electronic
image capture, more recently direct electronic digital image
capture by flat panel (see below). This indirect sciascopy is now
used to investigate dynamic processes (coronary
arteriography, transhepatic cholangiography, ...) and in interventional
procedures where visual inspection is
required - X-ray navigation of precise work
performed inside the body *) - insertion of various probes and
catheters, implantation of pacemakers , coronary angioplasty,
insertion of vascular or uterorenal stents, ... etc. - see below
"Subtraction angiography", fig.3.2.7. In radiotherapy,
it is the introduction of radiophores by afterloading
during brachytherapy (see §3.6, section
" Brachyradiotherapy") .
*) To reduce the radiation
exposure, pulse mode is now used in sciascopic imaging :
the X-ray does not glow continuously, but periodically turns on
only for short moments (approx. 0.1 sec. With a repetition rate
of approx. 4 frames / sec.)., During which produces an image. to
improve the visual quality of the images thus generated
sequential use is sometimes so called. recursive filter
, consisting of the weighted summation of several consecutive
images.. ....
X-ray tube and
an opposing image sensing system is often mounted on a special
rack-shaped "C" - called C-arm -
fig.3.2.7b. This arm can electromotor via pivot
to different angles, which allows quality display in different
projections. Even more flexible possibilities of movements of the
X-ray machine and the imaging detector around the patient are
provided by the so-called U-arm (independent movement of the X-ray machine
and the detector on the stand) - Fig.3.2.7c. Alternatively, so-called folding walls
can be used ; these possibilities were
mentioned above, the section "Mechanical design of X-ray
devices" .
Contrast
agents. Subtraction radiography.
One of the main difficulties in soft tissue X-ray imaging is the
small differences in the absorption of X-rays by individual
tissues *), leading to low image contrast
and difficulty in distinguishing some structures.
*) The tissues of the human body are mainly
formed by atoms of light elements (hydrogen,
carbon, oxygen, nitrogen, sodium, ...) and have a similar density
of just over 1 g / cm 3 . Therefore, the absorption coefficients for X-rays in
individual tissues do not differ much (with the exception of more
massive bones and lighter aerated lungs).
In certain cases, the natural
absorption differences between the tissues can be increased and
thus the resulting contrast of the X-ray image can be improved by
applying suitable contrast agents. Contrast
agents artificially increase the contrast of tissue imaging by
causing greater differences in the X-ray absorption of the
examined tissue relative to the environment. Usually we try to
increase the absorption of X-rays by using substances containing
atoms of heavy elements such as barium (cavities, eg stomach) or iodine (vessels, organs) . X-rays are
strongly absorbed by these substances , which highlights
the cavities that are filled with them (stomach, digestive tract, blood vessels) . If such a substance is introduced into the examined
area - the gastrointestinal tract, blood vessels, bile or urinary
tract, the structure filled in this way shows a significantly
increased absorption of X-rays and is clearly and contrastily
displayed on the X-ray image., including any defects and
anomalies. After application, contrast agents can enter the organ
under investigation either directly (direct
application to the gastrointestinal tract or blood vessels) or indirectly
via metabolism (imaging of structures in the
liver or kidneys).
Contrast
agents are classified according to various criteria. According to
water solubility: insoluble (barium suspension,
iodine substances oil and suspension) and soluble
( hydrosoluble ). According to their ionization
(dissociation) in solution: ionic (dissociate in
solution into anion bearing contrast iodine and cation) and nonionic
. According to pharmacokinetics, metabolism in the body and route
of excretion:nephrotropic (excreted by the
kidneys) used for angiography, urography, contrast CT; hepatotropic
(excreted by the liver and bile) for cholangiography. In terms of
the achieved change in X-ray absorption, we divide contrast
agents into two basic types:
¨ Positive
contrast agents , which increase
the absorption of X-rays. The most commonly used contrast agents
are based on barium and iodine
.
Barium sulphate (BaSO 4 ) is a water-insoluble compound whose suspension
("barium slurry") is used in the examination of the
digestive tract.
Currently, the most commonly used contrast agents are based on iodine
, which has two advantageous properties :
1. 127I
shows high absorption for X-rays of the energies used in X-ray
diagnostics - it provides a good positive contrast of the
structures into which it enters.
2. Iodine can form compounds with a number of organic substances
that behave in the body in the necessary well-defined way. In
such an organic substance, the absorption properties for X-rays
are given by the bound iodine atoms, while the other organic part
of the molecule determines the pharmacokinetics and distribution
of the substance in the organism - where the substance
"gets" or where it is taken up and excreted.
Iodine contrast agents are used in
the form of organic compounds in which iodine is tightly bound,
mostly in the benzene nuclei of cyclic (aromatic) hydrocarbons.
It is mainly triiodaminobenzoic acid, where 3 iodine
atoms are attached to the benzene nucleus (1,3,5-triiodo-2-aminobenzoic
acid derivatives, they are usually ionic and non-ionic
) . Furthermore, pyridine derivatives with
one or two attached iodine atoms in the molecule are used (they usually have the character of ionic
substances) .
Water-soluble (hydro-soluble)
contrast agents, especially ionic ones, can cause some
undesirable side effects in the body, allergic reactions
can be dangerous .
¨ Negative
contrast agents reducing X-ray
absorption. These are mainly gases (air, carbon dioxide) that are
applied to the cavities (eg the spinal canal). Today, they are
practically no longer used .
In some cases, especially in the
digestive tract, the so-called double contrast
is used : first a positive contrast agent (barium suspension) is
applied and then a negative contrast agent - air (from
effervescent powder), which stretches the positive contrast agent
to the walls of the examined volume.
X-ray subtraction radiography. DSA
A special method of increasing the contrast is the so-called subtraction
radiography , consisting in the subtraction of
two images of the same area, differing in the presence and
absence, or distribution, of the contrast agent. The goal of
subtraction is to highlight anatomical structures
that would be little clear, indistinct, and difficult to
recognize on conventional X-rays.
In the early days of the method (50s
and 60s), film (photographic) subtraction
was used, in which the X-ray image with the contrast medium was
combined and overlaid with the negatively re-photographed image
without the contrast medium. This combination (masking) created
the resulting subtraction image, in which only structures filled
with contrast material are visible. Further technical
development, leading through analogue television subtraction
, has resulted in the method of digital subtraction
, which is the most perfect and now used exclusively. This method
is used mainly for the selective imaging of the
arterial and venous vascular bed - the contrast
agent is injected at the appropriate time using a specially
inserted catheter. It is called digital subtraction
angiography (DSA) for arterial bed or phlebography
for venous imaging.
Fig.3.2.7. a) Principle scheme of digital
subtraction radiography operation. b) X-ray
machine with electronic image sensor mounted on a C-arm. c)
X-ray device in U-arm arrangement.
A simplified diagram of the principle of
digital subtraction radiography is drawn in Fig.3.2.7a. The X-ray
beam from the X-ray beam illuminates the patient's body and the transmitted
radiation is detected by a digital image sensor
( flat-panel ), consisting of a scintillator and a
sensitive CCD image sensor. The most perfect imaging detectors
are SPD semiconductor pixel detectors (see §2.5 " Semiconductor detectors ") , mounted in so-called flat
panels . The X-ray machine and the detector are placed
opposite each other on the so-called C-arm (Fig.
3.2.7b). First, a native X-ray image of the examined area without
a contrast agent (formerly called a mask
) is scanned into the computer's memory ., and then an X - ray image after
application of a contrast agent. Numerical digital
subtraction of the native image from the
contrast-enhanced image subtracts and cancels out all structures
that have not changed (eg skeleton) and remains only what makes
the two images different: contrast-filled cavities and vessels.
The resulting subtraction image is created , in
which only the structure filled with contrast medium is
selectively displayed, while all other anatomical structures are
more or less disturbed .
Proper subtraction can be
adversely affected or impaired by tissue movementsduring
the examination (in the time interval between the two images),
such as breathing movements, heart pulsation, patient movement.
To eliminate these adverse effects, a number of images are
recorded at short intervals, from which images suitable for
subtraction are selected. In addition, to monitor the kinetics of
cardiac activity, the sequence of scanned images is synchronized
with the ECG signal and images corresponding to end-diastole and
end-systole are subtracted; It is thus possible, among other
things, to obtain an image of the ejection fraction and to reveal
if necessary. heart wall motility disorders.
The historical name
" angio-line "
Frequently used name " angio-line
" comes from the time when angiography performed on X-ray
films (60th-70th years). At that time, a series- line
had to be prepared for the skiagraphic device - cassettes with
X-ray films in a row, which were exchanged and exposed in quick
succession after spraying the contrast medium. They were then
developed and examined to see where the contrast agent had
gradually reached - or not - due to the occlusion of the vessel.
X-ray navigated interventional
procedures
Subtraction angiography was originally developed as a diagnostic
method. With the help of modern angiographic equipment and
advanced methods of vascular medicine, in addition to
diagnostics, it is possible to immediately perform the necessary interventional
performance under detailed control of X-ray imaging
immediately after finding out the pathological conditions in the
vascular bed . These are, for example, coronary
angioplasty (PTCA) - dilation of the narrowed coronary
(coronary) artery of the myocardium using a special catheter
equipped with a balloon at the end, with or. by installing a
so-called stent , which remains stretched inside
the coronary vessel and prevents it from shrinking again.
X-ray
tomography - CT
Classical X-ray is planar - it is a two-dimensional
projection of tissue density to a certain plane.
However, real tissue is a three-dimensional
object , so a planar image that is a two-dimensional projection
of reality can capture only part of reality. We cannot find out
anything from the planar image about the arrangement of the
tissue in the "deep third dimension", perpendicular to
the displayed plane. Planar images have serious pitfalls in this
respect - the possibility of overlapping and
superposition of structuresstored at different depths.
We help here by displaying in several different projections, but
the risk of a false finding or non-detection of an anomaly in the
depths of the organism, covered by another structure, can never
be ruled out. In the planar display occurs radiography
the X-rays from different depths, the superposition and
accumulating information on the distribution density of
hloubkovývh all layers of tissues and organs in a common image.
The resulting response in the image is the sum of the
contributions from the individual layers of tissue - not only
from the sites of the examined lesion, but also from the layers
located above the lesion and below the lesion. This will detail
the structure of the organ under investigation in a certain depth
disguise image information from more distant and
closer layers. The individual tissues and organs are shown in summary
on the planar image , they overlap. We are not always able to
unambiguously determine which organs and structures the X-rays
have gone through and been weakened by. Superposition of
radiation from different depths of the imaged object further
leads to a reduction in the contrast of the
imaging of structures and lesions.
To overcome these disadvantages of
planar X-ray diagnostics and to obtain a complex imaging of
structures at different depths, transmission X-ray
tomography *) has been developed to provide a three-dimensional
imaging of tissue density in an organism. One of the
main advantages of tomographic imaging is significantly higher
contrast imaging of lesions that do not overlap on
radiation from surrounding layers on transverse sections.
*) Greek tomos
= section, rust - tomographic representation consists of
certain sections ( slice ), primarily
transverse, a larger number of which creates a three-dimensional
image. The examined area is divided into a large number of thin
layers (sections), which are each scanned separately at many
different angles, and from the local attenuation of X-rays, the
density image of the layer is mathematically reconstructed in a
computer. We can then view the examined area on the computer
screen in individual thin layers - as if we were
"cutting" the patient transversely, looking inwards at
each incision and then folding it again (without damage).
The forerunner of the current
CT computed tomography was motion tomography : the X-ray
machine and the examination table with the patient moved in
opposite directions to each other in such a way that for a layer
at a certain depth both movements were compensated and a sharp
image was obtained, while in the other layers the image was
motion blurred. distinct. However, the quality and contrast of
such an image were not great (completely incomparable with CT),
the method is long abandoned.
Tomographic X-ray is achieved by
irradiating the examined area at a number of different
angles (in the range 0-180-360 °): the X-ray machine
and the X-ray detector located opposite it rotate
around the patient's body *), with a narrow X-ray -radiation radiates
the examined tissue and its intensity is detected and converted
into an electrical signal (Fig.3.2.8a); the attenuation of the
beam due to tissue absorption is evaluated. From the number of
integral values obtained by irradiation under a series of angles
0-360 °, the absorption map is then reconstructed
by back projection , creating a cross-sectional
density image of the examined area in a plane
perpendicular to the X-ray and opposite detector rotation axis - see "Density image formation" below . In this image, structures stored at different depths
in the organism are sensitively and with high resolution - it is
a tomographic image . In such an image, we have
endless possibilities of viewing the scanned object from all
angles and in various layers (sections).
*) The X-ray machine and the opposite
detection system are mounted on a special annular stand called gantry
( gantry = portal, through-supporting structure ),
enabling the X-ray-detector system to rotate
around the examination bed by means of an electric motor .
By gradual
longitudinal linear displacement of the patient with respect to
the X-ray-detector system, we can create a series of
cross-sectional images (individual layers), which placed next to
each other create a three-dimensional tomographic image
of the examined area. Due to the computational
complexity of the reconstruction procedure, this can only be done
with the help of a computer - therefore this method is called computerized
tomography CT ( Computerized Tomography)
or computed tomography . The
exact name "X-ray Transmission Computerized Tomography"
did not take hold due to its length.
Fig.3.2.8. X-ray computerized tomography
CT.
a) Basic principal scheme of CT. b)
Principle of spiral CT. c) 64-slice CT
instrument.
In addition to spatial tomography imaging, the
main advantage of CT compared to conventional X-ray imaging is
significantly higher contrast- is able to
recognize and display even slight differences in the linear
coefficients of X-ray attenuation that penetrates the examined
tissue. This is primarily due to the principle of transverse
section imaging using a narrow beam without being affected by
adjacent layers and electronic X-ray detection, which is able to
capture finer differences and a wider range of dynamics than
conventional X-ray film. Methods of computer reconstruction and
image filtering, as well as the possibility of flexible setting
of optimal image modulation (brightness, contrast) also
contribute to the excellent density resolution. Computer software
for CT also has a number of tools for structural image editing,
creation of three-dimensional images of certain organs,
reconstruction of sections in other planes than the initial
transverse in which the patient was scanned.
The result of CT are real "anatomical
sections "of the patient's body, on which organs
and tissues can be seen separately , in contrast
to planar X-rays, where they are shown in summary and overlap.
Trial,
"exploratory" or "planning " radiographic
acquisition CT , abbreviated SPR ( Scan Projection
Radiograph ), also known as Scanogram or Topogram.
It is scanned by a stationary (non-rotating) system of X-rays and
detectors, mostly in AP or PA projection, in which the bed and
patient move over the gantry. This creates a planar image similar
to classical skiagraphy. This image is then used to determine the
beginning and end of the displayed area of ??the body.
Furthermore, the SPR image can be used for automatic exposure
- obtaining absorption (attenuation) data for automatic
regulation of the anode current [mA] by X-ray ATCM
( Automatic Tube Current Modulation ) in order to optimize
the relationship between quality image and radiation
exposure of the patient. This anatomical dose modulation
technology significantly
reduces the radiation dose in real time while maintaining the
quality of the images.
Development
of tomographic imaging method. 5 generations of CT devices.
General efforts to reconstruct a three-dimensional image
based on a two-dimensional image (or a set of one-dimensional
projections) date back to 1917, when J. Radon derived an integral
transformation (now called the Radon transformation )
between a set of line integrals and a set of transverse section
points. In 1963, A. Cormack applied these results and extended
them to the case of X-rays passing through partial absorption by
a three-dimensional object. And in 1972, G.N.Hounsfield
completed the development of the first CT device
.
In the
following years, the great advantages of CT were proven and these
devices became very widespread. During the technical development,
there were also significant changes in the design of individual
electronic and mechanical parts of CT devices. In view of this
technical development, CT devices are usually divided into five
generations :
¨ 1st
generation: X-rays from the X-ray tube were collimated into a thin
beam (cylindrical "pencil" shape) and after
irradiation with the patient detected by the opposite detector
(as shown in Fig. 3.2.4a), rotating together with the X-ray tube.
¨ 2nd generation: X-rays from the X-ray
tube are collimated into a fan shape and after
passing through the patient it is detected by a larger
number of detectors
, placed in a row on a circular section opposite
the X - ray, rotating together with the X - ray machine.
¨ 3rd generation:
X-rays from the X-ray tube are collimated into the shape of a
wider fan similar to the 2nd generation, but the transmitted
radiation is detected by a large number of detectors placed on a
circular arc in several rows (Fig.3.2.8b) - more
slices - multi-slice CT . The continuation of the 3rd
generation devices are the spiral high-speed multidetector MDCT systems
described below .
¨ 4th
generation: the detectors are arranged stationary
in a complete circle (rings, or several rings lying next
to each other) around the patient, while only the X-ray machine
rotates.
¨ 5th generation:
cardio-tomograph with electron beam - EBT - Electron
Beam CT , described below, fig.3.2.10.
Generation 4
and 5 devices are not very widespread, because at a higher price
they do not bring significant benefits for clinical practice
compared to modern design solutions for generation 3 devices (high-speed multidetector systems MDCT, see below
).
Along with the
technical improvement of X-ray CT, the tomographic principle was
also used in other imaging modalities. In addition to optical CT,
scintigraphic tomographic methods were developed
- SPECT single photon emission tomography and PET positron
emission tomography (Chapter 4 "Scintigraphy", §4.3
" Tomographic cameras ". And also the most
complex tomographic imaging method of nuclear magnetic
resonance NMRI (§3.4, part " Nuclear magnetic resonance
").
Note:
For special technical purposes of imaging the structure of small
objects, the so-called X-ray micro-tomography
( m CT)
mentioned below (§3.3, section " Radiation
defectoscopy ") .
Formation
of the density image
If, according to Fig. 3.2.4 on the left, the X-ray beam emitted
by the X-ray and falling on the examined area has an initial
intensity (photon flux in 1 s) I o , then its intensity I after tissue passage will
be I = I o
. e - Sm (i, j). D
x , where m(i, j) is the
linear attenuation factor of X-radiation penetrating the tissue
site at coordinates i, j and D
x is the magnitude (length in the beam
direction) of the tissue element. The values ??of the
coefficients m (i, j) depend on the local density and the proton number
of the individual sites (i, j) of the tissue. By logarithm, this
relationship can be adjusted to the form: ln (I / I o ) = Sm(i, j). D x, which states
that the logarithm of the ratio of the intensities of X-rays
entering and leaving the examined tissue is equal to the sum of
the products of the linear attenuation coefficients m and D x paths that the
X-rays photons at each point of the tissue overcome.
By measuring at different positions
(angles) of the X-ray machine and the detector, a number of
values of the attenuation ratio ln (I / I o ) are obtained. The computer then basically solves a
system of linear equations of the above shape, which obtains the
values of the linear X-ray attenuation coefficients of tissue
elements in individual sites (i, j) of tissue - a picture
of tissue density in a transverse section.
In practice, the above
straightforward procedure is not followed. The resulting
transverse CT image is obtained by computer reconstruction
from one-dimensional profiles of the intensity distribution of
the transmitted X-ray beam when rotating the X-ray machine and
opposite detectors around the examined object. For this
reconstruction, the method of filtered back projection
is usually used , sometimes even a more perfect (but
computationally demanding) method of iterative
reconstruction *).
*) Iterative
reconstruction is a mathematical algorithm for finding
the most accurate image by successive approximations and
refinement of the initial "rough" image. It is based on
an image obtained by back projection and consists of several
repetitionsfour consecutive steps - " reconstruction
loops ": 1. In the first step, the
image created by the rear projection is recalculated in the
opposite way as if the original data. 2. These
are then compared with the "raw" data actually captured
during detection. 3. New data for rear
projection will be adjusted according to the differences found. 4.
The image is recalculated and the whole operation is repeated.
After several repetitions of these iterations, we obtain a clear
and high-quality image. The number of iterations can be set and
optimized. Correction algorithms and noise filtering
methods are included in the procedure. This method provides
higher quality images with reduction of noise and artifacts
created during reconstruction. Furthermore, in some examinations,
we can significantly reduce the patient's exposure and radiation
dose, while maintaining sufficiently high-quality images.
These
reconstruction methods, which are analogous to SPECT, are briefly
described in §4.3 " Tomographic
scintigraphy ", passage " Computer reconstruction of SPECT " *). And central control software algorithm is
sometimes called reconstruction kernel
( core grain ).
*) I apologize to professional radiologists that it is not
included in this chapter. Our professional materials are
primarily focused on nuclear physicsand
radionuclide scintigraphy. This angle of view may be inspiring
for colleagues in the field of X-ray diagnostics ..? ..
The density of the examined tissue
is usually compared with the density of water
and in the CT image is numerically presented in the so-called Hounsfield
units HU = 1000. ( m
tissue - m water ) / m water , introduced by a
leading pioneer in the CT G.N.Hounstfield area
(along with ALCormack) . The use of a
factor of 1000 (instead of the usual 100%, where we would get
decimal values) reflects a high density resolution
CT. The value of HU = -1000 corresponds to zero density (vacuum,
air), for water it is HU = 0, bones have a density of the order
of HU = 100 ¸ 1000, sometimes even higher. Aerated lungs have HU
approx. -800, fat HU = -40 ¸
-120, soft tissue density is HU = 20 ¸ 80. Such a large
range of densities is not able to display linearly in brightness
linearly; also the human eye is only able to distinguish a few
tens of shades of gray. For optimal image presentation, we
therefore help by appropriate modulation of
image brightness and contrast . If we are
interested in differences in tissues with a similar density (this
is usually the case in soft tissues), we use this modulation to
select only a narrow part of the whole range of densities - the
so-called window, whose range of densities is
displayed in the entire brightness range of the screen. We get
well-drawn images of the required structures and by moving the
windows we can gradually obtain detailed information about
tissues with different densities.
X-rays
detectors for CT
The task of these detectors is to capture photons of X-rays
passing through the examined tissue and convert them into
electrical signals for further electronic processing for the
purpose of computer reconstruction of density sections. In
general, the principles set out in Chapter 2 "Detection and
spectrometry of ionizing radiation" apply to this area, with
the proviso that only detection is applied, not spectrometry. The
basic requirement here is a high sensitivity of
X-ray photon detection and a high detection rate
, ie a short dead time.
Two types of detectors are most
often used for X-ray detection :
Multidetector,
multi-slice and spiral CT; Cone-Beam CT
Gradual scanning of CT images by a system of one X-ray machine
and one detector, as described so far here according to Fig.
3.2.4a for easier explanation of the method, was used in the
first generations of CT equipment in the 70s and 80s. Its
disadvantage was considerable length (one cut
lasted several minutes). Newer generations of CT devices already
use a larger number of detectors (approx. 1000).
An X-ray is circled, the beam of primary radiation of which is
obscured by a collimator into the shape of a fan (with an angle
of approx. 40°), and opposite it a corresponding circular
section with a system of 300-1000 detectors (Fig. 3.2.8b). The
scanning time of one slice is reduced to less than 1 second.
The first types of CT devices
had a rotating part - X-ray machine and detectors - connected to
the static power supply and evaluation part by a cable ,
which did not allow continuous rotation (after one turn, the
X-ray machine did not twist). Newer types (from 80s) are used for
power and signal transmission technology " sliding ring
" ( slip-ring ) sensing electric toothbrushes,
permitting rapid and continuous rotation (with an unlimited
number of revolutions in one direction).
The original generation of CT instruments scanned only
one cross section of the examined area during one rotation. To
increase the speed of CT examination of larger areas, it is
always used in newer generations of devicesseveral
detectors , resp. several detector rings, placed side by
side in the axial (longitudinal) direction - MDCT
(Multi Detector CT). This allows (with a suitable shaping of the
X-ray beam from the X-ray machine) the simultaneous
scanning of several transverse sections side by side,
the examination of several thin layers simultaneously. We are
talking about " multi-slice ",
so-called multi-slice CT devices ( slice = slice ) - 4, 6, 8, 16, 64 - slice. The technical design of CT
devices is constantly improving. The number of detectors and the
speed of rotation of the gantry rotor increases (now approx. 0.3
s / revolution) - these are high-speed multidetector
systemsMDCT. Individual transverse sections can be
scanned in two ways :
- Sequential scanning , where only the
X-ray detector system rotates and the bed does not move with the
patient. The individual layers are scanned gradually -
independently by individual rings of detectors.
- In the case of so-called spiral CT ( helical
), in addition, during the rotation of the X-ray there is a slow
automatic movement of the bed with the patient
(the X-ray path effectively appears as a spiral) - Fig.3.2.8b, c,
followed by three-dimensional reconstruction; here, in principle,
it is possible to achieve whole-body CT imaging.
The horizontal distance by which the lounger moves between two
adjacent X-ray cycles - the "rise" of the spiral - is
called pitch factor [mm].
ECG-synchroized CT angiography
A significant technical advance in the field of cardiac
imaging is non-invasive electrocardiographically
synchronized angiography by multidetector computed tomography -
MSCTA . The main use of this method is
twofold :
1. MSCT native calcium
score - detection and quantification of calcificates in
coronary arteries (calcium content in coronary artery plaques).
Usually, risk groups are assessed according to Agaston's
calcium score (up to 5 groups).
2. MSCT coronarography
- contrast imaging of epicardial coronary arteries to diagnose
the extent and severity of coronary involvement in ischemic heart
disease.
By combining both methods, we can
display the soft and calcified part of the plaque, determine the
nature, extent and severity of the disease, with or. indications
for invasive examination with determination of the method of
revascularization.
Cone-Beam CT
For some purposes, a CT image with a widely collimated cone-beam
CT (CBCT ) is used, which illuminates the patient and
impinges on the opposite flat-panel imaging (its principle is described in §3.2, passage " Electronic
X-ray imaging ") . The X-ray tube and the opposite flat-panel rotate
around the examined object on a common gantry. Such a CBCT system
is installed on radiotherapy irradiators (linear accelerators)
using the image-controlled radiotherapy technique - IGRT
(§3.6, section " Modulation
of irradiation beams "), or is
used in small dental CT devices (listed below).
CT
with 2 X-rays tubes - DSCT: Dual Source and Dual Energy CT
Another technical improvement of CT consists in the construction
of devices that have 2 X - rays
- two X-ray/detector systems (placed perpendicular to each
other), which can scan simultaneously
(Fig.3.2.9) . The device is referred to as Dual
Source CT ( DSCT ). It can work in two
basic modes, providing two advantages:
¨ 1. Both X-ray tubes operate at the same voltage Þ
"dual system"
- increasing the speed and shortening the
acquisition time with reducing the time resolution to about 80ms.
This is especially important for CT of the heart (with a higher
heart rate).
Fig.3.2.9. CT device with two X-rays - Dual Source CT and Dual
Energy CT.
¨ 2. Two X-ray
tubes operate at different anode voltage (eg.
140kV and 80kV **) Þ possibility of scanning with dual-energy
( DECT - Dual Energy CT ):
each of the two X-ray tubes creates X-rays of different energies.
We get pictures of the same place. This makes it
possible not only to better quantify the density distribution,
but also to determine two different density analyzes
*) - similar analyzes of density images, as for tissue
composition using the Absorptiometers method ,
see below "Bone densitometry", Fig.3.2.6). It is
provided not only by DEXA (Dual Energy X-ray
detailed images of anatomy, but in perspective it will allow to distinguish
different types of tissue (distinguish eg bones, blood
vessels, adipose tissue), different types of kidney stones,
deposition of sodium urate crystals in joints (bottoms), or
quantify the distribution of contrast agent in myocardial
infarction (and to assess functional impairment in morphological
coronary artery disease).
*) Different types of substances
(and tissues) differ not only by specific values of linear
attenuation coefficients m for X radiation of a certain energy, but also by a
somewhat different dependence m(E X ) of absorption for different
energies E X of X-radiation. This is due to the different electron
density configuration for the different molecular composition of
the analyte. Mathematical analysis of the exponential laws of
absorption I = I o .e - m (Ex)
.d for individual energies E X and tissue types with
absorption coefficients m (E X ) (by logarithm the relevant exponential equations are
converted to linear) it is possible to determine the proportion
of absorption in different tissues. This can in principle be used
to additionally distinguish different types and
compositions of tissues based on differences in the
density images of the same site, obtained with different X-ray
energies.
**) X-ray spectra for 80 and 140keV are continuous and
partially overlap. In addition to the different anode voltages,
two different effective energies of X-rays are also achieved by
special sharp filtration using the K-edge
effect (mentioned above in the section "Filtration,
collimation").
Multiplex DECT
An alternative to dual DECT energy tomography is the use
of a single X-ray detector system, in which the voltage
is multiplexed to X-ray during spiral scanning.
Quality control and
imaging properties of CT devices
Testing of imaging properties of CT devices is performed using
special phantoms of cylindrical shapes - see " Phantoms and phantom measurements ", section " Tomographic phantoms for CT " .
Electron Beam CT (EBT)
In addition to the described CT design, now "classic"
with a rotating X-ray, a completely different, physically
interesting solution has been developed that does not
contain an X-ray at all . X-rays are created by the
impact of fast electrons, fired by an " electron gun
", on a metal target ring - anode, inside
which the object under investigation is located (Fig.3.2.10). The
electron beam from the electron gun is directed to the desired
location of the target ring by magnetic deflection
by means of deflection coils , powered by a
suitable electrical signal. By supplying the deflection coils
with alternating electric current of a suitable periodic course
the electron beam rotates at
an angular frequency w and, during this circular motion, gradually strikes
individual points on the circumference of the target ring. In
each affected area, braking X-rays are generated
, the beam of which illuminates the examined
object (patient's body) at a corresponding angle
. Thus, a rotating electron beam generates a rotating
source of X-rays around the circumference of the target
ring, as if an X-ray were rotating there. The braking X-ray
passes through an annular collimator with
radially oriented septa, which shapes it into a fan-shaped
bundle .
This X-ray, passed through the
examined object (patient's tissue), is detected
electronically(as with conventional CT) by means of an
annular array of detectors, overlapping the collimator from the
inside. With a suitable geometric arrangement of the collimator
septum, they shield the X-radiation that would come directly from
the target ring to the back of the individual detectors. Newer
types of EBT devices have several side-by-side target rings and
several ring arrays of detectors.
Fig.3.2.10. Basic principle scheme of X-ray
tomography using electron beams
This design solution has two advantages:
¨ It
does not contain any mechanically moving parts - the
rotation of the beam is electromagnetic.
¨ Allows
very fast tomography - the electromagnetically
deflected beam can rotate much faster than is achievable with
mechanical rotation. This is advantageous for monitoring fast
processes such as gated CT - in Fig. 3.2.5, ECG trigger pulses
are fed to the acquisition computer together with pulses from
X-ray detectors.
However,
the disadvantage here is the considerable complexity and cost
(price) of the device, due to which this type of device has not
yet become very widespread in practice. It is probably not
possible to expect a greater expansion of these systems in the
future either, as rapid technical progress in the construction of
conventional CT - high-speed multidetector MDCT systems (or with
two X-rays) solves most of the advantages of EBT, cheaper and
more advantageous for common practice.
X-ray
bone densitometry
Radiographic examination of the skeleton is one
of the most common and most important X-ray diagnostics. A
special method in this area is bone densitometry
- a method for determining the density (density)
of bone tissue based on the rate of X-ray absorption
, determined by X-ray absorption photometry
(Radiographic Absorptiometry - RA).
The simplest method is to
transmit a narrow beam of radiation with a single energy
(SPA - Single Photon Absorptiometry). The disadvantage of this
method is that it is not possible to determine from the total
absorption of X-rays which part is caused by bone and which part
by soft tissue.
A more advanced densitometric
method is X-ray absorption photometry using two energies
of the X-ray beam (DEXA - Dual Energy X-ray
Absorptiometers), such as a pair of effective energies of 50keV +
100keV, or 35keV + 75keV. Different ratios of X-ray absorption in
soft tissue and bone are used here at low energy and at high
radiation energy - different values of linear attenuation
coefficients m . Mathematical analysis of the exponential laws of
absorption I = I o .e - m .x for individual energies and tissue types (by logarithm
the relevant exponential equations are converted to linear) the
proportion of absorption in soft tissue and bone itself is
determined, from which it is possible determine bone
density.
It is calibrated with a
suitable bone phantom (or hydroxyapatite), the instruments have
their internal calibration phantoms. The bone mineral content is
quantified using the Bone Mineral Content ( BMC)
parameters in [g / cm] and the Bone Mineral Density ( BMD
) area density in [g / cm 2 ]. These parameters are compared with sets of reference
(normal) values ??and relative indices (ratios) called scores
are determined : the T-score compares the measured BMD
values with the average BMD value of young healthy adults of the
same sex; the Z-score compares BMD with mean normal values ??for
a given age and sex . Bone Homogeneity Index (BHI) is also
sometimes monitored.
Fig.3.2.11. Schematic diagram of a DEXA imaging digital X-ray
densitometer (on the right, an example of a DEXA device for
whole-body imaging).
Modern X-ray densitometric devices use
irradiation of the examined area with a diverging
("pyramidal") X-ray beam with subsequent detection of
the transmitted radiation by a digital image sensor
into the computer's memory - Fig.3.2.11. Here, appropriate
absorption calculations are performed between the low (L) and
high (H) X-ray energy images to obtain a final skeletal
density image that provides both bone mineral content
and density and morphological skeletal structure information. The
most advanced devices of this type make it possible to perform whole-body
image diagnostics of bone tissue, determine the content of muscle
mass, adipose tissue, water and minerals in individual parts of
the body.
Detectors for X-ray
densitometry
For the detection of transmitted X-rays,
either NaI (Tl) or CaWO 4 scintillation detectors are used , or semiconductor
detectors mostly based on CdZnTe (
cadmium-zinc-telluride - CZT), which have a high
detection efficiency. In modern imaging densitometers, the
detectors are arranged in a 2-dimensional mosaic configuration
with high spatial resolution - they form a digital X-ray
image sensor , such as a flat panel measuring 20 × 20cm
and a matrix of 512 × 512 elements that scans the entire scanned
area during a single exposure.
Bone
densitometry plays a key role in the diagnosis of
osteoporosis - pathological reductions in mineral and
organic bone mass, leading to a weakening of bone strength.
Osteoporosis is one of the most common disorders of bone
metabolism and is one of the most common causes of fractures in
the elderly, especially in postmenopausal women. Early diagnosis
of incipient osteoporosis (osteopenia) is important for the use
of effective treatment to slow or stop osteoporosis before
irreversible disorders in the bone structure.
Note: Non-radiation
methods of bone densitometry are also used. Ultrasound
densitometry determines bone density based on the
attenuation of the sound signal and the speed of its tissue
propagation.
................
X-ray
mammography
Another important specialized method of X-ray imaging is mammography
- imaging of possible inhomogeneities and areas of increased
tissue density in a woman's breast, which could indicate a tumor
process . In order to achieve the best possible image
contrast and resolution of the smallest possible lesions, it is
necessary to compress the breast with a
compression plate *) and illuminate the tissue thus formed into a
layer about 7 cm thick with soft X-rays with an
energy of about 20 keV. Low-energy X-ray photons interact with
tissue atoms primarily through the photoeffect, which provides a higher
absorption contrast between tissues with small
differences in density. Due to this low energy, a special x - ray
machine is usually used in the mammogrammolybdenum anode
and beryllium output window, focus size 0.1-0.3 mm. A molybdenum
or rhodium filter is used to filter the X-ray beam, which cuts
off photons higher than about 20keV (K-edge
Mo) or 23keV (K-edge
Rh) - the so-called K-edge effect
mentioned above in the passage is used. " Filtration,
collimation ".
*) Note:
Compression of breast tissue also leads to one minor advantage in
terms of radiation protection : compression
temporarily restricts blood flow and partially hypoxia
tissue cells. This somewhat reduces the radiobiological effect of
X-rays, as hypoxic cells are less sensitive to radiation (" oxygen
effect"- §5.2" Biological effects of ionizing
radiation, part " LQ
model ").
Imaging was performed with a
cassette with X-ray film equipped with an image intensifier, or
more recently using electronic image capture - a semiconductor
flat panel with direct image digitization. A secondary Bucky
diaphragm is placed between the imaged tissue and the film or
imaging detector to reduce the proportion of scattered radiation,
reducing the contrast of the image. The resulting X-ray of the
breast is called a mammogram or mastogram
. Under suitable circumstances, it is possible to detect a tumor
as small as about 4 millimeters. Mammography is suitable not only
for the examination of women with symptoms or suspicion of breast
cancer, but also for screening - searching for
early stages of breast cancer.
![]() |
Fig.3.2.12. X-ray
mammography The breast is inserted between the X-ray tube and the imaging flat panel and compressed with a plastic compression plate. On the X-ray mammographic image, we can observe normal density without defects (top right) , or lesions of increased density that may indicate a tumor (bottom right) . |
The X-ray mammography device can be
supplemented by a so-called mammographic stereotaxy
device , which captures two images of a given lesion in
oblique projections at two given angles (usually ± 15 °).
Evaluation of the change in the position of the lesion on these
two stereo images allows precise targeting of the displayed
structures suspected of the tumor process - their location and
marking with a suitable marker (such as mandrel, wire or dye),
with the possibility of sampling by biopsy for
histological examination.
Alternative
mammography methods
In addition to the most commonly used X-ray mammography, there
are some other examination methods based on different principles
:
¨ Ultrasonic mammography
showing or. lesions based on their different densities and
elasticities (ultrasonography is briefly discussed in §4.6 . , passage "
Ultrasound sonography ").
¨ NMRI
mammography - imaging by nuclear magnetic
resonance
¨ Radioisotope
scintimammography showing increased accumulation of
a suitable radiopharmaceutical in resp. tumor tissue (see
Chapter 4 " Scintigraphy
"); it can be performed as planar, SPECT or PET
scintigraphy. A specific method of PEM positron emission
tomography is described in §4.3, passage " Positron emission mammography (PEM) ".
¨ Electroimpedance
mammographysensing the electrical conductivity
(impedance) of mammary gland tissues. A weak electric current is
introduced into the tissue by means of electrodes placed on the
skin in the vicinity of the examined area, and also by means of
electrodes the distribution of electric potentials on the surface
is sensed. From these data it is possible to reconstruct the
spatial distribution of local tissue impedance - electroimpedance
image . A different electrical conductivity is
observed in the tumor tissue from the surrounding tissue.
Dental X-ray diagnostics
A separate category of smaller specialized X-ray devices are dental
or dental X-rays used in dentistry. There are
three types of devices :
¨ Intraoral X-ray is a very simple
device: a small X-ray machine of a compact design with a narrow
tube is placed on the movable arm (a high voltage source of
approx. 50 ¸ 70 kV
is usually encapsulated in its cover ). A small box of X-ray film
is placed on the back of the teeth and exposed to X-rays from the
front. After calling, the relevant tooth (or several teeth) and
its placement in the gums are displayed, including any defects.
¨ Panoramic X-ray OPG ( orthopantomogram
), also called DPR (Dental Panoramatic Radiograph ). The
X-ray machine and the X-ray film or imaging flat panel located
opposite it rotate during rotation
and describe a circular or elliptical trajectory around the
patient's head (jaw) so that the focal layer is compensated for
compensating for X-ray and film (or imaging detector). it passed
through the center of the jaw line along its entire length. This
creates a developed panoramic image of the
entire jaw. In the simplest case, this is achieved with a single
motor, but a better panoramic view is achieved with devices with
2 or 3 motors, which perform rotation in multiple axes with
better adaptation to the shape of the jaw. The best focusing of
all jaw areas is achieved with multifocalsOPG devices,
where a large number of images in different focal layers are
captured, with subsequent evaluation.
¨ Dental CT is a reduced version of the
classic cone-beam CT (mentioned above) with imaging
detectors of about 3 ´ 4 ¸ 15 ´ 15 cm. Sometimes panoramic X-rays are combined with
dental CT into one system. Dental CT is used in maxillofacial
surgery, dental implants and in the diagnosis of pathological
lesions in the area.
Radiation
exposure of patients during X-ray examination
Using the current modern X-ray technique, the radiation exposure
of patients is relatively low . The
absorbed radiation dose D [mGy] during
X-ray examination of a certain area of ??the body is basically
given by the product of the intensity of X-rays (this is given by
the X-ray current [mA]), exposure time [s] and corresponding
coefficients:
D
= G. mAs.
Coefficient Git includes a number of factors, such as the
efficiency of X-ray production by X-rays, its energy given by the
voltage [kV] for X-rays, filtration, distance, tissue absorption
coefficients. It is measured using phantoms, most often
water-filled "aquariums" (for planar X-rays), or
cylinders with a diameter of 16 cm (head) or 32 cm (chest) for
CT, equipped with ionization chambers, thermoluminescence or
semiconductor detectors. The probability of biological stochastic
effects is proportional to this absorbed radiation dose
[mGy] and the size of the irradiated area [cm 3 ].
The planar X-ray diagnostics
is quantified by this variable surface dose of DAP
( Dose Area Product ) [mGy.cm 2 ], which isproduct of the input dose of X-rays
and the size (area S) of the irradiated field: DAP = D. S. The effective
dose D ef [mSv] for the patient, expressing the effects of
radiation on the organism as a whole, is then calculated as the
product: D ef = E DAP . DAP, where the coefficient E DAP ( regionally normalized effective dose [mSv
mGy -1 cm -2 ]) includes averaged
tissue (organ) weighting factors w T for structures in the irradiated area.
Specially calibrated
radiometers, so-called DAP-meters, are used to
measure the radiation dose of patients during planar X-ray
imaging.*), measuring product of absorbed dose and irradiated
area ( Dose Area Product ). The DAP meter is a thin transmission
plane-parallel ionization chamber mounted on the output
collimator (aperture) of the X-ray device, the area of ??which
covers the entire (maximum) field of X-rays - Fig .
3.2.5 at the top left. The ionization current generated by
the passage of X-rays from the X-ray machine toward the patient,
after appropriate calibration, indicates the areal dose of DAP
that the defined imaged field of the patient's body receives. *) Radiometers of this type are sometimes also called KAP-meters
, measuring the product of kerma in the air and the irradiated
area ( Kerma Area Product ). For X-rays used in X-ray
diagnostics, the kerma and dose values ??are practically identical.
As discussed in §5.1 " Effects of
radiation on matter. Basic quantities of dosimetry . ",
Passage " Exposure, kerma, terma
", the relationship D = K applies between dose and kerma
particles that are lost during radiation processes in the
material. For diagnostic X-rays, the value of g is only fractions
of a percent.
The product of the
kerma and the surface is the integral of the kerma in the air
over the beam surface in a plane perpendicular to the central
axis of the beam. The value of the product of the kerma and the
area is almost independent of the distance from the focus of the
X-ray tube (if we neglect the attenuation of the
radiation in the air, the backscattered radiation and possibly
the X radiation arising outside the focus) .
For CT
imaging, the radiation exposure is quantified using a quantityDLP linear dose ( Dose Length
Product ) [mGy.cm], which is the product of the
absorbed dose D and the length L irradiated area: D
= DLP . L. The effective dose D ef [mSv] for an X-rayed
patient, expressing the stochastic effects of radiation on the
organism as a whole, is then calculated as the product:
D
ef = E DAP . DAP for planar
display, or D ef = E DLP . DLP for CT imaging, where coefficients E DAP or E DLP - regionally
normalized effective dose [mSv mGy-1 cm -1 ] - include averaged tissue (organ) weighting
factors w T for structures in the irradiated area (§5.1 "Basic quantities of dosimetry",
passage " Radiobiological efficiency of
radiation ") .
How
these measured exposure parameters are used to determine
radiation doses and their optimization in X-ray examinations is
briefly discussed in §5.7 " Radiation exposure
in radiation diagnosis and therapy ".
Other
imaging diagnostic methods. Hybrid imaging systems.
X-ray diagnostics is the oldest and so far the most important
imaging method in medicine. With technical progress, especially
in the field of electronics and computer technology, some other
alternative imaging methods of medical diagnostics have
developed. They are: Ultrasound sonography
, Nuclear magnetic resonance
, Thermography ; Recently, electroimpedance imaging of
tissue has begun to be applied . The whole chapter 4 then
describes in detail another important imaging method - Scintigraphy .
These methods are physically
compared in §4.6 "Relationship
between scintigraphy and other imaging methods ", where their diagnostic benefits and their
complementarity in the algorithm of complex
diagnosticsare discussed. In recent years, hybrid imaging
systems combining CT X-ray imaging with scintigraphic
PET or SPECT imaging, or with nuclear magnetic resonance NMRI, as
well as hybrid imaging + irradiation technologies
in radiotherapy (§3.6 " Radiotherapy
", part " Modulation of irradiation beams ", passage " Hybrid integration of
imaging and irradiation technologies ").
The basic aspects of evaluation and acquisition of diagnostic information from images of the mentioned radiological modalities are given in §4.7 " Visual evaluation and mathematical analysis of diagnostic images " .
------------------------ Small physical-technical interest ---------------------- -
X-ray telescopes
The X-ray diagnostics discussed above is a transmission method
based on the passage of X-rays through an object. X-rays are a
means of analyzing the structure of an object under
investigation. However, there are situations where we primarily
need to search for and display the sources of X-rays
themselves , their position and distribution in space.
And "at a distance", whether small (analytical and
examination methods of materials) or large (detection of X-rays
in space) - to perform X-ray telescopy .
X-ray telescopes must have
completely different optics than normal visible light telescopes.
In the optical telescope, spherical or parabolic lenses and
mirrors are used, on which light rays fall at a large angle
(almost perpendicular) and refract or reflect so that they
converge and intersect near the focus where the image is formed.
The lenses are not usable for X-rays at all. Under certain
circumstances, reflection on a mirror is applicable, but the beam
must strike the reflecting surface of the mirror at a
very small angle, almost tangentially. Due to the high
energy of the photons and the short wavelength of the X-rays, the
X-rays must fall very obliquely, practically "sliding"
on the surface, because when incident at larger angles (or even
perpendicular) the X-rays photons would penetrate below the
mirror surface and interact individually. with electrons and
atoms of its material (photoeffect or Compton scattering, see
§1.6 " Interaction of gamma and X-rays ") - part would pass, most would be absorbed in
it; no display would be created. At a very oblique impact, from
the point of view of the photon, the number of free electrons in
the metal surface per unit length will increase geometrically
(the electron density will increase effectively), so that the
X-ray photon will interact collectivelywith a
large number of free electrons, similar to the reflection of a
light wave from a metal surface: an electromagnetic wave-photon
is reflected from the metal surface at the same
angle as the angle of incidence , according to the laws of
electrodynamics . Or, from the point of view of the reflecting
surface, the wavelength of the incoming radiation (its
projection) is effectively extended, which will therefore behave
similarly to light. It's a bit like throwing a stone very
obliquely, almost parallel to the water surface and he bounces,
or. it bounces on the surface several times. However, in practice
this mechanism only works for soft X-rays , up
to about 30keV.
Fig.3.2.13. Principle of a mirror X-ray telescope
X-ray optics are therefore based on an almost tangential
impact , where the X-ray beam impinges almost parallel
to the surface, only then is it reflected. Such reflective
surfaces must be very precise and smooth, their
"roughness" must not exceed a thousandth of a mm. The
X-ray telescope consists of one or more very precisely shaped coaxial
metal surfaces, inclined at a very small angle with
respect to the optical axis of the system (Fig.3.2.13). This
reflecting surface may have a conical shape, but the combination
of paraboloid and hyperboloid provides optimal optical
properties. The reflecting surfaces are arranged almost parallel
to the incident rays, which are therefore reflected at a very
small angle - first from the paraboloid and then from the
hyperboloid - to the focal plane, where they form an image of the
X-ray source from which the X-rays came. . Here the radiation is
detected by detectors. The more advanced types of X-ray
telescopes are multi-mirror , consisting of a number of
very precisely shaped, carefully adjusted and interposed
coaxial parabolic and hyperbolic mirrors. The central part of the
system is blocked by an X-ray absorbing material.
X-ray telephoto lenses of this
kind were constructed in the 1960s and 1990s mainly by R.
Giaccomi and his collaborators. They constantly improved them and
installed them on space satellites: UHURU in 1970, HEAO-2,
Chandra in 1999. With these instruments was revealed many X-ray
sources in space - X-ray binaries, supernova remnants, neutron
stars, galaxies active nuclei, the cloud of ionized gas in galaxy
clusters (the X-radiation from space and
see §1.6 its origin, the " Cosmic ray " passage "Cosmic X and gamma rays") . Current X-ray telescopes achieve very good angular
resolution (<0.5 arcseconds), spectral (energy) resolution
(1eV), as well as high luminosity and sensitivity to X-rays and
higher energies. They are the basic tools of the so-calledX-ray
astronomy .
In the area of even shorter
wavelengths, ie higher photon energies, X-ray telescopes are
followed by the issue of gamma-telescopes ,
briefly discussed at the end of §4.2, section " High-energy
gamma cameras ").
3.3.
Radiation measurement of mechanical properties of materials
The properties of the interaction of different types of ionizing
radiation with matter provide a number of possibilities for non-contact
non-destructive measurement of some mechanical and
structural properties of various objects and materials. Most of
these methods work in the experimental setup schematically shown
in Fig.3.1.1a, b in §3.1. The analyte or sample is irradiated
with a suitable type of radiation, the detector
measuring the effect of this radiation on the analyte.
Radiation
measurement of thickness and density
If we irradiate a material with a given value of the linear
attenuation coefficient m , the absorption and attenuation of radiation is
exponentially dependent on the thickness of the
material - see the section " Absorption
of radiation in substances "
in §1.6 "Ionizing radiation". By measuring the
radiation absorption, the thickness of the material and its
changes can be determined without contact (in
the basic arrangement according to Fig.2.8.1 on the left). For
thin light materials such as paper or plastic foils, beta
radiation is suitable , the source can be radionuclides 90 Sr + 90 Y (harder radiation b E b= 0.546 + 2.27MeV, mass half-thickness of absorption d 1/2 = 90mg / cm 2 , suitable for
thicker layers) , 85 Kr (E b = 670keV, d 1/2 = 23mg / cm 2 ) , 147 Pm (E b = 224keV, d 1/2 = 5mg / cm 2 ) . To measure denser materials (such as metals), g- radiation
is used , emitted by radionuclides 241 Am (60keV), 137 Cs (662keV), 60Co (1173 + 1332keV). With these methods, it is possible
to measure (scan) the relevant objects, or even continuously
monitor the thickness of the produced foil or rolled
metallurgical material on the conveyor belt.
The attenuation of radiation
as it passes through the substance is also significantly
dependent on the density of the monitored
material. With a known (constant) material thickness, we can
monitor the density of the material and its changes based on the
attenuation of the transmitted radiation beam. Densitometers of
this type are used, for example, in monitoring the transport of
substances by pipeline (in the chemical or food industry) or belt
conveyors (coal treatment plants, dosing of components in
metallurgy, etc.).
Note: If the measured sample is
accessible from one side only, it is sometimes used to measure
the thickness and density of the scattering method.:
the object is irradiated with a beam of radiation and the
intensity of Compton backscattered radiation (Fig.2.8.1 in the
middle) is monitored, which depends on the thickness and density
of the material. This is the case with pipe walls, boilers and
closed vessels, or in boreholes (logging measurements). However,
the accuracy and sensitivity of these scattering methods is lower
than for transmission methods.
Radiation
level meters
meters Radionuclide level meters determine the height of
a liquid column based on the attenuation of the
radiation beam g by the liquid, depending on whether the radiation passes
through liquid or air. In addition to liquids, bulk materials can
also be monitored in this way. This non-contact
method is important where other methods cannot be easily used -
for example in overpressure and underpressure vessels, or for
liquids aggressive or heated to high temperatures. The most
commonly used g- emitters with radionuclides 137 Cs (662keV) and 60 Co (1173 + 1332keV), or 241 Am (60keV).
The geometric arrangement of
the radiator and detector is most often horizontal,
where the radiator and the detector are placed on the sides of
the tank opposite each other and detect the level (in the simplest case, one radiator and one detector are
used, whose response after amplification switches the relay
contacts when the level reaches the measured point) . In a vertical arrangement, the source
and detector are below and above the tank, so that the
attenuation of the radiation as it passes through the liquid
column is exponentially dependent on the level in the tank; the
level can be monitored continuously.
Neutron
measurement of hunidity
This method is based on the elastic scattering of
fast neutrons on hydrogen nuclei (contained in
water), which of all elements most effectively scatter and
decelerate neutrons. The humidity meter consists of a source of
fast neutrons (usually 241 Am in a mixture with beryllium, activity of about one
hundred MBq to units of GBq) and a detector of slow neutrons (see
§2.6). Either a transmission arrangement can be
used , where the attenuation of the flux of neutrons from the
source due to their scattering on the hydrogen nuclei is measured
, or reflective , where the increase in the flux
of slowed neutrons due to their scattering in the surrounding
material containing hydrogen nuclei is measured.
The neutron method of
measuring the moisture content of materials is used in many
industries, eg in the chemical industry, construction,
agriculture, mining. It is most often used to measure the
moisture content of bulk materials such as soil, sand,
mortar mixtures, ores, coal and coke, grain, etc.
Note: The response of
neutron flux is given by the total volume humidity . If
it is necessary to determine the mass humidity ,
sometimes combined neutron + gamma probes
containing a neutron source and a g- radiation source (eg 137 Cs) and a neutron
detector and a g detector are used (it is often combined into one compact
probe). From the response to radiation git is possible to determine
the density of a material, from the neutron response its
moisture; the conversion of bulk moisture to mass moisture can
then be realized electronically in the evaluation unit of the
device.
Radiation defectoscopy
Another method, based on differences in the absorption of
penetrating radiation in substances, is radiation defectoscopy
. During casting, cooling, welding, machining and operation of
products and parts of machines and equipment, inhomogeneities,
cavities, cracks and similar internal defects
can occur , which impair the mechanical properties of the part
and can lead to machine failure. Defectoscopy in general
is a method of non-destructive examination of structure
("defects") in the macroscopic consistency of a
material.
Radiation defectoscopy allows non-destructive
analysis of inhomogeneities to detect
possible cracks and other anomalies in construction materials and
finished products. The basic scheme of defectoscopic measurement
is similar to the above-described X-ray
diagnostics in medicine. The
analyzed object is irradiated with a collimated beam of
penetrating radiation X or g , while the transmitted radiation is displayed on a
photographic film - radiography , or is displayed on a
fluorescent screen or electronic detector to a computer - radioscopy
. The absorption of ionizing radiation depends on the thickness
and density of the material (see the exponential relationship in
the section " Absorption of radiation in
substances " in §1.6), so
that the weakened areas are reflected in greater blackening of
the film.
Any inhomogeneity or crack
will appear on the film after development as a local
defect in an otherwise homogeneous blackening of the
emulsion. Films and developers are used, ensuring the highest
possible steepness of the blackening curve , so that
even small inhomogeneities of transmitted radiation are displayed
in sufficient contrast. The blackening of the film is usually
evaluated visually using special transmission lamps, or they can
be evaluated photometrically. Now the films are gradually being
discontinued - the transmitted radiation is detected by a
sensitive electronic detector . The detector, a
digital semiconductor flat panel detector ( flat panel ), detects the intensity of gamma or X-ray radiation
that passes through the material and the occurrence of a defect
(cracks, cavities, etc.) is reflected in a change in the
intensity of the measured radiation at a given location.
For defectoscopy of steel objects, either
X-rays with an energy of about 60-400keV from technical X-rays
tube or g- rays from suitable radionuclides are used - iridium 192 Ir ,
selenium 75
Se , cesium 137 Cs , cobalt 60 Co ,
occasionally also hard bremsstrahlung g with energy up to 10MeV
produced by a linear or circular electron accelerator (braking of
electrons on a target). Hard gamma radiation or braking radiation
must be used especially when irradiating metals (steel) with a
thickness greater than 100 mm, where ordinary X-rays are no
longer sufficient. For radiography of thinner layers, on the
other hand, softer photon radiation is more suitable, which
provides a higher contrast of the displayed small defects(Of the radionuclides, the aforementioned Ir-192 or
Se-75 is suitable) .
Defectoscopy is used
especially where high demands are placed on
the quality of materials and components. These are, for
example, gas pipelines, turbine blades, reactor pressure vessels,
bridge structures, etc.
X-ray microscopy,
micro-CT
So -called micro-X-rays tubes are used for structural analysis of small objects (such as
electronic components or small castings). The special X-ray
machine has a very small impact focus (only a few micrometers),
so the X-ray beam emanates almost from a point source and
provides high sharpness and image resolution. The measured sample
is placed very close to the X-ray and the film or imaging
detector at a greater distance - there is a projection magnification
of the image . For this purpose, X-ray lamps with a thin
front so-called transmission anode are sometimes
used (see §3.2, section " X -rays", passage "Special types of X-ray
tubes") , which allows to maximally
bring the displayed object to the focus on the anode and thus
achieve high magnification at a small distance between the
illuminated object and the imaging detector. For X-ray microscopy
( XRM)) mainly soft X-rays of approx. 20 ¸ 60keV are used.
Low-energy photons of X-rays interact with the atoms of the
investigated substance mainly by the photoeffect, which provides
a higher absorption contrast
between areas with small differences in density. In large special
laboratories, very soft X-rays (approx. 2 ¸ 10keV - around the K- or
L-edge of the absorption spectrum of the examined material, where
the absorption and imaging contrast is greatest) from the synchrotron
undulator are used for X-ray microscopy (see §1.5, section " Accelerated
particle accelerators ", section
"Accelerators as synchrotron radiation generators") , with or. using a crystal monochromator and a Fresnel
zone plate, acting as a contact lens of X-ray optics. Either
scan mode or display using special pixel detectors
is used . These are very demanding laboratory methods!
X-ray microscopy with a special microfocus X-ray tube with a
transmission anode.
CT X-ray tomography or micro-tomography ( m CT) is also used for detailed 3D analysis of small objects , the principle of which is analogous to the above-described medical X-ray tomography (§3.2, section " X-ray tomography - CT ") . The main difference is that the X-ray machine and the detection system do not rotate during the measurement, but the displayed object rotates between the static X-ray machine and the imaging detector. The transmitted X-rays, measured by an imaging detector for a number of different angles of the rotating sample, are reconstructed into cross-sectional images, the set of which forms a 3-D image of the analyzed object.
Safety
inspection of materials
The principle of radiation measurement of mechanical properties
(density) of materials is also based on X-ray inspection
of luggage , used in recent years at airports. Small
X-ray machines - an X-ray machine and an opposite electronic
imaging detector - are installed at the baggage counter for air
traffic, between which checked baggage passes. The resulting
absorption image is immediately projected on the display,
sometimes with a "pseudo" color display (artificial
assignment of colors to grayscale), in order to recognize mainly
metal objects (such as weapons).
X-ray
diffraction analysis of the structure of the crystal lattice
Impinges when X-rays to a substance having crystal ou structure rou
, there is a diffraction portion of X-rays ,
at which the radiation reflected from the regular crystal lattice
structure - X-rays elastically scattered at electrons measured
crystal. Subsequently, this X-ray may be interfered with
. The diffraction
interference picture then encodes information about the internal
structure of the crystal.
At the incidence of monochromatic
X - rays with a wavelength
of l » 0.1 nm ( comparable
to the distance
between the ions forming the crystal
lattice ), the rays
may be amplified in one direction, weakened
or disturbed in
others . X-rays are amplified and form an
interference maximum if
the so-called Bragg condition is met, so that
the path angle of two rays is an integer multiple of the
wavelength of the radiation: n. L = 2.d.sin J , where J is the angle
formed by the incident beam with the crystal plane, d is
the distance between
two adjacent crystal planes (lattice constant) , l is the wavelength of the X-ray radiation
used and n = 1,2,3, ... is integer .
In this situation, the intensity of the scattered waves adds
up . For a given crystal having a lattice constant d
is thus interfering peaks at the diffraction d planted only at certain values of
L and J . Usually, 1st
order angular spectra (n = 1) are scanned, where the maximum is
most pronounced, only to distinguish some details, higher order
spectra are analyzed (low intensity -
significant prolongation of exposure time) .
Fig.3.3.2. Principle arrangement of X-ray diffraction analysis of
crystal lattices
Apparatus for measuring the diffraction called. Diffractometer is formed goniometer
, whose center is stored analyte and on whose one arm is a source
of X-radiation and the other arm a detector measuring the
intensity I X -ray radiation. By turning the goniometer, the angles J are measured , for
which the maximum intensity I X of the "reflected" X-ray, i.e. the interference
maximum, is detected in the reflection mode . The
measurement in the transmission mode is rarely used ,
when the diffraction of X-radiation passed through the sample is
measured. Possibly. display of the diffraction patternon
photographic film or electronic imaging detector. The X-ray
continuous spectrum monochromator is included either in the
primary beam or in the secondary diffraction radiation path. For
a detailed analysis of the structure of single crystals, the
angles of the X-ray J 1 and the detector J 1 are measured independently and another goniometer is
included, enabling the sample to rotate even in the perpendicular
direction ( Bragg-Brentan diffractometer ). X- ray
microfocus is used in X-ray microdiffraction (its construction was described above in the section
" Special types of X-ray tubes " and the use
in the previous paragraph " X-ray microscopy; micro-CT
") ; in the most demanding
applications isynchrotron X-rays (§1.5,
section " Synchrotron radiation generators ") .
X-ray diffractometry is used
in many areas of materials research, especially for the analysis
of the crystal structure of substances - both single crystals ( single
crystal X-ray structural analysis ) and polycrystalline and
powder materials ( powder X-ray structural analysis ).
Also in the non-destructive analysis of archaeological and
artistic objects.
Note: It can also
be used to decompose continuous (polychromatic) X-rays and obtain
a monochromatic component.
...............
Positron
annihilation spectrometry
Positron annihilation spectrometry is used to analyze local
electron densities and configurations in substances. It is based
on spectrometric measurements of the positron lifetime
in substance ( PLS - Positron
Lifetime Spectroscopy ) . If we
irradiate the analyzed material with positrons, fast positrons
slow down in the substance in the path of a few micrometers (in a time of about 10 picoseconds) and under normal circumstances they can (via an unstable positronium) annihilate
with electrons. However, they can be retained in places of
structural irregularities in the crystal lattice (pores) and
annihilate with a delay with electrons from the
surroundings. In order to determine the lifetime of positrons, we
first need to detect the moment of formation
(radiation) of the positron. This is possible when the
radioactive source of positrons synchronously emits gamma
radiation from the excited level of the daughter
nucleus.
The investigated material is
thus locally irradiated with a mixed b + - g
emitter (most often 22 Na ), while the lifetime of positrons is determined by
measuring the delayed coincidences between the
detection of the photon of radiation g from the radiating
radionuclide (u 22 Na is g 1274 keV) and
detecting the g 511 keV annihilation photon .
In the
case of the most common use of a b + - g emitter Na22 the detection
radiometric apparatus consists of two gamma-detectors
(scintillation or semiconductor):
1. A detector set to a 1274keV photopeak of
gamma daughter nuclide deexcitation radiation 22 No. This is the
" start " impulse of the time
coincidence analysis, indicating the moment of positron
formation .
2. Detector set to 511keV of annihilation radiation
generated by e - e + positron annihilation. This is the
" final "impulse of time coincidence
analysis, determining the moment of positron extinction
.
In
solids maters without structural defects the lifetime of
positrons is about 0.25ns, in positrons annihilating in defects
it is extended to about 0.75ns. With this method it is possible
to observe defects in material structure of about 0.1 to 1 nm -
dislocations, vacancies, clusters of vacancies, clusters, or
precipitates.It is used to monitor the technology of preparation
of various materials (plastics, metals, conductors, insulators,
semiconductors) and also to monitor the impact of the environment
and technologies on materials ( fatigue and
"aging" of materials, thermal and radiation effects,
etc.) .
3.4.
Radiation analytical methods of materials
The methods of atomic and nuclear physics, as well as the
properties of different types of radiation, provide important
tools for the analysis of the material and elemental composition
of various objects. Most of these methods work in the
experimental arrangement ideologically shown already in the
introductory Fig.3.1.1a, bv §3.1. The analyzed object or sample
is irradiated with a suitable type of primary radiation
, the interaction of which with atoms or nuclei creates secondary
radiation , which "brings out" information
about the composition of the material. This radiation is detected
and analyzes. From the large number of different atomic, nuclear
and radiation analytical methods, we will present only a certain
selection of the typical and more frequently used ones, with an
emphasis on the physical nature, without excessive technical
details.
X-ray fluorescence
analysis
This method of non-destructive determination of
the chemical (elemental) composition of substances is based on
the measurement of the secondary fluorescence characteristic
X-rays induced by the primary
irradiation of the examined sample. The measured sample is most
often irradiated with photon radiation - either X-rays from an
X-ray lamp or gamma radiation from a suitable radionuclide -
Fig.3.4.1 (irradiation with charged
particles is mentioned at the end of this passage) . The interaction of this photon radiation with the
atoms of the examined sample results in a photoeffect
(see the passage " Interaction of gamma radiation " in §1.6 "Ionizing radiation") mostly
on the K shell (if the radiation energy is higher than the
binding energy of the electron on this shell), after which when
the electrons jump from the higher shell (L) to the released
place, a characteristic X-radiation (K series) is emitted, whose
energy is unambiguously determined by the proton number Z of
the atom. If the shell on the photoelectric L , then
Hopping of electrons husk M is emitted characteristic
X-ray series L .
The energies (spectral lines Ka b ) of
fluorescent X-rays are characteristic for each element, the
amount of emitted photons of characteristic radiation is directly
proportional to the number of atoms of a given species, thus a
measure of the concentration of a given element. By spectrometric
analysis the energy (wavelength) of the resulting
fluorescent radiation can be used to determine which elements
are present in the sample under investigation, and the amount
(concentration) of these elements in the sample can be determined
according to the intensity of the individual
fluorescence peaks.
The method of exciting
characteristic X-rays by primary gamma rays is sometimes referred
to as XRF ( gamma-induced X-ray Fluorescent
Emission ).
![]() |
Fig.3.4.1. Typical arrangement of radiation source, analyte and detector in X-ray fluorescence analysis. At the top right is the detailed structure of the peaks K a, b of the characteristic X-ray, measured by a semiconductor Ge(Li) detector. |
The energy of the primary
excitation radiation g or X is most suitable only slightly higher than the
binding electrons on the shell K (or L) in the atoms of the
analyzed elements; then the highest effective cross section is
for the photo effect. Therefore, different irradiation sources
are used for lighter, medium and heavy elements. Thus, in
addition to the X-ray lamp, radionuclides emitting soft X-rays
such as iron 55 Fe (X Mn L-series 5.9-6.5keV) , curium 244 Cm (X Pu L-series 12 ) are used for the irradiation of the examined samples for
the analysis of light elements. -23keV) , for medium-heavy elements americium 241 Am ( g 60keV) , for analysis of heavy
elements such as gold, tungsten, lead, uranium, etc., then cobalt57 Co ( g 122 + 136keV) , cesium 137 Cs ( g 662keV) , cer 144 Ce ( g 140keV) .
Scintillation detectors are
used to detect characteristic X-rays for simpler and indicative
measurements (such as geological survey and ore prospecting,
metal content control in metallurgy, etc.), but a high-resolution
semiconductor detector must be used for more
accurate and complex laboratory analysis, and multichannel
analyzer . For quantitative analysis, a correction for
interfering Compton scattered radiation g must be madeand, of course,
careful calibration of the device.
Characteristic X-rays have four very
close energy lines (related to the fine structure of electron
levels K and L), which are referred to as K a 1 , K a 2 , K b 1 , K b 2 - Fig.3.4.1 top
right. E.g. for lead these energies are 72.8,74.97, 84.8,87.3
keV, for gold 66.99,68.81, 77.9,80.1 keV, for iron the energy of
X-rays is only 6.4 keV, for aluminum 1.5keV (for these low
energies it is practically no longer possible distinguish lines K
a and K b ). Thus, for light elements, the X-ray energy is very
low and difficult to detect. X-ray fluor. analysis is therefore
particularly suitable for determining content heavier
elements .
To excite characteristic X-rays,
primary irradiation with charged particles that
ionize the atoms of the substance is sometimes used , followed by
deexcitation and emission of X-rays. The method of particle-induced
X-ray emission is called PIXE ( Particle-Induced
X-ray Emission ). Usually, protons with an energy of about
2-4 MeV are irradiated, the surface layer of the sample is
analyzed to a depth of about 5 m .
X-ray fluorescence analysis has the
great advantage of being fast, accurate and reproducible, does
not require any chemical processing of samples in all states. The
examined material is not damaged in any way and
no artificial radioactivity is generated. It is possible to
examine entire objects , without the need for
sampling - this is a non-destructive method . It
is therefore suitable, among other things, for the analysis of
the composition of art objects , which can help
their temporal or authorial classification, finding out the
origin, as well as verifying their authenticity.
Activation
analysis
This nuclear-analytical method is based on the
irradiation of a test sample with such radiation (type and
energy) that enters the nuclei of the investigated atoms and
causes nuclear reactions there . During these
reactions, radiation (especially gamma) is emitted, but mainly unstable
isotopes are formed from originally stable nuclei - radionuclides
, which subsequently decay by radioactive transformation a or b with subsequent
emission of photons g . Either the secondary radiation emitted during the
nuclear reaction itself is measured, but above all the g- spectrum
is measured emitted radionuclides caused by nuclear
reactions due to primary irradiation. The analysis of this
spectrum determines the elemental composition of the
sample (qualitative and, if necessary,
quantitative) .
Neutron
activation analysis NAA (also called induced or instrumental neutron
activation analysis INAA , see below) is
a highly sensitive method of analysis of chemical composition of
substances, based on neutron capture (reaction
n, g )
in the nuclei of the test substance, thus forming radioactive
nuclei (see §1.3 "Nuclear reactions"): N A Z + n ® N + 1 B * Z ; B * ® B + g P ; N + 1 B Z ® N + 1 C * Z + 1 + e - ( b ) + n ; C * ® C + g D . During the reactions, two types of gamma radiation
are emitted: immediately after neutron capture, it is g P radiation , followed by radioactive decay of activated
nuclei, g D radiation is emitted
- lower part Fig.3.4.2. Irradiation of the examined sample with
neutrons thus results in the formation of radionuclides - the
" activation " of the sample, followed
by spectrometric analysis of energies and
radiation intensities (especially g ) emitted from the
activated sample, the relevant radionuclide can
be determined and the corresponding (inactive) starting
nuclide contained in the sample, the activation of which
radionuclide was created by "tracing" (Fig.3.4.2).
Using a suitable calibration, its content
(concentration) in the examined material can also be determined .
Fig.3.4.2. Typical procedure for neutron activation analysis.
Neutron irradiation of the analyzed samples is
performed either in irradiation chambers in a nuclear
reactor as shown in the figure (nuclear
reactor is a powerful source of neutrons, see §1.3, section
" Fission of atomic nuclei
") , or using neutrons from special
accelerators, so-called neutron generators ( §1.5, part "Charged particle accelerators",
passage " Neutron generators ") . In the laboratory and in the field is also used radionuclide
neutron sources , a blend of the alpha-emitter with a
light element (e.g. a -radionuklidu 241 Am in admixture with beryllium reactions occur and, n), or a heavy
transuranic radionuclide (most often californium 252), during the
spontaneous fission of which neutrons are released (§1.3, " Transurans ") . For neutron activation
analysis, mainly slow neutrons with energies of
about 0.001-0.55 eV are used , which have a
high effective cross-section of capture by many nuclei. From
neutron sources, which usually provide fast neutrons with
energies of the order of MeV, the neutron beam is first led to
the moderator and irradiated only by slowed
neutrons.
For complex NAA, the detection
of gamma radiation from neutron-irradiated samples is usually
performed by semiconductor g- spectrometers
with high energy resolution (§2.5 " Semiconductor detectors ") in order to identify the exact energies of
gamma radiation and to distinguish peaks often in close
proximity. For some simpler applications, where it is enough to
measure the representation of one or a few elements, scintillation
detectors can be used (which do not have such good energy
resolution, but have higher detection efficiency - §2.4 " Scintillation detection and gamma-ray
spectrometry "). If the
measurement of the activated sample is extended by the
simultaneous - coincidence - detection of two or more
quanta of emitted gamma radiation by means of two spectrometric
detectors, the method is referred to as coincidence
activation analysis CINAA ( Coincident INAA). The
method is suitable when the activation results in radionuclides
with a cascade deexcitation emitting a pair of photon
quanta (such as 60 Co). Coincidence measurement then sharply reduces the
background of interfering impulses. Detection can optionally be
combined with position-sensitive detectors (such as semiconductor
pixel detectors) that register soft g- radiation or charged
particles, especially electrons b - , which are emitted by activated nuclei in coincidence
with photons g . In this way, the spatial distribution of the
analyzed element in the sample can be displayed .
In terms of treatment of
measured samples, two methods of activation analysis are used :
¨ Instrumental INAA
activation analysis, where the irradiated sample is measured
directly, without chemical treatment, on a g- spectrometer. This is the
simplest and most common way to implement NAA. In the respective
device, the neutron source and the g- spectrometer are sometimes
integrated in one compact device, which can be used not
only in the laboratory, but also in the field. Such measurements
can also be performed in a non-destructive way:
We irradiate the analyzed object or its part with a neutron
source, measure the induced radiation g , after which we can return
the object to its original use (unless it
is activated too strongly by long-term radionuclides) .
¨ Radiochemical RNAA
activation analysis, in which the sample is first subjected to chemical
separation after irradiation - either to remove
interfering radionuclides (which could overheat the analyzed
radionuclides or to interfere with them), or to increase the
concentration of required radioisotopes. This method is used less
often for considerable labor and laboratory complexity.
In terms of the time
relationship between irradiation and measurement, neutron
activation analysis is divided into two categories :
l Subsequent - delayed gamma-neutron
activation analysis DGNAA ( Dellayed Gamma-ray Neutron
Activation Analysis ), where gamma radiation measurements
from the sample are performed after neutron irradiation as in
Fig.3.4.2 in the middle). "Subsequent" (delayed)
radiation g is measured here D arising from b -radioactivity of activated nuclei N
+ 1 B Z ® N + 1 C * Z + 1 + e - ( b ) + n by deexcitation of excited levels of the daughter nucleus:
C * ® C
+ g .
This is the most commonly used method suitable where neutron
activation produces radionuclides with a longer half-life
(minutes and longer).
l Immediate ( prompt
*) gamma-neutron activation analysis PGNAA ( Prompt Gamma-ray
Neutron Activation Analysis ), when the measurement of
emitted g
-radiation is performed during neutron irradiation (Fig.3.4.2 on
the right). Radiation g of two types (origins) is measured from the irradiated
sample with a gamma spectrometer : 1. Immediate
photons g P , usually emitted
very quickly after neutron capture from excited levels of
activated nuclei B * ® B + g . 2. Radiation g D arising subsequently from b -radioactivity of activated
nuclei N + 1 B Z ® N + 1 C * Z + 1 + e - ( b ) + n by deexcitation of excited levels of the daughter
nucleus: C * ® C + g . This method is
suitable when neutron activation produces short-term
radionuclides (which would usually decay during the time between
irradiation and sample measurement), or stable nuclides, or
radionuclides with pure b- decay or a small proportion of g- radiation (then immediate
photons g P generated after
neutron radiation capture). The NAA prompt automatically falls
into the category of instrumental activation analysis
mentioned above .
*) The method of neutron
stimulated gamma emission can also be included in this
category in a sense , when the sample is irradiated with fast
neutrons , the inelastic scattering of which leads toexcitation
of nuclei in the analyzed sample. During subsequent
deexcitation, g- radiation of characteristic energies
for individual nuclides is emitted . The
presence and concentration of the respective elements and their
isotopes can be determined by spectroscopic detection of this g- radiation,
performed during neutron irradiation. This method is also
experimentally tested for the purpose of in vivo gamma imaging in
medicine (see §4.3, passage "Neutron- stimulated
emission computed tomography NSECT ").
Neutron
activation analysis can achieve extremely high
sensitivity (it allows to detect even 10 -12 g of element in 1 g
of sample), so it is suitable for detecting trace amounts
substances, eg trace element content in plant and animal tissues,
water pollution, purity of semiconductor materials, etc.
Note: For
special purposes of biological research, in vivo neutron
activation analysis is sometimes used : the relevant
part of the organism is irradiated with neutrons (from reactor or
neutron generator) followed by a gamma plot of the
distribution of induced beta radioactivity (accompanied by
gamma), mapping the distribution of the test substance in tissues
and organs.
In addition to neutron
activation, proton and gamma-activation
analysis are also rarely used , in which protons
accelerated on an accelerator , such as a cyclotron, are
used to activate the nuclei of the sample .(causes
reactions of proton capture [p, g ], or reactions of type [p,
n], [p, d], [p, a ]) , or high-energy gamma
radiation (causes photonuclear
reactions [ g , n] , [ g , p], at higher energies more particles [ g , 2n], [ g , d], [ g , 2p], [ g, a ]) can be
ejected from the nucleus , arising as
bremsstrahlung by electrons accelerated in betatron, microtron or
linear accelerator.
Mössbauer
spectroscopy
Mössbauer spectroscopy is a non-destructive analytical
method based on the so-called Mössbauer effect of
resonant nuclear absorption of g radiation - see §1.6,
section " Interaction of gamma radiation ". The sample is irradiated with monochromatic
radiation g and the detector measures the intensity of transmitted
or "reflected" (resonantly scattered) radiation as a
function of subtle changes in radiation energy g , which varies in
a narrow range due to Doppler effect by
precisely controlled mechanical movement of the
source relative to the sample by a linear motor. Radiation git must have an
energy exactly corresponding to the excited level of the core of
the sample under examination. The Doppler effect compensates for
the energy loss of the reflected nuclei, resonant
absorption of photons g , accompanied by a maximum
of absorption and subsequently emission of a photon of
the same energy.
This method is applicable to
substances containing elements which form as daughter nuclei of
suitable radioisotopes and have excited levels emitting radiation
g ; the
samples are irradiated with radiation g from such a radioisotope.
The fine position of the absorption maxima depends on the
properties of the chemical bond in which the
atoms containing the analyzed nuclei participate, on the
properties of the crystal lattice, as well as on
the internal magnetic and electric fields in the crystals. By
analyzing the fine structure of the Mössbauer spectrum
(which is the dependence of the absorption of g on the feed rate
of the source relative to the sample), some internal
chemical and physical properties of the investigated
material can be determined .
The method is suitable for 57 Fe, 57 Co, 129 In, 119 Sn, 121 Sb *). It is mainly
used on materials containing iron 57
Fe. It allows the analysis of the distribution of iron
in the material in various crystallographic positions, its degree
of oxidation, analysis of ferromagnetic materials, alloys,
minerals, etc. For analytical purposes, the samples are made into
a thin film or powder (weighing several grams).
*) The number of suitable elements (nuclei having a suitable
radionuclide emitting g radiation from a suitable excited level of a stable
daughter nucleus) suitable for this analysis is very
limited , so the significance of Mössbauer spectroscopy
is not comparable to such methods as activation analysis, X-ray
fluorescence analysis or defectoscopy .
In the
Mössbauer spectrometry of iron, the radionuclide 57 is used as the
radiation source gCo, which decays to an excited 57 Fe nucleus with a half-life of 270 days by electron
capture . This nucleus emits 692keV (0.14%), 136keV (11%), 122keV
(87%) and 14.4keV (9%) g radiation when deexcited. It is the radiation g of the partial
transition from the excited level with an energy of 14.4 kV that
is suitable for excitation of resonant nuclear absorption due to
its low energy. Due to the high Debye temperature Fe (360 ° K),
the Mössbauer effect occurs even at normal laboratory
temperatures, while the Doppler frequency shift required to
compensate for the reflection of the 57 Fe
core is achieved by mechanical displacement of the source at
speeds of only the order of 1 mm / s.
Note:
High sensitivity Mössbauer effect of resonant nuclear absorption
g -radiation
14.4keV57
Fe was used in 1960 by R.V.Pound and G.A.Rebka to measure the gravitational
frequency shift in the Earth's gravitational field,
which was an important test of Einstein's general theory of
relativity as a physics of gravity and spacetime - see §2.4
" Physical laws in curved spacetime " in the book " Gravity,
black holes and space - time physics ".
Mass spectrometers and separators
Mass spectrometers and separators, used in physical chemistry and
radiochemistry, work in a similar arrangement as the magnetic
spectrometer of charged particles according to Fig.2.6.1
on the left - see §2.6, section " Magnetic
spectrometers ". The analyte is
ionized in the ionization chamber, the formed cations of charge e
are accelerated by an electric field and ions with a constant
velocity v are selected in a velocity filter (consisting
of, for example, a crossed electric and magnetic field) . These
then fly through the input slit into the magnetic field of
intensity (induction) B , in which they describe
a circle with radius R = (v / eB) .m, proportional to the mass m.
Ions of different weights describe different paths and thus fall
on different places of the base - the device thus separates
ions of different weights (given the weight of the core). By
changing the magnetic field, ions of corresponding masses are
gradually focused into the detector - a mass spectrum
is created . A suitable target is installed in the mass separator
instead of the detector, on which the incident ions of the
selected mass are absorbed.
Magnetic mass spectrometry is
a demanding method for the most accurate analysis of the
representation of elements and their individual
isotopes in the analyzed substances. Magnetic mass
separation makes it possible to isolate completely pure
samples of a precisely defined isotopic
composition, but only in very small quantities.
Gas
ionization analyzers
As ionizing radiation ( a or b ) passes through a gaseous medium, absorption and
ionization depend on the density and composition of the gas. The
flow ionization chamber with a built-in emitter a or b can thus serve as
an analyzer for checking the composition of the gases.
Fire
detectors
The ionization fire detector consists of two electrodes
with an air gap. Radiation and
from the applied layer of radionuclide
(most often 241
Am, approx. 30 kBq) generates an ionization
current between the electrodes. In the presence of smoke between
the electrodes, the absorption of the environment changes and
thus the ionization current changes, which is registered by the
electronic circuits of the fire alarm system.
Radiative electron capture detector - ECD
To detect compounds with high electron affinity
(such as the Freons, chlorinated pesticides and other halogenated
compounds ) may be a radiant electron capture
detector (ECD - Electron Detector Capure). It consists of a
cylindrical ionization chamber filled with an
inert gas (eg argon), one electrode (cathode) of which is
provided with a layer of a low-energy radiator b , usually 63
Ni (activity approx. 300MBq). The emitted radiation b creates an
ionization of the gas atoms, a certain ionization current flows
through the chamber. When a gas containing high electron affinity
atoms enters the chamber, these atoms absorb the electrons in the
ionized gas and the ionization current through the
chamber decreases , which is electronically registered.
Such chambers are often used as a terminal detector
in gas chromatography columns .
Nuclear
magnetic resonance -
analytical and imaging method
Nuclear magnetic resonance (NMR)
is a very complex physical-electronic method, based on the
behavior of magnetic moments of atomic nuclei
under the action of an alternating radio frequency signal in a
strong permanent magnetic field. This originally analytical
method was later improved and developed as an important imaging
method .
Note: We have
included nuclear magnetic resonance among nuclear and radiation
methods, even though it does not contain any ionizing radiation.
However, it is a method based on the knowledge of nuclear
physics - the properties of atomic nuclei. A physical
phenomenon called nuclear magnetic resonance - NMR,
was investigated in the 1940s (F. Bloch,
E.M.Purcell) and was initially used in
chemistry as sample NMR spectrometry . In the
1970s and 1980s, NMR imaging methods also began
to develop (pioneers were P. Lauterbuer, P.
Manfield, A. Maudsley, R. Damadian, 1977) -
see below.
We will try to briefly outline
the principles and methodology of NMR. However, due to the
considerable principal and technical complexity of NMR
(only scintigraphy can partially compete with it), we must
observe the maximum brevity ...
Physical
principle of NMR
Phenomenon of nuclear magnetic resonance it can
generally occur during the interactions of atomic nuclei with an
external electromagnetic field. Each nucleon (proton and neutron)
has its own "mechanical" momentum - spin
(nucleons belong to fermions with spin 1/2, see §1.5 " Elementary
particles "). According to the
laws of electrodynamics, this rotational momentum of nucleons
creates - induces - its own elementary magnetic
moment m p = 1.41.10 -27 J /
T, equal to 2.79 times the so-called Bohr nuclear magneton
*) - it is discussed in more detail in
§1.1, passage " Quantum
momentum, spin, magnetic moment ",
paragraph " Magnetic moment ". Due to the spins of their
nucleons, atomic nuclei therefore generate a very weak magnetic
field - they have a certain magnetic moment m . However, only
atomic nuclei with an odd nucleon number have spin and magnetic
moment, because the spins and magnetic moments of paired protons
and neutrons cancel each other out - they are zero. The magnetic
moment of the nucleus is formed by an unpaired nucleon - a proton
or neutron. Magnetic resonance imaging can therefore be observed
only in nuclei with odd nucleon numbers -
especially hydrogen 1 H, then in 13 C, 15 N, 19 F, 23 Na, 31 P, etc.
*) Nuclear magneton m Nis a
physical constant expressing the proton's own
dipole magnetic moment induced by its spin: m N = eh / 2m p
, where e is the elementary electric charge (proton,
electron), h is the reduced Planck's
constant, m p is the rest mass of the proton. In the
system of SI units, its value is approximately m N =
5,05.10 -27 J / T. It is analogous to
the Bohr electron magnet m e = eh / 2m e,
which, however, is 1836 times larger, in the ratio of the mass of
the proton and the electron. It is interesting that even a
neutron, although electrically uncharged, has a non-zero magnetic
moment m n = -0.966.10 -27 J /
T somewhat smaller and of the opposite sign than a proton. It
turns out that the magnetic moment of nucleons has its origin in
their quark structure (§1.5., Part " Quark
structure of hadrons "
and §1.1, passage " Magnetic moment ").
Magnetic
moments of nuclei in a magnetic field
Under normal circumstances, due to the thermal motion of atoms,
the directions of spins and magnetic moments of individual nuclei
are chaotically "scattered", their orientation is
random and disordered (Fig.3.4.4a), elementary magnetic fields
cancel each other out on average, on a macroscopic scale the
substance shows no magnetic properties (we
do not mean ferromagnetic substances, where it is the effect of
electrons in atomic shells) . However, if
we place the analyzed substance in a strong magnetic
field (of intensity or induction B of the
order of several Tesla), the magnetic moments of the nuclei are
oriented in the direction of the vector B of
this external magnetic field (at least
partially).- the magnetic moment of the
nuclei is parallel to the magnetic field lines (Fig.3.4.4b). The
stronger the magnetic field, the more perfect this arrangement
*). Outwardly, this results in non-zero magnetization
vector M in the direction of the external magnetic field
induction B . The magnitude of the magnetization
vector is proportional to the strength of the external magnetic
field B and the percentage of concordantly
oriented mag. moments of nuclei in matter. A sufficiently strong
magnetic field B is now mostly realized by means
of a superconducting electromagnet , the winding
of which must be permanently cooled by liquid helium (physical principles of superconducting magnets are
briefly discussed in §1.5, section " Electromagnets in accelerators ", passage "Superconducting
electromagnets ").
*) However, the extent of this
arrangement is actually very small ! In commonly
used magnetic fields 1-3T, for every 1 million hydrogen nuclei,
only about 7-20 nuclei are on average in a state of uniform
orientation. The vast majority of nuclei are as a result of
thermal motion, it is oriented in different directions, including
the opposite one (this is expressed by Boltzmann's law of
distribution.) In this sense, it is necessary to take Fig.3.4.4b
only as a symbolic scheme, which shows only those few nuclei that
acquire concordant orientations. .
Since conventional material, e.g., water
or tissue contains about 1 gram 10 22hydrogen nuclei,
even a small excess of oriented nuclei provides a measurable
magnitude of the magnetization vector and the radio frequency
response signal.
Larmor
frequency, radiofrequency excitation and relaxation
In the magnetic field B , the nuclei (with a
non-zero magnetic moment m ) behave as magnetic dipoles, which are acted upon by a
pair of forces m . B . This will cause the core to rotate
the axis of its magnetic moment around the direction B
- it will perform a precessional movement (similar to the precessional movement of a gyroscope or
children's "spinning top" around the vertical direction
in the gravity field) by the so-called Larmor
frequency
w L =g .B , or f L = g .B / 2 p ,
where g is the gyromagnetic ratio of the nucleus, which
is the ratio of the magnetic moment of the nucleus and its
"mechanical" moment of inertia [ rad
· s -1 · T -1 ] . The precession movement occurs when the external
magnetic field changes or the angle of the magnetic moment in
this field changes and lasts as long as the mag. the moment does
not stabilize in the rest position.
If we send a
short alternating electromagnetic signal into
such a magnetically polarized substance by means of another coil
(high-frequency - RF, or radio-frequency - RF) (whose frequency resonates with the above-mentioned Larmor
precession f L
of a given type of nucleus in a
magnetic field) , the
direction of the magnetic moment of the nucleus temporarily deviates
from the direction determined by the vector B of
the external magnetic field (Fig.3.4.4c) *). The deflection of
the magnetization vector is caused by the magnetic component of
the excitation RF pulse. The angle of this deflection is
proportional to the amplitude (energy) of the RF pulse and its
duration. The most commonly used RF pulses are 90 ° or 180 °.
*) Fulfillment of
the resonance condition: The nuclei are
able to efficiently receive energy from an alternating
electromagnetic field only if the Larmor frequency of the nucleus
precession and the frequency of the electromagnetic pulse are the
same. The preceding nuclei thus resonate with an
electromagnetic pulse at a given Larmor frequency - hence the
name " magnetic resonance ".
After the unwinding of the
excitation signal occurs relaxation (at a constant rotation Larmor frequency) at which they emit electromagnetic waves
with decreasing intensity until the magnetic moment of the spiral
return back again in the direction B . These
electromag. waves will induce alternating voltage in the receiving
coils - " echo "Radiofrequency
signal **). The relaxation signal (sometimes
referred acronym FID - Free Induction Decay) , a sine wave with an exponentially decreasing amplitude
(see below Relaxation times ) . It is a useful signal that carries information about
the inner structure of the analyte. Frequency of
this signal is equal to the above-mentioned Larmor precession and
for a given force B of the external magnetic
field is determined by the gyromagnetic ratio g of the nucleus, ie
the type of nucleus , the amplitude of
the relaxation signal is proportional to the concentration
of nuclei of the given type analysis of the
composition of substances : what elements and in what
concentration are contained in the sample. E.g. for hydrogen
nuclei (protons) the gyromagnetic constant has the value g = 2,675.10 -8 s -1 T -1 and in the magnetic
field of induction 1Tesla Larmor's NM the resonant frequency is
42.574MHz, at 1.5T it is 63.58MHz - the area of radio
waves (short waves) . It is proportionally lower for heavier cores.
**) Phasing of a
large number of nuclei : The NMR receiving coils
are of course not able to detect the relaxation radiation of one
or more nuclei. To obtain a measurable signal, deexcitation
of a large number of nuclei (> about 10 12 ) is required,
namelysynchronously and at the same stage ! If
phasing occurs, the MNR signal drops sharply or disappears (cf.
below " Relaxation times - T2 )
General note:
Quantum behavior: For the sake of clarity, we have not
yet explicitly included the quantum behavior of
the magnetic moment, we considered its continuous
behavior. The orientation of the magnetic moment vector of nuclei
in a magnetic field actually acquires discrete quantum
states - parallel (0 °), perpendicular (90 °) and
antiparallel (opposite, 180 °) with the direction of the vector B magnetic
induction of an external magnetic field. The basic, energetically
lowest state is parallel, while the perpendicular or antiparallel
configuration has a higher energy- excited state. From
the fundamental to the excited state of the magnetic moment, the
nuclei pass by absorbing a quantum of
electromagnetic energy, which must be exactly equal to the
difference in energy between the two states. The corresponding
frequency corresponds to the resonant Larmor frequency .
During deexcitation, an electromagnetic signal of the same
frequency is then emitted . The precession
rotation of the magnetic moment of nuclei in a magnetic field is
again just our model idea of how to clearly explain the behavior
of nuclei in a magnetic field ...
Fig. 3.4.4. Nuclear magnetic resonance -
simplified schematic representation.
a) The magnetic moments of the nuclei in the analyte
normally have chaotically scattered directions.
b) By the action of a strong magnetic field B
, the mag. moments of nuclei partially orient in the direction of
the vector B .
c) By emitting an RF electromagnetic field, these
oriented nuclei deviate from the B direction ,
eg by 90 °. After switching off this RF field, a relaxation
occurs, during which the deflected nuclei will emit an
electromagnet when they return during the precessional rotation.
NMR signal with exponentially decaying amplitude.
d) Simplified schematic diagram of NMR imaging
equipment. For simplicity, only one radio frequency (RF) coil is
drawn, which electronically switches alternately to transmit and
receive modes; usually there are separate transmitting and
receiving RF coils. (ADC =
analog-to-digital converter, DAC = digital-to-analog converter) .
Radio
frequency coils
RF coils are a kind of "antennas"
of the NMR system that transmit excitation RF
signals towards the analyte or receive response
RF signals from the relaxing nuclei in the analyte. In principle,
the same coil can be used as the transmitting and receiving coil,
which is electronically switched to the transmitting and then to
the receiving mode (as symbolically drawn
in the diagram in Fig. 3.4.4d). However,
better detection of the response NMR signal can be achieved by
using a separate receiving RF coil. Due to the relatively high
Larmor frequency (tens of MHz), RF coils have a very simple
design: they are formed by a loop of wire of circular or
rectangular shape, which is placed close to the analyzed material
(sample or area of interest in the organism). Sometimes they are
suitably shaped (bent into a saddle or
cylindrical shape) to achieve better
homogeneity of the RF signal in the analyzed area.
A short but very strong radio
frequency alternating current, of high amplitude
, is introduced into the transmitting coil in
various time sequences., instantaneous power up to tens of kW. In
the receiving coil, a response signal is then induced from the
relaxing nuclei, on the contrary, with a very low
amplitude (of the order of millivolts), which for
further electronic processing must be significantly amplified
in a narrowband high-frequency amplifier. For NMRI imaging (see
below), special RF receiving coils of various sizes and shapes
are used to tightly encircle the analyzed area - for imaging the
brain, joints, spine, etc.
NMR
spectroscopy and analysis
NMR spectroscopy is performed by increasing the
frequency of the excitation RF signal, this signal intermittently
supplies the coils in the transmitting mode, there is always a
switch to the receiving mode and the intensity of the rf signal
is measured - echo - transmitted by a sample placed in
the magnetic field B o during the back relaxation of the magnetic moments of
the nuclei. The frequency at which the resonant
maximum occurs, the Larmor frequency , determines the type
of nucleus (the highest is for hydrogen - 42.6MHz for B
= 1Tesla), the intensity of the resonant maximum
determines the concentration of the relevant
atoms in the sample. All nuclei of one isotope, inserted into the
same magnetic field, should resonate at the same frequency by
themselves. However, if the atoms of these nuclei are part of chemical
compounds , the distribution of electrons in their
environment differs and these electrons cause electromagnetic shielding
of the nuclei. . The effective magnetic field acting on the nucleus is
then no longer B o , but B = B o . (1- s ), where the
shielding factor s , describing the shielding intensity, slightly depends
on the chemical composition of the analyte. This change in the
effective magnetic field causes a so-called chemical
frequency shift in the NMR signal spectrum .
Another effect affecting the
fine structure of the NMR spectrum is the mutual interaction of
the nuclei of neighboring atoms mediated by valence electrons. As
a result of these interactions, the splitting of the resonant
maxima of the studied nuclei is observed into 2-4 lines at a
distance of about 20 Hz - there is a multiplicity of
signal .
Detailed analysis of
frequencies, intensities and multiplicities in the NMR spectrum
can therefore provide information on the chemical
composition and structure of organic
and inorganic substances. Modern NMR spectrometers are computer
controlled, and the induced NMR signal is analyzed using a Fourier
transform .
Relaxation
times
After switching off the high-frequency excitation field, the
deflected nuclei relax in the magnetic field -
they return in a spiral path to the original equilibrium state in
the direction B o
(which we refer to here as the "z" axis), which is
observed in the receiving coil as a free reverberation of the
induced RF signal with an exponential decrease in amplitude. The
rate of this relaxation (or decay time) is influenced by the
interaction of nuclear spins with surrounding atoms and the
mutual interaction between nuclear spins. The NMR signal also
encodes information about the surrounding atoms and molecules -
information about the chemical composition and structure
of the substance. The decay time of the resonant signal
is characterized by two relaxation times T 1 and T 2 .
Relaxation time T 1 , sometimes
called spin-lattice (the name
comes from the original use of NMR for the analysis of solids
with a crystal lattice) , represents the
basic time constant of relaxation of magnetic
moments of nuclei from the deflected position to the equilibrium
position in the direction of the permanent magnetic field.
Illustrates the speed with which the deflected core while
relaxing supplies energy electromagnetic waves, and the ambient
temperature, the longitudinal magnetization in the axial
direction from the initial value to the M by returning
exponential law: M Z = M a (1 - e -t / T 1 ) . It is
defined as the time taken for the longitudinal magnetization to
relax (1-e) times the original valueM o , whereby the signal drops to 63% (if the excitation of
the magnetic moment of the core by 90 ° was performed).
The relaxation time T 2 , sometimes
called spin-spin , expresses the time constant with
which, due to the mutual interaction of spins and magnetic
moments of adjacent nuclei, leading to the phasing out of the
precessional motion of magnetic moments, the magnetization
decreases in the transverse direction xy: M XY
= M XYo e - t / T 2 . T 2 is defined as the time during
which the transverse magnetization M XY decreases e-times.
Note:
The receiving coil in the MRI actually detects a shorter
relaxation time marked T2 * after the excitation
pulse has ended . In addition to the relaxation time T2, it is
caused by a steeper decrease in the transverse component of the
material magnetization due to small changes in the inhomogeneity
of the magnetic field, leading to desynchronization. In MRI
imaging, this phenomenon is usually negative, it can be corrected
or eliminated in the so-called " spin-echo
sequence" - see below.
The
relaxation times T 1 and
T 2 are the result of
the interaction of resonant nuclei with their surroundings and
characterize the chemical properties and structure of the
investigated material. In medical use, they are often
significantly different for healthy and tumor tissue.
In the most commonly used external
magnetic field of 1.5 T, the relaxation times T 1 and T 2 of
water and some human tissues (in the
physiological state) have the following approximate values :
Tissue type: | water | oxygenated blood |
non-oxygenated blood |
fat | muscles | proteins | gray matter brain |
white matter brain |
liver | kidneys |
T 1 [ms] | 4300 | 1350 | 1350 | 250 | 880 | 250 | 920 | 780 | 490 | 650 |
T 2 [ms] | 2200 | 200 | 50 | 70 | 50 | <= 1 | 100 | 90 | 40 | 70 |
Relaxation times are
characteristic of different substances and tissues - they depend
on the concentration of nuclei, temperature, size of molecules,
chemical bonds. It can be seen from the table that, for example,
hydrogen nuclei tightly bound in fat or protein molecules relax
much faster than protons weakly bound in water molecules.
NMR
imaging - MRI
The NMR method originally served as an analytical method
for the composition and structure of samples. Advances
in electronics and computer technology in the 1970s and 1980s
made it possible to use the NMR signal to create an image
of proton density in an object under investigation. This
created the NMR imaging method (NMRI - Nuclear
Magnetic Resonance Imaging; the word "nuclear" is often
omitted and the abbreviation MRI is used ) -
Fig.3.4.4d.
In order to be able to detect
NMR signals separately and locally from
individual places of the examined object (organism or tissue) and
use it to create an image , it is necessary to
ensure spatial-geometric coding of coordinates
in the examined object. This can be achieved by the main constant
homogeneous field B by superimposing an additional gradient
magnetic field in the axis direction X, Y, Z. These gradient
magnetic fields in the direction of each X, Y, Z axis are
generated by a respective pair of gradient coils.
By changing the gradient magnetic field, we achieve that the
magnetic resonance will always occur in a different place of the
examined object. By this gradient magnetic coding of spatial
coordinates we can then perform NMR imaging.
Gradient coils
are "additional" electromagnets located in suitable
places inside the main strong electromagnet. They are wound with
copper wire or metal tape, dimensioned for relatively high
currents of tens or hundreds of amperes. Gradient coils are
supplied in pulse sequences with a relatively strong current
(approx. 500A) from electronically controlled sources, which
allow fast and accurate setting of the strength and direction of
the excited magnetic field - an additional gradient field. They
produce gradients in the range of about 20-100 mT / m. In order
for MRI imaging not to take an enormously long time, the rate of
gradient changes needs to be relatively high - it reaches about
100-200 Tm -1 .s -1; it requires a certain
voltage (approx. 50-300V) to overcome the inductance of the
gradient coils - the power supplies of the gradient coils are
relatively robust (power). Strong current surges in the gradient
coils when interacting with the magnetic field cause mechanical
vibrations , which causes considerable noise
during MRI. Longitudinal gradient coils (in the Z
direction ) have turns wound in the same direction as the main
coil, X (gradient in the left-right direction) and Y
(gradient in the up-down direction) are formed by saddle-shaped
coils with vertically wound turns.
Note
first the longitudinal gradient field B z (z) in the Z
direction . His superposition with the main mag. field B o causes the actual
"local" value of the magnetic field B
= B o + B z (z) to depend on the z coordinate : B
= B (z). If we send a high-frequency pulse of a
certain frequency f to a sample placed in this slightly
inhomogeneous gradient magnetic field , the magnetic resonance
signal will be transmitted by atomic nuclei only from a thin
layer of the sample with coordinate z , for which
the resonance condition f = g .B (z ) / 2 p . By changing the frequency f of high-frequency
excitation pulses, or the intensity of the longitudinal gradient
field B z , the position of the layer in which the
magnetic resonance response signal is generated changes . In this
way, information about the dependence of the spatial distribution
of the density of the nuclei in the direction of the Z
axis is captured - the electronic-geometric coding of this
coordinate is achieved - the layer z .
The representation of the spatial distribution of the
density of nuclei in a given layer z in the transverse
directions X and Y is then obtained by the action
of another, transverse, gradient magnetic field in the direction
of the X and Y axis, whereby the investigated layer decomposes
into elementary volumes - " pixels"In
which the determined intensity of the dependence of the
relaxation of the NMR signal, and also the decay time. Changing
these gradient fields to obtain data for each place in the layer of
and computer reconstruction of the obtained cross-section
image of proton density of the examined layer from
(obr.3.4. 4d right). electronic analysis of relaxation times of
the NMR signal is also generated even images of cross sections in
relaxation times T 1 and
T 2 (referred to as T
1 or T 2 - weighted images). a plurality
of images of cross sections for the different values are from
then creates 3-dimensional tomographic imageinvestigated
areas in proton density and relaxation times in individual "
voxels ". Using computer graphics, it is
then possible to create images of any sections of the examined
area, which are brightly modulated in a wide range of shades of
gray (from white to black), to distinguish the structure of
tissues and organs.
The basic subject of NMRI
imaging is hydrogen nuclei - imaging of proton
density and relaxation times. This is why NMRI is sometimes
referred to as " hydrogen topographic imaging
". The intensity of such an NMR image mainly reflects the
amount of water at each locationin the examined
tissue and the nature of the binding and distribution of hydrogen
molecules in the cells and extracellular space, as well as the
distribution of fat and proteins. Based on these structural
differences, different tissues can be distinguished
from each other in MRI images - such as water, muscle, fat, gray
matter and white matter in the brain.
In general, two basic
information is captured locally in NMRI images :
1. Density distribution of nuclei
producing nuclear magnetic resonance - most often the proton
density of PD hydrogen in the tissue. PD images
essentially capture the anatomical structure of
tissues and organs, and are largely similar to CT X-rays, which
map the electron density of tissues.
2. Distributionrelaxation times
T 1 and T 2 related to the chemical
composition and structural state of the
tissue in individual places. Such images are called T 1 and T 2 - weighted
.
The extent to which the proton
density PD will be represented in the resulting MRI image, the
times T 1 and T 2 - how and how this image will be
modulated - " weighted
" - is determined by pulse sequences : time
sequence of transmitted RF pulses and "echo" response
signals (will be discussed in more detail
below) .
Fig.3.4.5 MRI images of the brain (transaxial
section, without pathology) in proton density, relaxation times T
1 and T 2 and in a special FLAIR sequence
to suppress the water signal.
(MRI brain images were taken by Jaroslav
Havelka, MD, head of the MRI RDG department at the University
Hospital Ostrava )
Proton densities and especially
relaxation times are different not only for
different types of tissues (see table above), but also differ
depending on the physiological or pathological condition of the
same tissue. This makes NMRI imaging an important diagnostic
method in medicine , including in the field of cancer
diagnostics.
Note:
As with X-ray diagnostics, NMRI uses contrast agents
to increase the contrast of images of certain structures (eg
cavities or blood vessels) , but not on a density but on a
magnetic basis - ferromagnetic compounds ,
mostly based on gadolinium . Pulse sequence in NMRI
In medical MR imaging, it is desirable to create images with
sufficient high contrast between different
tissue types so that the MRI radiologist can best answer the
clinical diagnostic question. Optimal image contrast between
different tissues with different densities and rexation times can
be achieved by suitable excitation of magnetic moments of nuclei
and subsequent measurement of their response MR signal: by
setting parameters of pulse sequence - time
sequence of transmitted electromagnetic excitation pulses RF
cores. The first parameter here is the intensity
(energy) of the transmitted radio frequency excitation pulse ( RF)),
which determines the predominant angle of deflection (tilt) of
the magnetization vector of the analyzed nuclei - 90 ° or 180
°. The higher the excitation intensity radiated into the
analyzed target tissue, the higher the percentage of mag flips.
torque and the stronger the response signal and more time is
needed for relaxation. Another parameter is the time interval TR
, in which we repeatedly apply individual
radiofrequency excitation pulses. The shorter this interval, the
less time there is for T1 relaxation. The third parameter is the
time TE (echo time)between the excitation pulse and the detection of the
response resonant signal. The longer this time, the less nuclei
with a shorter relaxation time T2 will contribute to the measured
resonant signal. The fully indicative values ??of the pulse
sequence times for obtaining the basic types of MRI images at B =
1.5 T are :
PD: TR
= 1000 ms, TE = 5-30 ms; T 1
-weighted: TR = 10 ms, TE = 5-30 ms; T 2 -weighted: TR = 1000-2000 ms,
TE = 80-100 ms.
In connection
with these addictions, several significant sequences of
transmission of excitation radiofrequency pulses and subsequent
detection of response relaxation signals have been developed (sometimes called "MRI techniques "
in MR jargon ) :
-> Saturation - recovery sequence in which
90 ° RF pulses are transmitted at regular intervals. Upon
arrival of each RF pulse, the magnetization vector rotates 90 °
and relaxation begins with different times T 1 in different tissues. When
another RF pulse arrives, the z-component of the magnetization
will be different in different tissues. With a suitable
repetition period TR of excitation RF pulses, we can set the
optimal contrast of the desired tissues at times T 1 . This simplest MRI technique is
now rarely used, it has been replaced by the inversion-recovery
sequence below, providing higher contrast.
-> Spin - echo a sequence consisting of a
90 ° RF pulse followed by a 180 ° RF pulse. After the
magnetization vector has been flipped into the xy plane due to a
90 ° RF pulse, T 2 (resp.
T 2 *) relaxes,
during which phasing occurs. However, the subsequent 180 ° RF
pulse has a "refocusing" effect - it flips the
individual spins in the xy plane by 180 ° and the spins are
phased again. The result is an echo signal in the receiving coil,
the amplitude of which depends on the relaxation times T 1 and T 2 of
the tissue (unfavorable
T2 * does not apply here, because the effect of magnetic field
inhomogeneity on phasing is eliminated by 180 ° pulse phasing) . The character and contrast of the display can be
adjusted using the times TR and TE. With short TR and short TE we
get T 1-weighted
image, long TR and short TE provide a proton density image, long
TR and long TE provide a T 2 -weighted image. Due to this variability of imaging
options, spin-echo is the most commonly used MRI
technique.
-> Inversion - recovery sequence,
consisting of a sequence of 180 ° and the following 90 ° RF
pulse. The initial 180 ° pulse inverts the
magnetization vector to the opposite, after which T 1 relaxation takes place . With a
time interval TI - inversion time , a
90 ° RF pulse then follows, which flips the magnetization vector
into the xy plane. A RF signal dependent on T 1 is detected in the receiving
coilrelaxation time of the displayed tissue. The contrast of the
image can be adjusted appropriately using the TI time. A
significantly more contrasting image can be achieved than with
the saturation recovery technique.
By a special setting of the time T1 = T 1 .ln2, the suppression of the image of
the tissue having this relaxation time T 1 is achieved . By setting the short inversion time TI
(approx. 140ms with a 1.5T magnet) - the so-called short
time inversion recovery STIR - the suppression
of the fat signal is achieved in the image . Conversely,
by extending the time TI (to about 2600ms) - fluid
attenuation inversion recovery FLAIR - we can achieve suppression
of the water signal. Other fine details and anomalies in
the structure of the examined tissues can then be better assessed
on such "cleaned" images.
-> Gradient - the echo sequence begins
with a 90 ° RF pulse (which tilts the magnetization vector to
the xy plane), after which a magnetic field gradient is applied.
The nuclei in adjacent atoms will thus show a precession with a
slightly different Larmor frequency, which will cause spin
phasing. The application of the second mag. gradient with the
opposite sign, which rephases the spins and at this point the
echo is measured. Used to obtain a T 2 -weighted image.
->
..........
sequence ............ ? add more sequences? ........... ?
complete the picture of the graphic sequence diagram? ...
Computer analysis of MRI
images obtained with appropriate sequences (mentioned
above) can create special image
modulations - such as water or fat signal suppression images
. Other special sequences are used for functional
MRI (mentioned below) :
->
Susceptibility weighted imaging ( SWI
) shows tissues with slightly different magnetic susceptibility.
It uses an extended gradient-echo sequence for display in T 2 * . Its
main variant is Blood oxygenation level dependent
(BOLD) , see fMRI
below .
->
Diffusion weighted imaging (DWI)shows the diffusion of water inside tissue
elements, manifested by Brownian motion of molecules. Using a
spin-echo sequence with the application of 2 gradients, a subtle
effect is registered, in which Brownian-moving water molecules
show a different phasing-phasing relationship when reversing the
mag. gradient; this leads to a slightly weaker T 2 signal.
MRI Magnetic Resonance
Spectrometry MRI
Magnetic resonance imaging (MRS) can be supplemented by the magnetic
resonance spectrometry (MRS) described above, which
enriches this examination with additional physiological
information . Chemical analysis is
performed here by analyzing the chemical shift of the
Larmor frequency imaging structures in-vivo, eg choline or lipid
levels. Chemical shifts are very fine, so this method is
demanding not only in terms of signal analysis, but also requires
high intensity (recommended at least 3 T) and homogeneity of the
magnetic field.
Functional magnetic
resonance imaging - fMRI
Magnetic resonance imaging may be a suitable method for
non-invasive imaging of the function of various
tissues and organs (along with "molecular" imaging in
nuclear medicine - .....). So far, fMRI has found application
mainly in functional brain imaging , mapping neuronal
activity . Neurons (which do not
have internal energy stores)they need to
get sugar and oxygen quickly for their increased activity. The
hemodynamic response to this need causes an increase in blood
perfusion at a given site, but mainly a greater release of oxygen
from the blood than inactive neurons. This leads to a change in
the relative levels of oxygenated oxyhemoglobin and
non-oxygenated deoxyhemoglobin in the blood at sites of neuronal
activity.
In this respect, two basic
methods of indirect mapping of neuronal activity are used:
-
Local increase of perfusion
at the site of increased neuronal activity - perfusion fMRI
.
-
Change in the ratio
of oxygenated and non-oxygenated blood at the site of
neuronal activity. The method is called BOLD fMRI
(B lood Oxygen Level Dependent). Changes
in the relative levels of oxy- and deoxy-hemoglobin can be
detected based on their slightly different magnetic
susceptibility. Basic hemoglobin without bound oxygen
(deoxyhemoglobin) has slightly paramagnetic properties,
but when oxygen is bound to it (oxyhemoglobin), it behaves
slightly diamagnetically . If more deoxyhemoglobin
accumulates at a certain site in the brain tissue, a slightly
stronger MRI signal is obtained from it than from the sites where
deoxyhemoglobin predominates.
MRI functional imaging of the brain is
performed after neurological activation , either
motor (eg movement of fingers) , visual, linguistic or cognitive.
The
physical-electronic implementation of NMRI
NMR imaging isthe most complex imaging
method. The operation of the device for NMR imaging is
electronically very complicated and demanding, so it must be
controlled by a powerful computer with
sophisticated software - Fig.3.4.4d. In the multiplex
mode , the process of transmitting a sequence of radio
frequency pulses, modulation of gradient magnetic fields, sensing
and analysis of relaxation signals of magnetic resonance,
reconstruction and creation of the resulting images, as well as a
number of other transformation and correction procedures are
synchronously controlled. Since these are harmonic (sinusoidal)
waveforms, scanning and reconstruction are performed using Fourier
analysis - in the frequency so-called K-space.
It is a set of matrices defined in the memory of the MRI
evaluation computer, into the individual elements of which the
frequencies, amplitudes and coordinates of MRI signals are
recorded. From these "raw" data, the resulting MRI
images are created using Fourier transform and other
analytical methods.
Note:
Electron paramagnetic resonance (EPR) is based on a
similar principle as NMR . The magnetic moments of the electron
shells of atoms are used here .........
3.5.
Radioisotope tracking methods
Radioisotope tracking or indicator
methods are used to monitor the hidden movement and distribution
of matter within physical, chemical or biological systems, or in
various technological devices. A suitable "labeled"
substance with bound radionuclide is introduced into the system -
the so-called radio indicator , whose movement
and behavior in the system is then monitored on the basis of
detection of ionizing radiation emitted during radioactive
transformations of nuclei in the radio indicator. The movement
and distribution of the radio indicator can be monitored in two
basic ways :
Radioisotope tracking methods are used in many
fields of science and technology, industry, agriculture and
especially medicine. Here we will briefly mention a few technical
and general biological applications, we will focus in more detail
below on applications in nuclear medicine.
Radioisotope
tracking methods were first tested in 1913 by the
chemist G.Hevesy, who found that radioisotopes have the same
chemical behavior as stable isotopes of the same
element. However, unlike stable isotopes, radionuclides can be
"visible" through the penetrating radiation
generated by the transformation of nuclei.
Radioisotope
scintigraphy and nuclear medicine
Nuclear medicine is a field dealing with diagnostics
and therapy using radioactive substances
in open form , applied to the internal environment of
the organism.
Radioactive isotopes react chemically
in the same way as stable isotopes of the same element -
therefore they behave in the organism's metabolism in the same
way as non-radioactive isotopes of a given element. However, due
to the fact that radioactive isotopes are "visible"
through penetrating radiation, which arises during radioactive
transformations of their nuclei, it is possible to monitor
the movement and metabolism of elements and compounds
containing radionuclides - radioindicators - in
the body and thusinvestigate the functions of
individual bodies. Depending on the organ whose function is to be
examined, the specific substance ( radiopharmaceutical )
shall be labeled with an appropriate radioisotope. After
application to the body, the movement and metabolism of this
substance is monitored - either by imaging with a gamma camera or
by measuring the samples taken (blood or urine).
Radioisotope
diagnostics in vivo - scintigraphy
In radionuclide diagnostics in vivo in nuclear medicine,
the patient is administered (usually intravenously, sometimes
orally or by inhalation) a small amount of a suitable g -
radioactive substance - the so-called radioindicator
or radiopharmaceuticals. The radioindicator used is specific to
individual organs and types of examinations. The applied
radioactive substance enters the metabolism of the
organism and is distributed there according to its
chemical composition - physiologically or pathologically it accumulates
in certain organs and their parts and is subsequently excreted or
regrouped. Gamma radiation emanates from the deposition
sites of the radioindicator , which, due to its penetration,
passes through the tissue out of the organism. Using sensitive
detectors, we measure this radiation g and thus determine the
distribution of the radioindicator in individual organs and
structures inside the body.
The most perfect devices of
this kind are gamma cameras (scintillation cameras) -
using themwe display in radiation g the distribution of the
radioindicator in the organism. This method, called scintigraphy
, thus makes it possible to obtain not only anatomical
information, but mainly to tell about organ functions and
metabolism. By mathematical evaluation of scintigraphic studies,
we can obtain curves of the time course of the radioindicator
distribution and calculate dynamic parameters
characterizing the function of the relevant organs.
Schematic imaging of the entire process of
scintigraphic examination - from the application of a radio
indicator to the patient, through the process of scintigraphic
imaging with a gamma camera, evaluation, mathematical analysis
and quantification, to the interpretation and diagnosis.
The tomographic SPECT
(Single Photon Emission Copied Computerized Tomography) gamma
camera slowly rotates around the
patient's body, scans scintigraphic images from various angles
and then uses computer reconstruction to create cross-sectional
images (sections perpendicular to the camera's axis of
rotation), from which computer graphics can be used to construct spatial
(3-dimensional) images of the distribution of the radio indicator
in the organs inside the body.
The PET gamma camera
(Positron Computerized Tomography) detects photons of
gamma annihilation radiation (511 keV energy)
flying in opposite directions during the annihilation of
positrons emitted by b +radioindicator
administered to the patient. These photons of annihilation
radiation are coincidentally detected by an
annular scintillation detector, and by computer reconstruction of
the line projections of the coincidence sites, images of
cross-sections are generated and, if necessary, 3D images similar
to SPECT.
Nuclear medicine provides
specific methods for the examination of virtually all organs and
thus cooperates with a wide range of clinical disciplines. The
most widespread use is mainly in cardiology , nephrology
, neurology , oncology , thyrology , gastroenterology
.
Nuclear medicine methods are
among the least burdensome non-invasivediagnostic
examination methods. Due to the high sensitivity of the
detectors, only a very small amount of radiopharmaceutical is
applied to the patient, which is needed to obtain quality image
information. The radiation exposure in methods in nuclear
medicine is comparable (and often smaller) as in X-ray
examinations *).
*) During X-ray examination, the source of
ionizing radiation is a device and the radiation dose depends,
among other things, on the number of images performed or on the
extent of the area scanned during CT. In scintigraphy, the source
of radiation is not a diagnostic device, but the patient himself,
resp. its investigating body. Thus, we can take any number of
scintigraphic images without changing the radiation exposure of
the patient.
Radionuclide scintigraphy is described in detail in
Chapter 4 " Radioisotope
scintigraphy " .
Radiation-guided surgery - sentinel nodes
An important radioisotope tracking method of nuclear medicine is
local radiation measurement with a closely collimated miniature
gamma-ray detection probe in radiation-guided surgery in the
detection of so-called sentinel nodes .
In the surgical treatment of cancer, it is important to remove
not only the primary tumor, but also, if possible, other tissues
into which the tumor cells could be infiltrated. These tumor
cells spread from the primary site mainly through the lymphatic
pathways, so that the lymph nodes around the
tumor site are the first to be affected . If we apply a suitable
radioindicator of colloidal state to the peripheral part of the
tumor lesion (most often 99mTc nanocolloid, particle size approx. 50-600 nm,
activity approx. 40-150 MBq), will propagate through the
lymphatic pathways and capture and accumulate in
those nodes that are lymphatically associated with the tumor
site. The first such node in the lymphatic "basin" of a
tumor foci is called the sentinel node . The
accumulation of the radio indicator in the nodes can be displayed
scintigraphically. However, the most important thing is to
monitor the radioindicator during the actual surgical procedure,
when using a collimated detection probe, the surgeon can find a
sentinel node containing the radioindicator directly in the
operating field.
*) Along with the radioindicator, a blue
dye is applied at the same time, which also penetrates the nodes,
so that the surgeon can recognize the sentinel node by its blue
color.
After application of the
radioindicator, scintigraphic imaging is performed with the
imaging nodes drawn, then the patient goes to his own surgery
, during which a detection gamma probe is used both for
perioperative sentinel node detection and for radioactivity
detection in an already operated node. This is followed by
histological examination of the sentinel node to classify the
type of tumor, which will help optimize the further course of
therapy.
In vitro diagnostics. Radioimmunoassay
- radiosaturation analysis
In nuclear medicine, in vitro radioisotope diagnostic methods
are also used , where (non-radioactive) samples taken from
patients are analyzed using radioisotope
techniques - radiochemical and at the same time biochemical. Most
often it is a radioimmunoassay ( RIA
) or radiosaturation analysis (RSA), which is
used to highly sensitively determine the concentration of complex
biological substances in the blood serum - hormones, tumor
markers and other biologically important substances . It is based on an immunochemical
reaction antigen with a specific antibody (Ab -
antibody). A competitive immunoreaction is used in which
the radiolabeled Ag * antigen "competes" for binding
sites on the antibody (which is present in a limited amount in
the reaction mixture) with the unlabeled antigen. An appropriate antibody
labeled with the appropriate Ag * radionuclide
(usually I-125 radioiodine ) is added to the
sample analyzed.), which reacts with the hormone
to form an insoluble Ag * -Ab complex. After removal of the
unbound fraction (rinsing with water), a compound remains in the
sample, the activity of which will depend on the concentration of
hormone in the analyzed sample - the amount of labeled
antigen-antibody Ag * -Ab complex is inversely proportional to
the concentration of antigen to be determined. The more test
substance present in the primary sample, the smaller the amount
of labeled Ag * -Ab antigen-antibody complex formed and the lower
the activity in the final sample. It is measured in a well
scintillation detector (see §2.7, section
" Automatic
measurement of a series of samples ") . These methods are of
great importance for endocrinology.
...................fill in
RIA or RSA methods reached their greatest
development in the 1970s and 1980s, when they were widely
performed in radiochemical RIA laboratories in
the departments of nuclear medicine. Then they gradually moved
from nuclear medicine workplaces to clinical biochemistry
laboratories . Since the 1990s, they have been gradually extruded
and replaced by fluorescent and chemiluminescent optical methods,
without the use of radionuclides and ionizing radiation ...
Radioisotope
therapy
In addition to diagnostics, nuclear medicine also includes therapy
with open radionuclides, eg treatment of hyperthyroidism and
thyroid cancer, blood diseases, palliative and curative therapy
for various types of tumors, joint diseases - see below for more
details in §3.6 "Radiotherapy", part " Radioisotope therapy ".
Nuclear medicine -
interdisciplinary field
Nuclear medicine is due to the physical nature of its methods
and instrumentation used branch interdisciplinary .
Besides doctors (specialist and
board-certified nuclear medicine) , nurses
and laboratory technicians, are working in teamwork as
well as experts from other professions - physicist , electronics
, radiochemik , pharmacist . Along with medical and
physical-technical aspects, considerable attention is also paid
to radiation protection of workers and patients in the
workplaces of nuclear medicine when working with radioisotopes (see Chapter 5 "Biological
effects of ionizing radiation. Radiation protection ").
A detailed description of the
principles, methods and clinical use of nuclear medicine is in
Chapter 4
" Radioisotope scintigraphy " .
Autoradiography
- photographic representation of the
distribution of the beta-radioindicator in the examined
preparations in close contact of the photographic
emulsion with the sample is described in §2.2 " Photographic
detection of ionizing radiation ", passage " Autoradiography ".
3.6.
Radiotherapy
Radiotherapy is a physico-medical field using the biological
effects of ionizing radiation for therapeutic purposes.
The vast majority of it is a therapy for cancer - radiation
oncology , to a lesser extent, some degenerative and
inflammatory disorders are treated with radiation. Recently,
so-called radiosurgery has sometimes been used ,
especially for vascular and neurological malformations (see the " Stereotactic radiotherapy
" section) . Before we focus on our
own radiotherapy, we will mention some biological aspects of
cancer, diagnostics and non-radiation therapeutic methods
(chemotherapy, biological therapy) - to put the issue in a
broader context.
Tumors - their nature and origin
Tumors, especially malignant, are among the most common and most
serious diseases, threatening the health and lives of patients.
During the formation of a tumor, pathological tissue mass ( neoplasm
) is formed , usually irreversible, in which uncontrolled
proliferation of tumor cells takes place ,
at the expense of healthy tissue; there is no feedback in the
body to stop this growth. Tumor cells can grow into the
surrounding tissue and migrate through lymphatic or blood vessels
to other parts of the body (establish metastases ). With
its uncontrolled division of the meat of tumor cells, it
suppresses the surrounding healthy tissue, disrupts it and can
thus disrupt the function of important organs. The cause of such
a condition it is not exactly known *) , it lies deep inside the cell
structure, probably in mutational changes in DNA.
Prevention and causal treatment of cancer is therefore difficult.
*) Only some risk factors were
observed, which contribute to the development of tumors or
increase the probability of their occurrence. They are various
chemical substances, so-called carcinogens
, such as some cyclic hydrocarbons and cigarette smoke, the
composition of food. Or biological effects - some viruses
(so-called oncoviruses ), whose RNA can (via so-called reverse
transcriptase) enter the DNA of eukaryotic cells and alter
their genetic information, they can cause tumor transformation of
cells (or they may not lead directly to tumor formation, but
prevent an immune response that would be able to recognize tumor
cells and destroy them). Then there are genetic
factors , hereditary predisposition ( hereditary genomic
imprinting eg in Nyemegen syndrome, Ataxia teleagiectasia,
Bloom's syndrome, Fanconi anemia, Xeroderma pigmentosum,
Li-Fraumeni syndrome of the mutated TP53 gene encoding p53); it
is caused by a specific mutation in the tumor suppressor
genes (TP53 gene mutation in Li-Fraumeni syndrome, NF1,2 in
neurofibromatosis, BRCA1,2 in hereditary breast and ovarian
cancer, APC in colorectal polyposis, WT1 and Wilms' kidney tumor,
RB1 in retinoblastoma, MLM gene mutation in malignant melanoma).
Of the physical influences, it is ultraviolet radiation
acting on the skin and especially harder ionizing
radiation , as discussed in detail in §5.2 " Biological effects of ionizing radiation ".
Carcinogenesis
- the formation of tumors
Under normal circumstances, a multicellular organism is a system
of individual tissues and organs, consisting of a large number of
cells, performing their function in a harmonious community for
the benefit of the whole organism. This cooperation and
"social behavior" of cells is ensured by very complex
and complex regulatory processes, including signals from
monitoring the external environment, transmission of signals to
the internal environment of the cell, cellular response,
evaluation of signals and their coordination with other signals.
Cells that do not fit into this regulatory mechanism (due to
damage or loss of their function) are eliminated by the
mechanisms of "programmed" cell death, apoptosis.
Also, cell proliferation is precisely controlled to meet the
needs of the tissue and the organism - dynamic balance, tissue homeostasis
. Disruption of regulatory mechanisms can cause various
pathological conditions and diseases of the body. One of them is
a violation of the regulation of cell division: in some cell a
genetic change (mutation) occurs that allows it to survive,
divide and produce daughter cells that do not "listen"
to the regulatory mechanisms of tissue homeostasis. This can
create a gradually expanding population of mutated cells - a
clone of tumor cells , multiplying at the
expense of healthy tissue.
Tumor formation ( carcinogenesis ) is a complex
multi-step process in which several mutations gradually
accumulate, which do not harm the altered cells, but on the
contrary favor them and allow their rapid division regardless of
the needs of the organism. The following factors are important
for the origin and development of cancer :
¨ Cell cycle deregulation
To maintain tissue homeostasis (a balanced number of
functional cells of a given tissue) it is necessary to control
the rate at which cells form, develop and die - cell
cycle regulation. Due to some mutations, autonomic
growth (mitogenic) factors in the cell, their autocrine
production, or loss of sensitivity to signals that stop the cell
cycle may occur. In particular, p21 and p27
proteins are involved in cell cycle regulation and division ,
which may bind to and inhibit the activity of certain kinases
(serving as regulators of DNA replication and cell division); the
content of these regulatory proteins in tumor cells tends to be
reduced. On the contrary, the activity of some kinases (§5.2, section " Cells
- basic units of living organisms
", passage " Proteins, enzymes, kinases
") is increased in tumor cells. It is
mainly a tyrosine kinase - an enzyme which
transfers phosphate to the hydroxyl group of the cyclic amino
acid tyrosine, thereby affecting the function and activity of the
protein in question. Increased epidermal growth factor receptor
( EGFR ) tyrosine kinase activity leads to
increased intracellular signaling, disrupting cell cycle
regulation. This increased EGFR activity may be due to increased
expression of the EGFR ligand (which is the epidermal growth
factor EGF), or by a mutation in the EGFR tyrosine kinase domain
that results in sustained ligand-independent activation of the
mutated receptor. Another receptor which promotes cell growth and
division, the epidermal growth factor receptor HER2 (Human Epidermal Receptor) , also called erbB2 , in the increased presence
of which there is an excessive division of cells, which can lead
to the formation of a tumor. Also, deregulated signal
transduction through the P3K / Akt / mTOR
phosphatidylinositol-3-kinase signaling pathway provides
cells with stimuli for unrestricted growth and survival, which
can lead to tumor growth.
Disruption of cell cycle
regulation can lead to the proliferation of such altered cells
independently of the environment, independent of the needs of the
tissue and the organism - it is usually the first stage of
carcinogenesis.
¨ Inhibition of apoptosis
Another important mechanism for maintaining tissue homeostasis is
the regulation of the rate at which "excess" cells in
the tissue population die. The usual way in which cells undergo
controlled death is apoptosis
(described in more detail in §5.2, section
"Effect of radiation on cells", passage " Mechanisms
of cell death ", where
the internal and external signaling pathways of apoptosis are
discussed) - "programmed" cell
death, actively controlled by the cell . The apoptotic
program is potentially present in all cells, it is triggered by
internal signals (DNA damage, hypoxia, ...) or external
"death signals" that the cell receives from regulatory
mechanisms in the tissue. Properly functioning apoptosis,
triggered by external regulatory mechanisms from the tissue,
provides effective protection against excessive cell
proliferation. Apoptosis triggered by internal mechanisms then
acts as a protection against the survival and proliferation of
mutated cells with damaged DNA. Inhibition (blocking,cells -
allows developing tumor cells to survive and multiply, despite
the body's interest. Apoptosis can be disrupted, for example, by
altering the TP53 gene encoding the p53 protein, increasing the
concentration of the anti-apoptotic Bcl-2 gene in mitochondria (protecting mitochondrial membranes - preventing cytochrome
c penetration and caspase chain triggering proteolytic
degradation in the cytoplasm) and other
unexplored factors. .
Note: This is
mainly a suppressed apoptosis induced by external
regulatory mechanisms of the tissue. However, with strong
irradiation of tumor cells, which causes severe irreversible DNA
damage, internally activated apoptosis occurs .
¨ Immortilization
of cells
Most common somatic cells can only reach a certain limit
in the number of their divisions, the so-called Hayflick
limit (about 40-60 cycles); then the cells lose their
ability to divide . This is due to mitotic
shortening of DNA telomeres (about cell cycle, telomere
shortening, cell senescence, apoptosis, etc. see also §5.2
" Biological effects of ionizing radiation ") . This limit in the number of divisions
would automatically stop the growth of the tumor population.
Increased occurrence of an active enzyme called telomerase
(in co-production with tankyrase ), or mechanisms of
homologous recombination of telomere sequences (discussed in
§5.2, part "
DNA, chromosomes, telomeres"), however, they are able to
ensure complete replication of DNA ends (prevent telomere
shortening) - gaining unlimited
replication potential , so-called immortilization
-" immortality "of cells. Unregulated and unrestricted
division of clonogenic tumor cells disease.
¨ Inhibition of immunogenity
The immune system is fundamentally capable to recognize tumor
cells and destroy them. Some tumor cells, however, they lose
their immunogenicity *) or the immune system is impaired - these
cells are outside the control of the immune mechanisms and may
cause their uncontrolled proliferation. *)
Many tumor cells have the CD47 protein on their
surface, which protects them from white blood cells
(physiologically, this protein occurs on the surface of blood
cells to protect them from its own white blood cells) and
therefore cannot be destroyed by the immune system.
¨ (neo)Angiogenesis
In the initial stages (tumor size up to about 0.5-1 mm), tumor
cells are supplied with oxygen and nutrients by diffusion from
the surrounding intercellular environment of the tissue in which
the tumor grows. As the number of tumor cells increases, this
supply is no longer sufficient - there is hypoxia of the
tumor tissue, accompanied by the expression of special interleukins
, especially HIF1 ( hypoxia-iducible transcription factor
), inducing the production of vascular endothelial growth
factor VEGF (as well as VEGF mRNA expression). The
regulatory mechanisms in the tissue can respond to this by angiogenesis
- the formation of new blood vessels, ensuring the blood supply
to the tumor tissue and its rich supply of oxygen and nutrients,
as well as flushing out metabolic waste. Tumor growth is
dependent on angiogenesis - it necessarily requires a sufficient
supply of nutrients and oxygen, which are provided by newly
formed blood vessels. Each increase in tumor volume is associated
with the growth of new capillaries.
N adore neo-angiogenesis or neovascularization
is an important milestone in the progression of cancer, allowing
tumors to grow to macroscopic size, threatening tissue and whole
organism. Blood flow to the tumor tissue also allows the spread
of tumor cells through the bloodstream - the formation of metastases(see
below).
The issue of carcenogenesis is
very complex, with a number of unexplored factors. In addition to
mutations of known and coding genes in DNA, so-called " genetic
litter " or " unnecessary DNA "
sequences can also be used , which can act as regulatory
"triggers" or "switches" of intracellular
processes via the respective RNAs (see also
§5.2, part " DNA, chromosomes, telomeres ") .
Types of tumors
Tumors and tumors disease (often collectively referred to as carcinoma
or cancer ) are characterized by a large number of
species and great variability. They are divided according to
several criteria :
l According to health severity
× Benign tumors (lat. Benignus = harmless, friendly, generous )
are usually localized and isolated from the
surrounding tissue by encapsulation, do not grow into other
tissues and do not form distant metastases. They do not have to
create major damage or difficulties for the organism (they can
often remain in the tissue - but beware of the risk of malignant
collapse!), If necessary, they can usually be successfully
surgically removed.
× Malignant tumors (lat.
malignus = evil, evil-bearing ) ,
or tumors (lat. tumor
= swelling, swelling ) , grow destructively
and infiltratively - tumor cells grow into the
intercellular spaces of the surrounding tissues (which suppress
and disrupt), the cells are released and spreads through the
blood or lymphatic route to other tissues and organs, where they
often form distant secondary "daughter deposits",
so-called metastases (Greek
meta = change, stasis = place ® change of place,
relocation ) . Even after removal of
the primary tumor site, metastases can continue to grow and form
more metastases. Due to metastatic spread (
dissemination ) can lead to the
uncontrolled spread of the disease, often to the whole organism (
generalization ).
l According to the organ from which the
tumor primarily originates
- eg breast, lung, bronchogenic, prostate, etc. Some
types of tumors have, depending on the place of origin and
origin, special names with the suffix " -om "
- eg melanoma or melanoblastoma (skin cancer) .
melanocyte cell tumor), glioma or glioblastoma (primary
brain tumor, also astrocytoma ), lymphoma
(tumor growth of lymphoreticular tissue), etc. A malignant tumor
of hematopoietic tissue, manifested by an increase in white blood
cells (which are immature and do not perform their normal
function), is called leukemia .
l According to the location of metastatic
involvement - eg metastasis of breast cancer to the
liver, skeleton, etc.
l By tissue and cell nature
- Epithelial tumors
called (in the narrower sense) carcinomas are the most
common type of cancer. According to the cell layer from which
they originate, they are further divided into squamous cell
and basal cell carcinomas (these names come from skin
tumors).
According to the microscopic appearance of cancer cells (for
histologic observation) and shape of the tumor growth is
sometimes used designation papillary (warty - tumor
forming warty or fimbriate formations), tubular (forming
a tubular structure), medullary (bone marrow), ductal
(PTO), lobular (lobe ) and the like.
Benign tumors arising from the glandular epithelium are called adenomas
.
- Mesenchymal tumors , called sarcomas ,
come from connective tissues. They occur less often.
The resulting terminology of
specific types of tumors is often formed by combining the names
of individual categories - eg prostate adenocarcinoma , osteosarcoma
in the skeleton, etc.
Anatomical extent -
progression - cancer (staging)
To assess the possibilities of optimal therapy ,
the progression of cancer is crucial - how the
tumor growth in the body has spread, how far it has penetrated. The
anatomical extent (progression, staging ) of
cancer is often assessed according to three " TNM
" criteria : T-tumor, N-nodes, M-metastases; the higher the
number, the greater the range and propagation :
T- extent of the primary tumor: T0 (no signs of
primary tumor), T1 (tumor up to 2 cm in size), T2
(2-4 cm), T3 (tumor larger than 4 cm), T4
(larger tumor growing into other structures).
N - presence and extent of infiltration in
regional lymph nodes: N0 (no infiltration in nodes), N1
(metastasis in one node, <3cm), N2 (bilateral
metastases <6cm), N3 (metastases> 6cm).
Alternatively, N2 indicates 2-4 and N3 more
than 4 metastases in regional nodes. There are different T and N
numbering conventions according to the type and location of the
tumor.
M- presence of distant metastases: M0- without
metastases, M1 - occurrence of distant metastases.
Tumor TNM classification is
not used for hematological and lymphatic malignancies (leukemia,
lymphomas), which are not localized but diffuse.
A simpler classification of
the progression is into four stages of cancer,
also called FIGO classification ( Federation International of Gynecology and
Obstetrics ) :
Stage I. - a smaller tumor site with local growth,
without any dissemination (corresponds to T1, N0, M0).
Stage II.- larger tumor with local growth, without
dissemination or with minimal regional infiltration (corresponds
to T2, N0-1, M0).
Stage III . - large local
tumor with regional infiltration (T3-4, N2, M0).
Stage IV. - tumor involvement with
infiltration into other tissues or with distant metastases
(corresponds roughly to T2-4, N2-4, M1).
The choice of
treatment method and its success depend
on all these aspects . In general, the success of therapy is
greatest in isolated well-differentiated tumors in the early
stages without metastatic infiltration (eg T1-2, N0-1, M0). In
the late stages with extensive metastatic infiltration ( generalization
), treatment is difficult and usually not very uccessful ...
Degree of tumor cell
differentiation - grading
Tumor tissue cells were formed by mutation and malignant
transformation (see above " Carcinogenesis
- tumor formation ") of originally normal cells of a certain healthy tissue or
organ in which the tumor originated. Thus, they carry many of the
properties of these original cells, but some of their other
properties differ. The degree of tumor differentiation
- the extent to which tumor cells differ from
the cells of the normal tissue from which they originated - is
referred to as grading (lat. Gradus = state, degree of a particular
process ) . If the tumor cells retain
some of the properties of the original tissue that they formed
when they fell, it is a differentiated tumor. However,
tumor cells often lose the properties of the original tissue - an
undifferentiated ( anaplastic ) tumor is formed
, which is largely autonomous, without binding to the regulatory
mechanisms of the original tissue. Tumor grading is sometimes
quantified using scores : G1 (well
differentiated), G2 (moderately differentiated), G3
(poorly differentiated), G4 (undifferentiated -
anaplastic). The prostate ca system uses a multi-level Gleason
grading score system (up to 10 degrees).
The risk of cancer also
depends on the size of the tumor cells. Small
cell the tumor type usually has rapid infiltrative growth
with frequent metastatic dissemination.
Cellular heterogeneity
of tumor tissue
In the initial stages, after its formation, the tumor is formed
by a substantially homogeneous population of
mutated cells that have escaped the regulatory mechanisms of
tissue homeostasis and initiated uncontrolled division. In later
stages, however, histocytological analyzes have shown that tumor
tissue often contains two or more clones of cells
with different biological properties - it is already heterogeneous
. This is due to the increased fragility of DNA and the genetic
instability of tumor cells, which may undergo further
mutations upon repeated division . Tumor heterogeneity
complicates treatment because different parts of the tumor may
have different radiosensitivity . A similar
effect is also caused by possible hypoxia of
some parts of the tumor (see "6R"
below, section "Oxygen effect") .
The specific type and nature of the tumor can be most
reliably determined by histological analysis of a
sample of tumor tissue under a microscope. An experienced
pathologist usually recognizes the origin and type of tumor cells
*) and also whether the tissue is benign or malignant.
Histological examination should always precede therapy .
*) However, tumor cells that look similar under a microscope and
are histologically classified in the same category may have genetically
different causes malignant behavior. Regulatory
mechanisms not encoding RNA derived from as yet unexplored
"genetic litter", "unnecessary" DNA (it is
also mentioned in §5.2, section " DNA,
chromosomes, telomeres ")
may also be involved . This can significantly complicate the
chain of diagnostics ® therapy of cancer.
A more detailed classification of tumors and their
clinical properties is beyond the scope of this physically
focused discussion.
Diagnosis of cancer
The success of any therapy depends to a large extent on careful diagnosis
- both on the primary examination before treatment and monitoring
the response during therapy and subsequent long-term follow-up.
This is increasingly true of cancer. Malignant tumors are
characterized by some specific characteristics :
- They are structures with a higher density
than the surrounding tissue; also for ultrasound they usually
show increased echogenicity than the surrounding tissue.
- They consist of metabolically active cells
- they usually have increased metabolism.
- They usually have increased vascularization,
increased blood flow and increased energy consumption. However,
they may also contain hypoxic districts.
- Tumor cells may contain some general cellular antigens
on their surface, or they may carry specific antigens.
- In addition, tumor cells may contain some special
receptors in their cell membrane.
All of these features can be
used for diagnostic imaging and targeted
therapy .
×
Primary tumor
diagnosis
This involves the detection of the primary tumor, its location
and extent before surgery, as well as the detection of possible
metastases to determine the progress of further treatment. In
addition to visible or tactile superficial and shallow lesions,
primary tumor diagnosis is performed primarily using physical imaging
methods - X - ray diagnostics (planar, now mainly CT - §3.2), ultrasound sonography , radionuclide gammagraphy (planar, SPECT, now mainly PET - chapter 4 ), NMRI
nuclear magnetic resonance . Tumors located on the walls of body cavities and
tubes (stomach, intestines, uterus) can be recognized by optical endoscopic
methods. . It should be noted that none of the imaging methods alone
will determine the malignant nature of the disease!
Imaging methods must therefore be combined with biochemical
and especially histological methods (see below).
Because some tumors can
produce specific substances (either by the tumor cells themselves
or when they interact with the body's immune system), biochemical
analytical methods of blood or tissue samples are also important
. These are mainly various types of tumor markers
- complex organic molecules (mostly protein composition), whose
increased expression in the body is the result of the tumor
process - such as determining the concentration of PSA
in the prostate, or markers CA19-9, CEA, AFP. Recently, the
(immuno) histochemical determination of Ki-67
antigen (or MKI67 weighing 360 kDa; the
name comes from a study in Kiel, Kiel - clone 67 in bowl 96) , which is associated with cell proliferation - with
ribosomal DNA transcription. Furthermore, determination of the
apoptotic gene p53 (or its mutation) or the
anti-apoptotic gene Bcl-2 . Or cytological
examination by flow cytometry .
"Molecular"
gammagraphic imaging
Most imaging methods provide only morphological-anatomical
information on the presence, size and shape of tissue, differing
in density from the environment. In the CT and NMRI images, we
show the tumor mass, which with its density or proton density and
relaxation times T1, T2 differs from the surrounding tissue, but
we do not capture whether there are viable and proliferating
tumor cells in the displayed anomalous tissue . Although
gammagraphy (scintigraphy) does not excel in spatial resolution,
it captures the functional metabolic properties
of lesions - blood circulation, metabolism, drainage and other
functions of tissues and organs - at the " molecular-biochemical
" level (see §4.9.6 " Oncological radionuclide diagnostics ") . In particular PET
display distribution 18F-fluoro-deoxyglucose (FDG), or 18 F-3-fluoro-3-deoxy-thymidine (FLT), or 18 F-fluorocholine,
provides contrast images of viable and
proliferating tumor lesions.
![]() |
Example
of PET / CT scintigraphy with 18 FDG in a patient with lymphoma. (PET / CT images were
taken by |
This method is also suitable for monitoring
the response of tumor tissue to radiotherapy , as it
displays metabolically active tumor tissue, in contrast to
inactivated cells; it is thus possible to monitor the
"success" of the therapy. Among other things, it is
able to recognize tumor recurrence (with proliferating
cells) from other structures, necrotic or connective tissue. The 18 F-FMISO and 18 F-FETNIM
radioindicators show cellular hypoxia , which is
important for tumor angiogenesis and for planning radiotherapy
(radiosensitivity, oxygen effect - see below " Physical
and radiobiological aspects of radiotherapy ").
Normal whole-body
scintigram bone multiple metastases (breast ca) in the skeleton
To display bone metastasis, at
an early stage of infiltration, proves best bone
scintigraphy (whole-body scintigraphy in PA and AP, with
eventually. Targeted SPECT images of suspicious sites) after
osteotropic radiopharmaceuticals, which are phosphate complexes
whose accumulation reflects increased osteoblastic activity in
response to tumor bone destruction. Planar whole-body
scintigraphy of the skeleton is useful to supplement with a
combined SPECT / CT image with image fusion, to
specify the anatomical location of the lesions. In thyroid
cancer, the diagnosis is based on scintigraphy after application
of radioiodine 131 I.
Labeled peptides that
bind to peptide receptors on the surface of some types of tumor
cells are mainly used in neuroendocrine tumors containing somatostatin
receptors (the cyclic peptide somatostatin
is a hormonal substance that has a inhibitory effect on the
production of certain hormones, especially growth; soma)
. = body, body, statizo = stand, stop ) . An artificial somatostatin analogue, octreotide
, labeled with indium - 111 In-pentetreotide (OctreoScan), or 68 Ga -DOTATOC for PET scintigraphy is
used to visualize the respective tumors and to predict the effect
of somatostatin analog therapy.. The logical sequence of
diagnostics using these radioindicators is their labeling with
therapeutic radionuclides with application for radioisotope
biologically targeted radiotherapy, see below " Radioisotope therapy
", section " Radionuclide therapy of tumors and
metastases ".
In addition, some non-specific
indicators of tumors are used, the increased accumulation of
which in tumor tissue is based on their ability to penetrate
pathologically altered permeability of walls and capillaries and
bind within viable cells. Used 99 m Tc-MIBI and tetrofosmin mainly in lymphomas and mammary
tumor (mamoscintigrafie). In oncological diagnostics, gallium
scintigraphy (mostly planar whole-body imaging, supplemented
with possibly SPECT images) with67 Ga-citrate. Chemically, Ga ions are analogs of Fe ions,
bind to the transport protein transferrin, and accumulate in
proliferating tumor tissues, particularly lymphomas. Gallium
scintigraphy is now abandoned and replaced by PET scintigraphy
with 18
FDG. Other scintigraphic examinations, such as dynamic
scintigraphy of the kidneys and liver, can also be inferred
indirectly from tumor processes.
If anomalous tissue (neoplasm)
that could be of tumor origin is found by imaging or other
examination methods, histological examination
must be performed : by biopsya small
sample of tissue is taken and then examined under a microscope.
Histological examination is also performed on
"suspicious" tissues removed during surgery. According
to the shape, size and other characteristics of the cells, it is
usually possible to distinguish whether it is a benign or
malignant tissue and what kind or. the tumor cells are (as
mentioned above). All this macroscopic and microscopic diagnostic
information determines the optimal way to treat cancer.
×
Diagnostics
for planning cancer therapy
If the primary diagnosis of cancer is confirmed, the stage of
preparation of therapy begins - a decision on the basic strategy
and methodology of therapy: whether it will be a surgical
solution, chemotherapy, radiotherapy, respectively. about what
combinations (see "Cancer therapy" below). If
radiotherapy is planned, X-ray CT, NMRI and gamma (especially
PET) images can be used to determine the exact location
and extent of the tumor site and to plot the
areas of interest (ROI) of the irradiated volume - GTV,
CTV and finally PTV in the irradiation plan (see below the
section " Planning radiotherapy'). The base is now used CT images, respectively. NMRI
but these mainly reflect morphological page, but do not capture
the behavior of biological tissue. It is therefore useful to also
gamagrafické views, especially PET images of the distribution of
18 FDG or 18 FLT, respectively. 18 F- By analyzing
these PET images (eg by determining SUV levels - see §4.2,
section " Scintigraphic image quality and detectability of
lesions "), we can determine the " Biological
Target Volume " ( BTV ) of tumor tissue
formed by viable proliferating cells. transfer of these images to
the radiotherapy planning system and computer image
fusion (CT, NMRI) + PET we can thenspecify the
volume of the target lesion, especially CTV for IMRT
radiotherapy. According to the distribution of tumor cell
viability, we can further modulate the dose within the tumor site
and increase (escalation, boost) doses to risk areas within the
tumor.
l Predicting
the response to cancer therapy
Predicting the biological response to planned treatment is a very
difficult task in medicine in general. In cancer therapy, certain
basic information can already be obtained from the results of
primary imaging and histological diagnostics. However, there are
ways to directly assess the specific behavior of tumor tissue for
the planned type of treatment using gamma imaging methods
, especially PET.
l Monitoring
the distribution of cytostatics and monoclonal antibodies
The success of chemotherapy depends, among other things, on
whether the cytostatics or monoclonal antibodies used accumulate
(uptake) sufficiently in the tumor foci. Nuclear medicine can be
used to predict the chemotherapeutic effect. Methods for radionuclide
labeling of some chemotherapeutics have been developed :
after "trial" diagnostic application of a small amount
of such labeled radioindicator, we can display its distribution
and assess how selectively it is taken up in tumor tissue (as
well as in healthy tissues that could be undesirably loaded) - in
this way, the respective chemotherapeutic agent will be taken up
during the actual therapeutic application. A similar
"trial" diagnostic application of a smaller amount of g- radioindicator
can be used in radioisotope therapy(see
" Radioisotope Therapy " below) .
l Imaging
Dendritic Cell Migration
One of the basic preconditions for the success of immunotherapy
with dendritic cells activated by antigens of a particular tumor
tissue (see "Cancer Therapy" below, " Immunotherapy " section) is their migration to peripheral lymph
nodes and then to the tumor locus. If we label these activated
dendritic cells before their re-application to the body using a
suitable radioindicator ( 111 In-oxin is tested), while maintaining their viability,
we can scintigraphically map their migration to the lymph nodes
after their application.
The predictive role of imaging
cell apoptosis is discussed in the following paragraph.
×
Monitoring
the biological response to cancer therapy
In addition to the primary diagnosis, it is desirable to monitor
how successful the therapy is and what its side effects are on
healthy tissues, organs and the whole organism. In terms of time
relation to therapy, monitoring of biological response can be
divided into prediction of biological effect
before therapy (mentioned above) or at the beginning of therapy,
monitoring of early response during therapy and
monitoring of late response and overall
long-term development disease after treatment.
To assess the late tumor response, the basis for monitoring the
tumor site in CT or NMRI images - a comparison of the size
(volume) of the displayed tumor lesion before and after therapy
to assess the reduction of tumor mass. However, CT and NMRI
images capture only the morphological situation
, not the biological development of tumor tissue and the
metabolic activity of cells - we do not recognize in them what
part of the depicted lesion of different density is formed by
viable tumor cells and what part by necrotized or connective
tissue. It is therefore useful to use "molecular"
gammagraphy using SPECT and PET methods to reliably monitor the
tumor response. These are mainly the already mentioned images of
the 18 FDG
or 18
distributionFLT, performed before and after therapy (or during
therapy), on which possibly we compare SUV values. Molecular
gamma imaging allows the visualization of important factors
influencing the response of tumors to therapy. Another
"line" - radiobiological modeling - is the
assessment of the radiotherapeutic effect using the quantities
TCP, NTCP, UTCP, discussed below in the section " Prediction
of the radiotherapeutic effect - the probability of cure of a TCP
tumor and damage to normal NTCP tissue
".
Immediately after the end of
radiotherapy, no macroscopic change can be detected in the
irradiated tumor - the changes take place first at the molecular
level. Only a few weeks to months apart, these nitrocellular
processes result in the extinction of most of the cells in the
tumor population, which can only be accompanied by observable
morphological changes.
l Early
tumor response - imaging of cell apoptosis
However, functional molecular imaging in gammagraphy
provides other unique possibilities. Radioindicators have been
developed to monitor one of the main radiobiological mechanisms
of cancer therapy (both radiotherapy and chemotherapy): cell
apoptosis . In cell apoptosis (see
§5.2, section " Effect of radiation on cells ", section "Cell apoptosis") in the early phase, among other things, irreversible membrane
depolarization occurs , the detection of phospholipids
on the cell surface, increased permeability of the plasma
membrane, later in the later phase the integrity of the cell wall
is violated and finally the cells disintegrate and phagocytose.
It is in the early phase of apoptosis that the
radiopharmaceutical shows an affinity for apoptotic cells
*): they either bind to phospholipids on the
surface or penetrate the cell membrane and accumulate in the
cytoplasm of apoptotic cells. The result is a selective
accumulation of radioindicator in apoptotic cells and tissues,
while they hardly enter in tissues formed by normal viable cells
or necrotic tissues.
By gammagraphic imaging of the distribution of these
radioindicators (it is appropriate to use dynamic
gammagraphy - time factor of accumulation) we obtain positive images of those places where
apoptosis occurs most intensively - whether due to irradiation,
cytotoxic substances or ischemia. By molecular imaging of the
distribution of cell apoptosis, we can monitor the very
early response of cells and tissues to therapy
(radiotherapy or chemotherapy), already at the beginning and
during therapy. It basically allows the prediction of the
tumor response : we apply "experimentally" one
or two fractions and on gammagraphic images we can assess whether
the target tissue is sufficiently intense apoptosis, or. whether
there are regions of apoptotic resistance in the heterogeneous
tumor. Early imaging of apoptosis can play a significant role in
biologicalindividual (" personalized
") therapy of a particular patient.
*) Three types of
radioindicators of apoptosis are in the stage of laboratory
development and preclinical studies (see also §4.8 " Radionuclides and radiopharmaceuticals
for scintigraphy "):
- Protein
99m Tc-Annexin V
(for SPECT imaging) - binds to phospholipids on the surface of
apoptotic cells;
- 18
F-ML-10 [2- (5-Fluoro pentyl) -2-methyl malonic acid] -
a small molecule that penetrates the wall of apoptotic cells and
accumulates in their cytoplasm. Approx. 400MBq is applied.
- Peptide
18 F-CP18
[triazole-containing pentapeptide] - maps Caspase-3 activity,
accumulates in apoptotic cells.
Combination of diagnostics
and therapy - teranostics
New diagnostic imaging methods, especially molecular
imaging in nuclear medicine, allow to integrate
individual (personalized) diagnostics and targeted therapy (or
prevention) of serious diseases into a common field, for which
the name teranostics (created
composition names: tera pie + diag Linkers
=> teranostika expires. Theranostics
). Scintigraphy makes it possible to
determine the concentrations of biologically active substances
directly at the sites of their targeted action, which enables
optimal and individual dosing, with the possibility of predicting
effects and monitoring the results of therapy - it is discussed
in more detail in §4.9, section " Teranostics ".
Cancer therapy
In terms of goal and effectiveness, we generally distinguish
between two types of treatment: Curative therapy
(Latin cura = treatment ) with the aim of complete cure of cancer, especially in
the localized stage. In more severe and advanced cases, palliative
therapy (Latin pallium =
mantle ) , alleviating and slowing
down the course of the disease and its difficulties. In terms of
time sequence, we also recognize two procedures: Induction
therapy - initial treatment to achieve remission of the
disease. After this primotherapy (possibly also simultaneously), adjuvant
therapy is often applied - auxiliary, supportive or
securing treatment (lat.adiuvo =
support, help ) , especially to reduce
the risk of recurrence due to possible microarray in the vicinity
of the original tumor.
The treatment of cancer is currently based
on three main methods: surgery , chemotherapy
and radiotherapy , and these three main
therapeutic approaches are often combined - multimodal
treatment . In the surgical treatment of cancer,
physical removal is performed - resection or ablation
(lat. Ablatio = removal, delay )tumor tissue. It is desirable to remove not only the
primary tumor with the "safety margin", but also, if
possible, other tissues into which the tumor cells could be
infiltrated: these are mainly the surrounding lymph nodes located
in the lymphatic "basin" of the tumor location (see also above). §3.5, passage " Radiation-guided
surgery - sentinel nodes
") . In addition to classical surgical
techniques, radiofrequency ablation and stereotactic
ablative radiosurgery SRS ( sterotactic radiosurgery
) are also used - see the " Stereotactic radiotherapy
" section .
For non-surgical
treatment of cancer, we would ideally need some "magic
bullets" that would penetrate the body in a non-invasive
manner, target and destroy only the tumor cells,
while maintaining undamaged healthy surrounding tissue. Because
tumor tissue is made up of cells that are not very different from
the healthy cells of the surrounding tissues, we do not have such
an ideal and selective "shot": anti-tumor cell
treatment will always more or less affect some healthy cells,
tissues and organs. However, there are certain physical and
biological factors that at least partially promote the targeted
destruction of tumor cells and minimize damage to healthy
tissues.
In terms of the place of action in the
body, we can divide the therapy of cancer into two methodological
approaches :
l Local tumor
control , in which we try to stop tumor growth and
destroy cells in a particular tumor site of known location and
extent. It is performed mainly by the method of radiotherapy -
targeted delivery of a high radiation dose to the tumor site.
This approach is effective for well-defined tumors of small or
medium size, without distant metastases.
l System therapy
carried out by applying suitable
drugs to the body which enter the tumor foci and stop the
proliferation or kill the tumor cells there. These include
chemotherapy with cytostatics and biological therapy, and in part
targeted radionuclide therapy. System operation has its
advantages and disadvantages. The advantage is the action on
multiple tumor foci and hidden metastases, the presence and
location of which we sometimes do not even know. The disadvantage
is the side effects on healthy cells and tissues. Systemic
therapy is chosen in cases of larger cancers with metastatic
infiltration. And also as an adjuvant therapy to reduce the risk
of recurrence and metastasis.
Below, the methods of systemic and
targeted chemotherapy and biological treatment
will be briefly described below, followed by the methods of
targeted radiotherapy in more detail. using
physical and radiobiological aspects.
Chemotherapy
and biological treatment
Under chemotherapy generally means treating
diseases by administering chemicals - drugs that are the product
of chemical synthesis or isolated from natural materials
(especially plants) - and that produce the desired organism (bio)
chemical reactions. Chemotherapy of cancer is most often
performed using cytostatics - substances that
stop or inhibit the growth and division of cells (Greek: kytos = cavity, cell, staticos = stopping
). Their preferential antitumor effect is
due to the fact that they act primarily on rapidly dividing
cells. However, they also affect healthy physiologically dividing
cells in the body, which leads to undesirable side effects. A
number of cytostatics are known to act by different mechanisms
and at different stages of the cell cycle. There are two basic
mechanisms of action of cytostatics :
1. Action on DNA , which disrupts
cellular function, prevents replication, can be evaluated by cell
cycle control nodes as irreparable damage ® activation of the internal
signaling pathway of apoptosis (in this respect the
mechanism is similar to ionizing radiation).
2. Effects on other cellular structures,
especially microtubules, which violates the very act of
cell division - it acts as a " mitotic poison
". The cells are thus inactivated , they cannot
divide further, they undergo apoptosis either directly
or following a "mitotic catastrophe" (see §5.2,
passage " Mechanisms of cell death ").
More four distinct mechanisms
of action of cytostatics by which these substances are decomposed
into :
l Alkylating agents - are reacted with bases in the DNA, e.g. guanine, the alkylation
of - transferring a carbon radical group C 2n H 2n + 1 ( alkyl
). This leads to DNA cleavage or the formation of a
two-stranded junction. This damage to DNA inactivates cells,
prevents them from dividing (DNA strands cannot unravel and
separate), and ultimately leads to apoptosis . A
cytostatic effect has long been observed with nitrogen mustard
analogues . From this group, chlorambucil,
cyclophosphamide or ifosfamide are used (the
metabolite oxycyclophosphamide formed in the nucleus has
its own cytostatic effect ), as well as fludarabine and bendamustine
. Platinum cytostatics
also belong to this group . The longest used cytostatic of this
species is cisplatin (cis- [PtCl 2 (NH3 ) 2 ]), an inorganic molecule that binds to guanine bases
in a DNA molecule; more recent are the organic compounds carboplatin
and oxaliplatin , where platinum atoms are attached to
cyclic ("aromatic") hydrocarbons.
l Microtubule inhibitors - react with microtubules in cells, prevent
the formation of a mitotic spindle - mitotic poisons .
These are two types of chemicals that have opposite mechanisms of
microtubular action, but result in similar cytotoxic effects:
- yew terpenides - taxanes . The
alkaloids paclitaxel (contained in yew Taxus brevifolia )
and docetaxel (from yew Taxus
braccata) are used ,
which stabilize microtubule polymers (inhibition of microtubule
depolymerization) and prevent chromosome
separation during anaphase.
- vinca alkaloids - vincristine,
vinblastine, vinorelbine , which bind to tubulin and prevent
its polymerization into microtubules.
l Antimetabolites blocking the synthesis of purine and pyrimidine DNA
bases required for cellular replication. Substances with a
structure similar to purines and pyrimidines - fluoropyrimidines
, especially methotrexate or 5-fluorouracil
preparations are used (5-FU). More recently, the 5-FU
precursor, capecitabine (capecitabine), is preferably
used , from which the active substance 5-fluorouracil is formed
by enzymatic transformations only in the body, preferably in
tumor tissue (enzyme thimidine
phosphorephilase , which participates in the final phase of
inactive capecitabine conversion). -FU, is contained in tumor
cells usually in a significantly higher concentration than in
cells of healthy tissue - selective effect) .
l S-phase
cell cycle topoisomerase
inhibitors prevent the
development of the DNA double helix during the replication
process (in which the enzyme topoisomerase is involved
). This leads to the induction of single-stranded DNA breaks that
can cause cell death. The original substance of this kind was
camptothecin , an alkaloid isolated from the
Chinese tree Camptotheca acuminata . However, its
synthetic derivatives topotecan and irinotecan
have more suitable pharmacological properties .
l Antitumor antibiotics are initially drug inhibiting growth and reproduction
of microorganisms, therefore, when used in the treatment of
infectious diseases, as well as antifungal agents and the like.
They are secondary metabolites of microorganisms (bacteria,
fungi), many of which are now prepared artificially (by synthetic
or semi-synthetic methods). As most of them contain in their
chemical structure several groups of cyclic hydrocarbons
("benzene nuclei") characteristic of anthracene, they
are also called anthracycline antibiotics
. In addition to the antibiotic effect of some of these
substances, an immunosuppressive effect and a cytostatic
, antitumor, antiproliferative effect were also found .
The mechanism of the cytostatic effect is probably binding to DNA
- their molecules have the ability to be incorporated between DNA
base pairs; DNA breaks occur, intercalation bonds are formed with
a transcription disorder (tight connection of both strands of DNA
prevents its copying before cell division and transcription into
RNA), DNA breaks down (the effect is similar to that of radiation
or alkylating cytostatics). The enzyme topoisomerase is also
blocked, which is involved in changes in the spatial
arrangement of DNA during replication prior to cell division;
when it is blocked, the individual parts of the DNA that break
down do not come together. An example is doxorubicin , bleomycin,
epirubicin, idarubicin, mitomycin C .
This group also includes, in
part, rapamycin , originally isolated from the bacterium
Streptomyces hygroscopicus discovered in soil on Easter
Island Rapa Nui ; it is also called sirolimus (lat. siro = pit dug in the soil, limus = mud,
sludge ) . It ranks among the macrolide
antibiotics that block protein synthesis in microorganisms by
binding in ribosomes. Due to its immunosuppressive effects, it is
used in transplants as protection against adverse immune
reactions that can lead to transplant rejection. By inhibiting
the protein kinase ( mTOR *), it blocks a number of
intracellular processes, leading to a decrease in cell
proliferative activity. It prevents cells from moving from the G1
phase of the cell cycle to the S phase, causing cell cycle
arrest. It increases the sensitivity of tumor cells to
radiotherapy and the effectiveness of chemotherapy. Rapamycin
thus also belongs to the group of kinase inhibitors
listed below , where its new derivatives temsirolimus
and everolimus are used .
*) Rapamycin, mTOR
mTOR (mammalian Target Of Rapamycin ) - this
very misleading name comes from the fact that the relevant
protein kinase was first discovered when rapamycin was applied to
the breast. An alternative name is " mechanistic target
of rapamycin ". It was later shown that mTOR also works
in other types of tumor cells. The PI3K / Akt / mTOR signaling
cascade is significantly involved in the process of
carcinogenesis, and its inhibition may be an important factor in
cancer therapy.
l Antioxidants are known primarily as cancer prevention. However, it
has been shown that some antioxidants (such as reveratrol,
genistein, baikalein ) damage DNA and kill
dividing cells. This could be used in anticancer therapy. Their
advantage is that, despite their genotoxicity, they do not have
mutagenic effects. So far, it is in the stage of biological
research.
l Bisphosphonates act as inhibitors of osteoclastic bone resorption. They
can therefore be used for the secondary treatment of bone
tumors, especially metastases, where they act primarily against
bone erosion; it is not a cytostatic. The most effective nitrogen
bisphosphonate is mainly zoledronic acid . In
combination with eg docetaxel, there is an additive synergistic
antitumor effect - potentiation of the cytostatic effect.
Individual cytostatics are
sometimes combined eg FOLFOX (oxaliplatin +
5-fluorouracil + folic acid), XELOX (capecitabine + oxaliplatin),
FOLFIRI (5-fluorouracil + irinotecan) and others. A common
disadvantage of classical cytostatics is their systemic non-specific
effect - they act not only on tumor cells, but also
on healthy physiologically dividing cells. This leads to a number
of often serious side (toxic) side effects. Therefore, a new
variant of targeted "transport" of a suitable
cytostatic preparation directly to cancer sites is being tested,
using microcapsules up to 5 m
in size.m. Such tiny capsules, formed from
a suitable organic substance and carrying a cytostatic inside,
pass through the vascular system and the fine blood capillaries
after application. They can be monitored sonographically or by
magnetic resonance imaging; the moment they reach the tumor, they
can be disrupted by an ultrasound wave, releasing the cytostatic
at the required place - in the tumor.
Chemical structure of some cytostatics used in chemotherapy of
cancer
Targeted
biological therapy
In recent years, knowledge of molecular biology
and genetics has developed rapidly , revealing, among other
things, complex mechanisms of cellular communication and
specific molecules that are important for malignant cell
transformation. These could become the target of specific
therapeutic interventions: to identify and target certain
structures in tumor cells in order to prevent further
proliferation of tumor tissue. Targeted biological
treatment is based on these mechanisms , the strategy of
which is directed against selected types of molecules and their
signaling pathways involved in the malignant behavior of cells of
the respective tumor types. Together with more effective therapy,
these procedures make it possible to reduce undesirable
side effects Currently, the main interest is
focused on the so-called growth factors (stimulating
cell growth and division) and their receptors, especially EGFR,
HER2 and VEGF (see below).
A new class of drugs is being
developed that selectively block the activity of these oncogenic
proteins, with minimal damage to normal cells. These are mainly
two groups of substances with different mechanisms of action :
l Monoclonal
antibodies
are special proteins from the group of immunoglobulins (or fragments thereof) , which
are obtained from a cloned population of one
species of activated B-lymphocyte from the plasma of an immunized
organism. The monoclonal antibody therefore has precisely defined
properties and specifically binds to the
respective receptors. Some monoclonal antibodies seek to approach
an ideal therapeutic - a " magic
arrow " that would only target target
pathological cells and have no detrimental effects on
other healthy cells. However, this cannot yet be achieved 100%
..! ..
Structure of monoclonal antibodies
The molecular weight of monoclonal antibodies is around 150 kDa. The
structure of immunoglobulin protein molecules is often
schematically represented by the shape of the letter " Y
" (in the figure on the left - a). The branched part - arms
- consists of two heterodimers, it is formed by four polypeptide
parts, arranged in two mirror-identical pairs of " heavy
" and " light " chains. They are
internally linked by a disulfide bond (SS). Light and heavy
chains contain constant and variable
regions. The variable regions, located at the
ends, contain short amino acid sequences (sometimes
called "hepervariable") ,
antibodies. Therefore, these arms are referred to as Fab
( Fragment antigen binding ) . The "foot" in the antibody scheme consists
of two heavier chains, referred to as Fc ( crystallizing fragment ) . This constant region of Fc is responsible for the effector
functions of the antibody (interaction with
T-lymphocytes, macrophages) - activation of systems leading to
the destruction of target cells.
Preparation of
monoclonal antibodies
Since we cannot cultivate directly the desired clones of
activated B-lymphocytes efficiently enough, the preparation
of monoclonal antibodies iscomplex biochemical
technology. Myeloma cells (otherwise known as tumor cells of myeloma
, a hematooncological disease of the bone marrow caused by
uncontrollable proliferation of myeloma cells) have proven to be very suitable "auxiliary
carriers" for the preparation of monoclonal antibodies ,
which, due to their unlimited replication capabilities and
longevity in vitro. Thus, the formation of these
"helper" myeloma cells is first
induced in experimental laboratory animals. These are then
harvested and cultured in vitro. Meanwhile, in another laboratory
animal, an injection of a particular antigen elicits an immune
response with B-cell activation.and subsequent
production of antibodies. These B-lymphocytes are taken from the
lymphatic system (usually a spleen sample) of the animal used and then fused in
vitro to a colony of myeloma cells. From this fusion, hybrid
cells (called hybridomas
) are formed , which retain the properties
of both myeloma cells and the desired B-cell clone, divide
rapidly, and produce B-cell antibodies
used in the fusion. Using special separation methods, only
hybridomas producing only one desired antibody
clone - a monoclonal antibody - are selected
from them .
This
ingenious biotechnology was first developed in 1975 by
G.F..Kohler and C. Milstein in the Molecular Biology Laboratories
of the University of Cambridge and the Institute of Immunology in
Basel (for this method they received the Nobel Prize in 1984).
![]() |
Monoclonal
antibodies . a, b) Schematic representation and illustration of the basic structure. c) Mouse monoclonal antibody. d, e, f) Chimeric, humanized and human antibody. |
The laboratory animals
used in the process of preparing monoclonal antibodies are almost
always mice, so that the mouse monoclonal antibody
(c) is primarily generated . For its human use can sometimes lead
to undesirable immune reactions - immunogenicity
due to the development of human-anti-mouse antibodies HAMA
( Human Anti-Mouse Antibodies ). On the one hand, this
prevents the binding of the monoclonal antibody to the target
antigen and, on the other hand, can also lead to immune
anaphylactic reactions. Therefore, there is an effort to replace
parts of the molecules (which do not encode antigen binding
regions) with human immunoglobulin sections - to
humanize antibodies using sophisticated
biochemical-genetic methods ("genetic
engineering ") . From the
original hybridonové line producing mouse antibodies that
target, the RNA preparation and further reaction catalyzed by the
enzyme reverse transcriptase, a complementary cRNA
-. polymerase reactions were propagated segment encoding the
antigen binding site. This genetic sequence are replaced The
corresponding new gene is inserted into a suitable recipient
mammalian cell, which then synthesizes a monoclonal antibody with
a predominant human immunoglobulin content.. The
humanized monoclonal antibody has constant regions from a human
immunoglobulin, and only the variable region encoding antigenic
specificity is derived from a murine antibody. The antibodies
thus transformed have the desired antigenic specificity and show
only minimal immunogenicity. In this way, chimeric
(cross) antibodies (content of about 60% human antibody), humanized
(content of more than 90% human antibody) or 100% human
antibody are generated - in Fig. D), e), f). The more
"animal" the antibody, the greater the risk of
immunogenicity can be expected. Humanization of monoclonal
antibodies, on the other hand, leads to a reduction in unwanted
immunogenicity, but on the other hand also to a possible
reduction in their efficacy ...
Antibody fragments
The larger the protein molecule, the slower and more difficult it
is to penetrate the target tissues. Therefore, instead of
"whole" antibodies, suitable antibody fragments
are prepared , containing only regions with preserved antigenic
specificity. Most commonly, these are Fab´ fragments containing
domains necessary for antigen binding, but not the
effector-interacting portion of Fc.
Nomenclature of
monoclonal antibodies
The nomenclature of monoclonal antibodies is elaborated so that
the basic type and the most important properties
(targeting) of a specific preparation (antibody) can be
identified from the name . The name consists of
4 parts: prefix - designation of the target structure -
biological type (origin) - suffix (it is always - mab:
m onoclonal a
nti b ody ):
Monoclonal antibody name : | ||||
prefix - | - target structure - | - biological origin - | - suffix | |
variable (individual) |
- ci
(r) - vascular system - tu (m) - tumor - li (m) - immune system |
- m
(o) - mouse - xi - chimeric - zu - humanized - u - human |
- mab ( m onoclonal a nti b ody) |
Examples are ......, or rituximab
, a chimeric monoclonal antibody (-xi-) whose variable portion
mediating contact with the tumor cell CD20 antigen (-tu-) is of
murine origin and the remainder of the antibody is of human
origin.
In the literature, other more detailed
divisions are sometimes given - in the target structure for
specific types of tumors ( -co (l) - colon
tumor, -go (v) - ovarian tumor, -ma (r) - breast tumor, -me (l )
- melanoma, -neu (r) - nervous system, -pr (o) - prostate tumor,
-vi (r) - viruses ..... ), in biological
origin other possibilities ( -a- rat, -e -
hamster, -i- primates, ..... ); however, we
do not encounter these names in practice ... In some
preparations, in addition to the monoclonal antibody itself, the
name is also given biochemically conjugated substances
(eg ibritumomab tiuxetan - ......).
Biological effects of
monoclonal antibodies
In order to produce the desired effect (therapeutic
or diagnostic) , the antibody must first
reach the target tissues and cells. Monoclonal antibodies are
administered intravenously by slow infusion of the solution. ....
Monoclonal antibodies have relatively large molecules with masses
around 150kDa, min. 100 times larger than conventional
cytostatics. Therefore, they have slower distribution kinetics
and are less difficult to penetrate tumor tissue, with slow
diffusion through the interstitial space. Their distribution in
the tumor is usually inhomogeneous, especially in larger tumors.
Monoclonal antibodies have the
ability to react with the particular antigen against which they
are targeted. If the target structure is a receptor ligand, this
ligand is neutralized. If the target structure is a receptor on
the surface of the cell membrane, the signaling pathway
associated with it is blocked. Many monoclonal antibodies thus
have inhibitory effects on certain ligands and
signaling pathways (or sometimes
stimulatory ones) .
A frequent goal of treatment
is the elimination of a certain type of cells -
the depletion process. The condition for binding to
target cells is the presence of appropriate receptors.
The antigen-binding complementarity of an antibody is given by
the variable regions at the ends of the Fab chains, while the
fixed Fc region mediates subsequent effector functions on target
cells. After successful binding of the antibody, three different
mechanisms of the resulting cytocidal effect can occur :
- Activation of complements - membrane
glycoproteins C1-C9, which by their proteolytic effects attack
cytoplasmic cell membranes and cause their penetration
. The cell dies and the released chemicals cause
an inflammatory reaction with the accumulation of leukocytes (cf. §5.2, passage " Mechanisms of cell death i ") .
- Induction of phagocytosis - fixed Fc region of
bound antibody(lower part of the letter
" Y "
in the scheme) specifically binds to the Fc
receptor of some types of leukocytes, especially macrophages,
which thus recognize and subsequently phagocytose tumor cells.
- Induction of apoptosis after antibody binding
to the cell surface, with destruction of mitochondria and
proteolytic caspase chain (detailed
explanation in §5.2., Passage " Apoptosis
"; in the picture on the top right " External
signaling pathway of apoptosis ") .
Immunogenicity of
Monoclonal Antibodies
Monoclonal antibodies, as immune-active agents, can produce
" anti-antibody antibodies " when administered
to the body , which can neutralize their effect.
in addition to causing adverse anaphylactic effects
- discussed above. Immunogecality most often occurs in murine
antibodies (HAMA, in about 10%), rarely in chimeric antibodies,
very rarely in humans. Before using murine antibodies, it is
therefore desirable to perform a laboratory biochemical test
for HAMA antibodies, or positivity should then be a contraindication
to the use of these products.
Use of monoclonal
antibodies
In addition to oncology (see below), monoclonal antibodies are
also used against autoimmune diseases, organ transplant
rejection, inflammatory diseases. Also as antibacterial and
antiviral.
Monoclonal antibodies are
mainly used in oncology for self-caretargeted biological
therapy for cancer (see below). In addition, cytotoxic
substances or radioisotopes can bind to them, which only
"guide" these antibodies, approach or bind them to the
target cells - antibody conjugates with suitable
effector components are formed .
Radiolabeled
antibodies - radioimmunoconjugates
An important new method of biologically targeted therapy
of cancer is the combination of targeted binding of
monoclonal antibodies with the biological effects of ionizing
radiation from radionuclides . Radioimmunoconjugates
have a beta or alpha radionuclide bound to a biologically
targeted radionuclide therapy in an antibody molecule -
see below "Radioisotope
therapy with open emitters .
" crossfire " has a radius of several tens of
cell diameters (see below obr.3.6.8 in " radioisotope therapy ").
They are therefore effective in the neighboring cells which have
insufficient expression of a tumor antigen.
Some monoclonal antibodies labeled with a gamma or positron
radionuclides,are used in nuclear medicine as
radioindicators in scintigraphic diagnostics-
§4.8 " Radionuclides
and radiopharmaceuticals for scintigraphy ", passage " Immunoscintigraphy
". It is mainly in tumor diagnosis , but
also, for example, in the diagnosis of inflammatory foci
using antigranulocyte monoclonal antibodies.
Monoclonal Antibodies
in Oncology
A number of monoclonal antibodies are used in oncology
therapy , some of which are briefly listed :
Cetuximab - a chimeric monoclonal antibody that
competitively binds to the extracellular domain of epidermal
growth factor EGFR (HER1) and inhibits the binding of other
possible tumor growth activators; panitumumab
has similar effects .
Trastuzumab (
herceptin ) acts as a monoclonal antibody against HER2
(Human Epidermal Receptor), binding to the extracellular domain
of HER2 and thereby blocking epidermal growth factor access to
its receptor; this prevents activation of the signaling pathway
of cell processes and tumor growth (HER2 -
positive). Pertuzumab , which
binds to the dimerization domain of HER2 and thus prevents its
dimerization with other HER receptors,has similar effects. The
combination of trastuzumab + pertuzumab is being
tested to increase the effect of HER2-signaling blockade
(possibly + docetaxel), which shows synergistic activity. The
combination of herceptin with aromatase inhibitors (such as
anastrozole or ietrozole) has also been tested in
hormone-dependent tumors. And in general, herceptin in
combination with the chemotherapeutic agents capecitabine
or 5-fluorouracil and cisplatin is indicated in
various HER2-positive metastatic tumors.
Bevacizumab ( Avastin
) is a humanized monoclonal antibody to Vascular
Endothelial Growth Factor (VEGF), which captures circulating VEGF
in plasma, thereby inhibiting tumor neoangiogenesis . A frequently used preparation is rituximab-
a chimeric monoclonal antibody of the IgG1 type, specifically
directed against the CD20 antigen in malignant B-lymphomas.
Ipilimumab is a monoclonal
antibody that activates CTLA-4 targeting, where
cytotoxic T cells can recognize and destroy tumor cells (it turns
off the inhibitory mechanism and allows T cells to function). It
is used to treat melanoma, non-small cell lung cancer, ca bladder
and ca prostate.
Nivolumab is a human IgG4 anti-PD-1
monoclonal antibody, also acting as a control node inhibitor,
that blocks activated T cells from attacking tumor
cells. It is also used in malignant melanoma (in combination with
ipilumomab ), lung ca and kidney ca.
Atezolizumabacts as an inhibitor of
PDL1 programmed cell death ligand. It is mainly used in non-small
cell lung ca.
Another possible mechanism
involved in the anti-tumor effect of some monoclonal antibodies
is the "labeling" of a cell on the surface of which the
relevant receptor is present; the cells thus labeled are then
attacked and destroyed by the body's immune processes. The
efficacy of monoclonal antibodies in tumor therapy depends on the
presence and function of appropriate receptors
on tumor cell membranes. If these receptors are scarce, or are
dysfunctional or mutated, the antibody is ineffective ...
Monoclonal antibodies can also
be " carriers " to which a suitable chemotherapeutic
or radionuclide binds.. The most commonly used
radioactive preparation of this species is Ibritumomab
Tiuxetan labeled with 90 Y ( Zevalin ) for non-Hodgkin's lymphomas; see
" Radioisotope Therapy " below, "Radioimmunotherapy" section
for more details .
l Mimetic antibodies, Affibody
In addition to "real" monoclonal antibodies, so-called mimetic
antibodies are also used - peptides or small proteins
(with a molecular weight of about 3-20 kDa), which like
antibodies can bind to antigens, but which are structurally not
similar to the relevant antibodies (the
name comes from the Greek mimesis = mimicry, to imitate,
imitate ). The main representative of
these substances are the so-called affibodies
consisting of three helices with 58 amino acids with a molecular
weight of about 6 kDa. Their use is for diagnostic imaging and
targeted therapy.
l Kinase inhibitors (thyrosine kinase inhibitors) are substances
that block the signaling pathways of certain kinases
(one or more), thereby inhibiting cell division and stimulating
apoptosis. This can lead to slower tumor growth and attenuation
of tumor angiogenesis. Kinases are enzymes (§5.2, section " Cells
- basic units of living organisms
", section " Proteins, enzymes, kinases
"), which transfer the phosphate group
from the adenosine triphosphate ATP to the acceptor, which has an
OH group - the phosphorester of the acceptor molecule is formed. The
tyrosine kinase transfers the phosphate to the hydroxyl
group of the cyclic amino acid tyrosine bound in the protein,
thereby activating the protein. Tyrosine kinase
inhibitors ( tinibas ) are small
molecules that bind to an appropriate site in ATP
(adenosine triphosphate) to prevent phosphorylation of substances
that are part of the intracellular signaling pathways by which a
chemical signal captured by a receptor on the cell surface is
transmitted to target structures in the cytoplasm or in the core.
One of the important targets of biologic therapy is the
epidermal growth factor receptor EGFR
signaling pathway( Epidermal Growth Factor Receptor ),
also known as a human epidermal receptor, Her-1 ( human
epidermal receptor 1 ), a transmembrane glycoprotein
(molecular weight about 170000). Another kinase that affects the
regulation of cell growth, including angiogenesis, is the serine
/ threonine kinase mTOR ( mammalian target of
rapamycin ). Thus, mTOR inhibitors may interact in
particular by attenuating angiogenesis.
Inhibition of kinases involved
in oncogenic signaling pathways may suppress the proliferation of
a given tumor cell clone. A certain advantage of these substances
is that (unlike large protein molecules) they can penetrate cells
by passive transport ,so that
their activity is not linked to the presence of the respective receptors on the membranes of the tumor
cells.
Gefitinib
is a quinazoline derivative that inhibits EGFR growth receptor
tyrosine kinase activity (especially in the EGFR activating
mutation), with erlotinib having a similar effect . Lapatinib binds to
the intracellular portion of the HER2 growth receptor and
inhibits its tyrosine kinase activity; it also acts as a dual
inhibitor - in addition to HER2, it also acts on the
intracellular activity of the HER1 receptor (ie EGFR). Imatinib
primarily blocks BCR-ABL tyrosine kinase in some
leukemia species; newer and more effective inhibitors of this
type are nilotinib and dasatinib
. The multikinase inhibitors sunitinib and sorafenib
suppress the kinase activity of platelet-derived growth factor
receptors, VEGFR and others (KIT, FLT3, ...) - they act as inhibitors
of angiogenesis . For this purpose, the new mTOR kinase
inhibitors temsirolimus and everolimus
(derivatives of rapamycin - sirolimus mentioned above in
the " anthracycline antibiotics " category ),
which block the P3K / Akt / mTOR
phosphatidylinositol-3-kinase signaling pathway, are also being
tested . The kinase inhibitor vemurafenib , which
specifically inhibits the V600-mutated form of the B-raf protein,
is also being tested ; shows promising results in the treatment
of malignant melanoma.
In some cases, it is useful to combine
monoclonal antibody therapy with an appropriate tyrosine kinase
inhibitor - for example, in a HER2-positive tumor, trastuzumab
followed by lapatinib .
l Aptamers (lat. aptus = capable , Greek meros = part
) are short fragments of RNA or DNA
(oligonucleotides, peptides; molecular weights 8-12kDa) -
specially prepared and sequenced ligands with high binding
affinity to specific target molecules. They take on different
three-dimensional structures, they are able to bind to
different biomolecules (antibodies, growth factors,
hormones, enzymes, amino acids). They can act as targeted inhibitors
and also as "carriers" suitable therapeutic substances
- "escort" aptamers . Their
use, so far experimental, is an alternative to monoclonal
antibodies. Aptamers can be produced artificially by biochemical
methods in a wide range: RNA serves as a "library" of
nucleotides, from which ligands of desired properties are
prepared by repeated combinations with tumor antigens and
selections (SELEX method). The selected aptamers thus formed can
then be sequenced and produced artificially by biochemical
methods; in this they have an advantage over monoclonal
antibodies (which are prepared by immunization). An example is pegaptanib
, which binds to the vascular growth factor VEGF and thus
prevents it from stimulating angiogenesis (so
far used in ophthalmology). The designation
of aptamers by radionuclides could be promising
- either g- radionuclides for scintigraphic diagnostics, or b or a radionuclides for
biologically targeted radionuclide therapy. For example, an anti-tenascin-C
aptamer labeled with 99m Tc and 111 In (for glioblastoma), or an Anti-MUC1 aptamer
labeled with 99m Tc or 186 Re (for breast cancer) is tested.
Biological treatment of cancer includes several other
special procedures :
l Gene therapy of tumors is still in the stage of laboratory
development, but its more significant application can be expected
in the near future. Two different pathways of gene tumor therapy
are being developed:
- A straightforward
procedure within tumor cells seeks to "correct" a
genetic variation that has led to malignant cell transformation
by a targeted change. The difficulty of this approach lies not
only in the laboratory biochemical complexity of introducing
specific genetic information using a suitable RNA vector and
reverse transcriptase, but also in the fact that several
different genetic changes (mutations) are involved in the
malignant transformation of cells. This is probably not only the
changes in known DNA coding sequences, but also in the as yet
unexplored "genetic junk", "unnecessary" DNA.
-In an
alternative approach, the target of gene therapy is not directly
tumor cells, but other cells and tissues that, under the
influence of targeted genetic intervention, are modified so that
they can begin to produce certain active substances that
effectively block tumor growth.
l Telomerase inhibition is so far an experimental method directed against one
of the above-mentioned factors of carcinogenesis: overcoming the
Hayflick limit of cell division - their immortilization - due to active
telomerase acting in tumor cells. Antitelomer
vaccination is performed by applying
telomerase to the body in order to elicit an immune response that
would kill the telomerase in the tumor cells and thus prevent
their unrestricted division. Unfortunately, telomerase inhibition
also affects other cells, such as hematopoiesis, where telomerase
performs its physiological function. Experiments with combined
telomerase inhibition together with inhibition of tankyrase
to potentiate the effect are also being experimented (telomerase
and tankyrase work "synergistically in tandem
cooperation"). Therapy based on telomerase inhibition can
only be successful where telomerase is active. Recently, however,
it has been found that telomerase is not the only factor in the
immortilization of tumor cells, but mechanisms of homologous
recombination of telomere sequences work similarly (it is
discussed in §5.2, part "DNA, chromosomes, telomeres ") . This" bad news "somewhat reduces the
promising therapeutic potential of telomerase ...
l Hormone therapy of tumors is based on the fact that some types of tumor
cells contain receptors for hormones - they are hormone
dependent , their origin and development is dependent on
the level of certain hormones.In breast cancer cells there are
estrogen receptors, in prostate tumors for androgens.The growth
of tumor cells can inhibit hormones with the opposite effect
(hormone antagonists) or prevent the synthesis of hormones
(castration in the prostate, ovariectomy in the mother ), both
methods are often combined, with the possibility of blocking
receptors in hormone-dependent forms of
tumors (especially breast cancer), which leads to the cessation
of tumor cell proliferation. Selective estrogen receptor
modulators such as tamoxifen are used for this purpose .
Aromatase inhibitors (an
enzyme involved in the synthesis of estrogens from testosterone,
estradiol is formed) such as anastrazole,
ietresol, formestane , also block the production of
estrogens.
l
Immunotherapy generally represents a targeted intervention into the
body's immune system for a therapeutic purpose - to restore,
strengthen, or modify the functions of the immune system.
Unfortunately, in advanced cancer, the immune system usually does
not respond to the tumor cells of one's own body ( immunosuppression
). One of the goals of tumor immunotherapy is to
label and "make visible" tumor cells for the body's
immune system, which can then "take care" of their
destruction. Genetic changes in tumor cells result, among other
things, in the emergence of new antigens, different from
non-tumor cells. These tumor antigens may become a desirable
target for immune responses, but only if we "serve"
them properly to the immune system.
As the vector
for the purpose of immune antitumor
vaccination are particularly useful group of
special cells from white blood cells called dendritic
cells of the immune system, with many numerous
protrusions on the surface (Greek dendron =
tree , the cells have dendrites ) . These cells initiate immune responses, differentiate
foreign and the body's own substances (they can recognize various
antigens, including tumor cells), they are particles.
Subsequently, they mature, exposing on their surface parts of
absorbed proteins (in our case tumor antigens) and thus
activating T-lymphocytes, which completes the
"destructive" immune response involving effector
monocytes transforming into macrophages. Dendritic cells
can thus become an effective tool for stimulates the body's own
immune system to "engage in the fight" against cancer autologous
cellular immunotherapy , which
![]() |
The procedure of anti-tumor
immune vaccination consists of several stages : - Sampling of tumor tissue, isolation and culture of tumor line cells; - Collection of peripheral blood, separation of leukocytes and monocytes by leucopheresis; - Growing in vitro cultures of native (immature) dendritic cells; - Activation of dendritic cells by uptake of cells of a given tumor line (their antigens); - From the activated (mature) dendritic cells, which expose tumor antigens on their surface, a final vaccine is prepared, which is applied back to the organism; -Activated dendritic cells migrate to the lymph nodes, where they activate effector T cells; - Activated cytotoxic T-lymphocytes recognize and kill tumor cells ( N ). |
Dendritic cells can be obtained by culturing
for several days from monocytes extracted from the patient's
peripheral blood *). In addition, a sample of tumor
tissue is taken . If we then ( in vitro , using
disrupted or apoptotic tumor cells) absorb dendritic cells tumor
antigens from the tumor tissue and then stimulated them back into
the body, they have the ability to stimulate the immune system to
"fight" the original tumor cells. . Subsequently,
activated effector T cells are released into the tumor site and
selectively attack the tumor cells. The method is still in the
stage of experimental clinical studies.
*) To obtain a larger number of leukocytes
and monocytes, a special sampling separation method called leucopheresis
or leukapheresis (Greek leukosis = white
, these are white blood cells - leukocytes ; afairesis
= take ) is used.: the blood circulates through a
centrifugal separation unit, where the leukocytes are separated,
while other components of blood (especially plasma) return
to the patient's circulation.
Although tumor cells produce
antigens that, in principle, the immune system can use for their
identification and subsequent targeted killing by cytotoxic
T-lymphocytes (CTL), there is an inhibitory mechanism.an
antigen associated with the CTLA-4 protein, the binding of which
to the CTL receptor shuts down the cytotoxic response. This
mechanism, on the one hand, prevents excessive adverse immune
reactions (autoimmunity), but on the other hand allows tumor
cells to survive. The anti-CTLA-4 monoclonal antibody ipilimumab
( MDX-010 ), which binds to CTLA-4, blocks its
inhibitory function and allows CTL to continue to destroy tumor
cells, has been shown to enhance anti-tumor CTL immunity .
Another newly tested method based on the
immune system is the blocker protein CD47 - anti-CD47.
The CD47 protein is physiologically present on the surface of
blood cells and its task is to protect them from its own white
blood cells. However, many tumor cells also have the CD47 protein
on their surface, which protects them from white blood cells and
therefore cannot be destroyed by the immune system. By applying
an anti-CD47 blocker , the immune system is stimulated
to kill the tumor cells. Although there is also a loss of blood
cells, which need to be supplemented ...
The above-mentioned monoclonal
antibodies also belong to the category of immunotherapy
. Molecular biological chemotherapy (immunotherapy, monoclonal
antibodies) is often suitable to combine
with classical cytostatics - to enhance the therapeutic effect.
For example, the combination docetaxel is used with
trastuzamab , 5-fluorouracil + oxaliplatin
(FOLFOX), or 5-fluorouracil + irinotecan (FOLFIRI), with
bevacizumab or cetuximab , capecitabine
with trastuzumab or lapatinib, and many others.
Recently, the application of cytostatics and monoclonal
antibodies labeled with therapeutic beta-radionuclides
, which represent combined molecular chemo-radiotherapy
, has been tested . Some such methods and preparations are
mentioned below in the section " Radioisotope therapy
", section " Radionuclide therapy of tumors and
metastases " and "Radioimmunotherapy ".
Abscopic effect
in some cases the observed synergistic effect of
immunotherapy and radiotherapy. Rarely occurs so.
abscopic effect ( i.e. off
target - lat. B = outside, away; scopium = t,
target angle )when after local
radiotherapy certain tumor lesions recede systemically and other
lesions that have not been irradiated. Radiotherapy may induce an
immunoeffect against further metastases of the same
tumor (for more details, see §5.2, passage " Bystander-Abscopal effect ").
Alternative
methods
In addition to chemotherapy and radiotherapy, some alternative
methods of cancer therapy are sometimes used or tried. We will
mention two based on temperature :
¨ Hyperthermia
- local heating of the target tissue to a temperature higher than
43 ° C, causing inhibition of DNA and protein production,
together with a reduction in tumor vascularization. Tumor tissues
usually respond more sensitively to heat than normal healthy
tissues. In healthy (normally perfused) tissue, vasodilation
occurs when heated, which removes heat more efficiently through
the blood and reduces heating. The vessels formed by
neoangiogenesis in the tumor are chaotic, functionally imperfect
and possibly compressed with tumor mass. Tumor vessels are not
able to effectively regulate blood flow, so when the tumor is
heated, vasodilation does not occur and the tumor heats up more
than the surrounding healthy tissues. In particular, large and
hypoxic tumors, which are less sensitive to radiotherapy, are
therefore suitable for the treatment of hyperthermia.
At temperatures above 43 ° C, denaturation of
proteins (including cell membrane proteins
and microtubules, causing changes in membrane potentials and ion
concentrations) begins to occur , leading
to cell death , predominantly by necrosis
. In addition, heat stress proteins express HSP heat stress
proteins (Heat shock proteins ), the most common is
Hsp70, which in addition to its anti-stress effect (bind to a hydrophobic amino acid sequence partially
damaged proteins, which allow the correction to the correct
spatial arrangement; further promote the degradation of damaged
proteins), their "chaperone"
activities allow binding to the antigen, and transport to cell
membranes, where these antigens are presented (via the transmembrane glycoprotein MHC 1) and thus stimulate the immune system -
the formation of cytotoxic T-lymphocytes specific for a given
type of tumor. Furthermore, enzymatic cell repair
mechanisms (such as excision
repair, homologous recombination, non-homologous end-joining -
see §5.2, passage "Repair
processes ")are heat-sensitive - thermolabile .
This can be used for the synergetic effect of
combining hyperthermia with radiotherapy or chemotherapy -
thermoradiotherapy ( hyperthermic radiotherapy ) or
thermochemotherapy .
Non-invasive heating of the tumor inside the body
can be achieved by electromagnetic waves or ultrasound.
perspective method of high-intensity focused ultrasound
HIFU ( High-Intensity Focused Ultrasound). Focusing of
ultrasonic waves is achieved using a specially shaped (concavely
curved) transducer. High-intensity ultrasound focuses on the
tumor, within which energy is converted into heat. The tissue
temperature rises to 65 ° C, during which thermal
ablation occurs - the temperature kills the tumor cells,
but when properly targeted, does not damage the surrounding
healthy tissues. A rapid and short-term increase in local
temperature (within 2-3 seconds) destroys the target tissue by coagulation
necrosis - we literally "cook" the tumor, while
the surrounding structures are not damaged. HIFU therapy is
suitable for MRI navigation .
Furthermore, the hyperthermic
method could activate chemotherapeutic drugs directly in tumors.
The chemotherapeutic is "wrapped" in heat-sensitive
microscopic particles ( liposomes - particles coated
with a fat layer) and applied to the bloodstream. At a normal
body temperature of about 37 ° C, the particles pass through the
blood vessels undisturbed and have no toxic effects on the body.
When they enter the tumor in this way, they can be locally heated
by the focused HIFU waves to a temperature higher than 42 ° C,
at which point the liposome envelope becomes porous and the drug
is released directly into the tumor. The therapeutic effect of
the drug is thus targeted in the tumor, with the minimization of
undesirable side effects in other parts of the body.
¨ Cryotherapy (Greek cryos = cold )
(also called cryosurgery ) consists in the application
of very low temperatures in order to destroy the target tissue ( cryodestruction
). It is used in various medical fields (dermatology,
ophthalmology, gynecology, surgery) and for the treatment of
non-malignant diseases. In oncological indications, it is the destruction
of a tumor by freezing using an established freezing
probe - a cryocauter , cooled mostly by liquid
nitrogen. The rapid freezing of the tissue causes its damage by
the formation of ice crystals inside and outside the cells, with
subsequent necrosis of the frozen cells. To achieve the desired
effect, the target tissue must be cooled to below -20 ° C with a
high freezing rate approx. 30 ° C / sec. Slow freezing would dehydrate the
cells, which could survive thawing. On the contrary, the
subsequent thawing should be much slower so that the cells are
exposed for a long time to mechanical damage by recrystallizing
ice and also to the toxic action of the intracellular fluid, in
which the concentration of salts and ions has risen sharply. The
cryotherapy method is used for tumors accessible by direct
application of the cryocauter, most often for skin lesions.
Note:
Issues of chemotherapy and other non-radiation
methods we have outlined here only briefly and marginally, due to
the complexity of the interpretation of the principles and
current possibilities of cancer therapy; further details of
complex biochemical reactions (often not yet fully explored) in
chemotherapy and biological treatment lie beyond the scope of our
discussion of radiotherapy , in addition to
physically focused ...
Radiotherapy
of cancer is based on the effects of ionizing radiation on living
tissue (the mechanisms of these effects are
described in more detail in §5.2 " Biological effects of ionizing radiation " ) ,
where sufficiently high doses of radiation are able to inactivate
and kill cells , in this case tumor cells. In
tumor tissue, it is necessary to destroy mainly clonogenic
stem cells , the unrestricted division of which causes
cancer. Radiation damage to the tumor's vascular
supply can also play a significant role in stopping tumor
growth . Radiotherapy can thus be an effective local
(or local-regional) method of cancer therapy
(and possibly also some other focal diseases and disorders) .
The goal of classical
radiotherapy is the reproductive sterilization of
clonogenic tumor cells by radiation-induced apoptosis. In
addition, stereotactic radiotherapy allows for an ablative
approach - immediate destruction of cells by necrosis,
caused by a high single dose of radiation.
Radiation eradication of tumor cells can
be part of effective curative therapy to
completely cure cancer, especially at the localized stage. In
more severe and advanced cases, palliative therapy
, alleviating and slowing down the course of the disease and its
difficulties. After surgical removal of the tumor lesion, the
so-calledadjuvant radiotherapy - auxiliary, supportive
or securing treatment after surgery, to reduce the risk of
recurrence due to possible microarray in the vicinity of the
original tumor. In certain cases, preoperative so-called neoadjuvant
radiotherapy is used before surgery - to reduce the extent of the
tumor (" downstaging ") and thus improve its operability, as well as to reduce
the viability of tumor cells and thus reduce the risk of local or
metastatic infiltration. may release tumor cells into the
environment, lymphatic system and bloodstream). The surgery is
then performed about 6 weeks after radiotherapy, when the acute
radiation symptoms have disappeared and late changes have not yet
occurred (see below "Side
effects of radiotherapy - radiotoxicity ") .
Perioperative
(intraoperative) radiotherapy is
rarely used - direct irradiation of the tumor site or its
remnant, exposed during surgery. From this point of view, mobile
devices with a miniaturized X-ray machine or an
electron gun and a target, which is applied to a target lesion
(eg a cavity after resection of the tumor itself) and irradiated
with low-energy X-rays ( with an energy of several tens of keV)
with a high dose and ionization density, which can in principle
also be used in laparoscopic operations.
The
majority of this §3.6 will be devoted to radiotherapy of cancer.
Combination
chemo-radiotherapy
To improve the results of cancer therapy is useful in some cases
both above mentioned therapeutic modalities in combination ( concomitant
s - accompanying, additional therapies, a special case
of multimodal therapy ). The benefits of
simultaneous application of chemotherapy with radiotherapy can be
basically of three types :
l Additive effect
- the effect of radiotherapy and chemotherapy for the destruction
of tumor cells adds up (without direct interdependence). The
additive effect of chemotherapy occurs on both the irradiated
cells of the target volume and chemotherapy can also cause the
elimination and attenuation of micrometastases outside the
irradiated volume.
l
Radiosensitizing effect - chemotherapy enhances the
biological effect of ionizing radiation on cells (increased DNA
fragility due to chemically bound cytostatics,inhibition
of DNA repair mechanisms, or appropriate time cycle of the cell
cycle to a phase more sensitive to radiation, eg G2) -
potentiation of radiotherapy. One such cytostatic
agent that increases the sensitivity of tumor cells to
radiotherapy issirolimus (rapamycin- mentioned
above as an anthracycline antibiotic); the combination of
sirolimus + radiotherapy is better tolerated in terms of side
effects than the combination of radiotherapy with most other
chemotherapeutics.
Tumors with increased expression of EGFR (= HER1) and HER2 growth
receptors generally have increased radioresistance, as the
intrinsic signaling pathways of these receptors are involved in
activating DNA repair processes upon ionizing radiation damage.
By applying targeted biological treatment against growth factor
receptors - cetuximab, trastuzumab, gefitinib, lapatinib, etc.,
the growth pathways of growth factors are interrupted, DNA repair
capacity is reduced and thus the radiosensitivity of the
tumor can be expected .
l Anti-repopulatory
effect - cytostatics, and in particular
some targeted biologic therapies, such as monoclonal antibodies
against growth factors, reduce the repopulation of tumor cells
during time-prolonged fractionated radiotherapy, leading to a
more efficient killing of a larger fraction of tumor cells by
radiation.
In chemosensitive tumors, chemotherapy can
also cause a reduction in the volume ,
a "shrinkage", of the tumor (similar effect to neoadjuvant
chemotherapy ). Such a reduced tumor is then easier to treat
with radiotherapy, both by reducing the number of tumor cells.
improved blood circulation and oxygenation , leading to
increased radiosensitivity due to the oxygen effect. The
resulting effects of chemo-radiotherapy are analyzed in more
detail below in the section " Prediction
of the radiotherapeutic effect ".
Physical
and radiobiological factors in radiotherapy
The optimal therapeutic effect of radiation is achieved by
co-production of two types of factors:
¨ Physical factors -
selective introduction of a sufficiently high dose of radiation
into a pathological lesion by a suitable irradiation technique,
using physical properties of radiation. We
will discuss these physical aspects in detail in most of the text
of this chapter; here we first briefly analyze the
radiobiological aspects :
¨ Biological factors -
the type of tumor and the properties of the surrounding healthy
tissue. For radiotherapy is very important radiosensitivity
of specific tumor type, as well as the difference in radiation
sensitivity between tumor and healthy tissue *). Lymphomas,
leukemia, seminoma are highly radiosensitive. Carcinomas, such as
prostate adenocarcinoma, are moderately radiosensitive. Gliomas,
sarcomas, melanoma, squamous cell carcinoma of the skin are
radioresistant.
*) It is the risk of damage to the
surrounding healthy tissues and organs that is the main
limiting factor in delivering a sufficiently high dose to the
tumor site. By critical organ or tissue we mean
a structure in the organism whose radiation damage would have
serious health consequences, or in the case of vital organs even
death. Therefore, a certain so-called tolerance dose
must not be exceeded during radiotherapyin these critical organs
to prevent their irreversible damage.
Therapeutic ratio
For the possibility of achieving a good curative effect of
radiotherapy, the most important thing is often not the actual
radiosensitivity of the tumor tissue, but rather the ratio of the
radiosensitivity of the tumor and surrounding healthy tissue -
the so-called therapeutic ratio TR ( Therapeutic
Ratio ). It can be quantified in different ways *): by
comparing the dose-response curves of cell survival N /
N 0 (Fig.
5.2.3c) for tumor and surrounding healthy tissue (from the ratio
of gradients or areas under these curves), or with the help of biologically
effective dose BED , or by comparing the probability
quantities TCP and NTCP (see
below " Prediction of radiotherapeutic effect - TCP,
NTCP ") . To quantify the therapeutic ratio of TR, we obtain
different indices TR N / No , TR BED , TR TCP , whose numerical values are different and must be
considered separately. The therapeutic ratio can be improved by
fractionation of radiation, combination with chemotherapy,
improvement of oxidation of the tumor site (overcoming hypoxia,
use of densely ionizing radiation with high LET) - is discussed
below.
*) Therapeutic options were previously
evaluated using the so-called Paterson graph,
which shows the dependence of the relative number of killed tumor
cells on the radiation dose. The same graph also shows the dose
dependence of the risk of irreversible damage to the surrounding
healthy tissue. In the favorable case, the curve for tumor tissue
is on the left, the curve of the probability of complications of
healthy tissue is shifted on the right. The width of the gap
between these two sigmoidal curves is sometimes called the therapeutic
width . More complex evaluations are now performed using
special TCP and NTCP graphs - see below " Prediction of radiotherapeutic effect - TCP,
NTCP " .
Irradiation
time fractionation
Tumor tissue that is in a state of intense (pathological) cell
division is usually more sensitive to radiation
than healthy tissue (it is discussed in
more detail in §5.2 " Biological
effects of radiation ") . Fractional irradiation is usually
used , where the total dose is divided into a number of smaller
daily doses *), applied over a number of days (approximately 3-5 weeks, see below " Fractionation in practice
") .
*) Single irradiation of
small lesions with a high dose (or substantial reduction of the
number of fractions to 2-5) allows sterotactic radiotherapythanks to the possibility of very precise targeting of
cancerous (or radioablative) dose with less load on the
surrounding critical tissues and organs.
There are basically two reasons for the time
fractionation of the radiation dose :
1. Healthy tissue cells usually have a higher
ability to repair radiation damage than tumor cells.
When dividing the dose into a number of smaller fractions,
applied individually after completion of the repair processes in
the cells, the resulting cumulative biological
effect on tumor tissue is generally higher than on healthy
tissue, which has a greater regenerative capacity. Radiobiological aspects of radiation fractionation are
discussed below. The radiotherapeutic effect on the tumor tissue
itself is sometimes expressed by a probabilistic quantityTCP
, defined below.
2. In each tissue, including tumor tissue, there are cells
at different stages of the cell cycle, in which
they have different radiobiological sensitivities. Therefore, a
single dose of radiation may not be optimal for all cells, which
may not be in the most sensitive phase. If the total dose is
divided into several fractions with a suitable time interval,
then after each such dose, the part of the cells which has just
reached the most sensitive phase at that time can be most
efficiently destroyed.
Dependence of radiation-biological effect on dose and its time
schedule - LQ model
The dependence of deterministic radiation effect on dose and its
time schedule is analyzed in detail in §5.2 " Biological effects of ionizing radiation ", part "Dose-biological effect
relationship ", where the so-called linear-quadratic
model (LQ) is introduced - see the section" LQ
model ", Fig.5.2.3c.
There is also a basic equation of dependence between dose D
and the surviving fraction of cells N / N o in (semi) logarithmic scale :
-ln (N / N o ) = a .D + { 2. [(1-e - l .T ). (1-1 / l .T)] / l .T } . b .D 2 -
ln2.T / T 2r ,
where a and
b are
the factors indicating the probabilities of damage a and b -processes, T is
the irradiation time, l is the rate of cell repair, T 2r is the doubling
time of the number of cells by repopulations. The coefficient in
angle brackets {...} is the so-called Lea-Catcheside factor , which
captures the effect of cell repair during irradiation. The linear
member a .D is dominant for early-reacting tissues (with higher
cell proliferation), the quadratic member b .D 2 is more
pronounced in late-reacting tissues. Basic linear-quadratic
dependence N / N oon the dose (D) is shown on a reduced scale for
illustration below, in Fig.3.6.0.a. The general equations of the
LQ model have rather theoretical significance ; for
practical applications in radiotherapy, simpler special
relationships for specific irradiation conditions and
techniques are derived from them (see below "Irradiation
fractionation"). These general radiation-biological
mechanisms are approached in practice by some other individual biological
influences , which are sometimes difficult to include in
one LQ model.
Individual biological
factors - " 6 R "
Biological effect of ionizing radiation in
relation to the radiation dose, its time schedule and possibly.
volume distribution is influenced by several factors and
biological processes during irradiation (the names of which
may be formulated beginning with the letter " R
") :
×
The radiosensitivity
of the irradiated tissue is given by the sensitivity of
individual cells to radiation damage; it generally varies
considerably for different types of tissues. In the
linear-quadratic model, radiosensitivity is implicitly contained
in the coefficients a and b . However, each tissue is in fact a heterogeneous
cell population , containing cells with different
radiosensitivity - with different coefficients a, b : the resulting
survival curve [ln (N / N 0 )] (D) is then a superposition of several different LQ
curves.
× Repair
is the ability of cells to repair their important structures,
especially DNA, damaged by ionizing radiation or other influences
(cell repair processes are described in
more detail in §5.2 ,
section "Repair processes") .
Repair processes have a time dimension : they take a
certain amount of time (given by the coefficient l - the rate of cell
repair), and the repair must be carried out before further damage
prevents successful repair. The repair processes, which take
place continuously during irradiation, thus lead to a " dose
rate effect ". In the LQ model, the repair is included
in the additional coefficient RG º {...} for the b- member.
×
Repopulation
Upon exposure to ionizing radiation, some cells die, but other
cells normally divide and may eventually. to replace destroyed
cells. This cell repopulation and tissue regeneration is
provided by clonogenic stem cells. Repopulation is quantified by
the rate of recovery of a number of cells, or the time T 2r of doubling of the number of
cells. In the LQ model, the repopulation is captured in the
additive term RP º ln2.T / T2r . Exponential tumor growth is assumed here ,
which is approximately met only in the initial stages of growth
of miniature tumors, with the growth of the tumor the growth rate
slows down.
×
Redistribution
Different cell types at different stages of the cell cycle
are differently sensitive to ionizing radiation. During the
actual exposure, the so-called redistribution of
cells can occur - a change in the representation
of different types of cells in the tissue *). During irradiation,
more clonogenic stem cells and G1 and G2 cells of the cell cycle
decrease, while effector daughter cells and M and S phase cells
in general will be relatively larger. Stem cells are more
radiation-sensitive than mother cells (see also §5.2 ); the goal of radiotherapy is to kill tumor stem
cells. The redistribution effect leads to changes in
intratumorous radiosensitivity during irradiation, as well
as to specific side effects on healthy tissue *).
*) The processes of cell redistribution
during irradiation have a complex time dynamics
and occur both in the tumor target tissue and in the surrounding
healthy healthy tissues. In the first part of the exposure,
clonogenic stem cells are declining faster, which are (due to the
faster cell cycle) more sensitive. This is followed by a gradual
loss of daughter effector cells, which reduces the function of
the irradiated tissue. A regulatory mechanism is in place to
preserve tissue functionality, leading to a partial loss
of division asymmetrystem cells, which begin to divide
symmetrically into two effector cells each; thereby (at the cost
of loss of stem cells) the functionality of the tissue is
temporarily preserved. If exposure continues, as the number of
clonogenic cells falls below a certain critical level (threatened
by stem cell disappearance and subsequent tissue death), another
regulatory mechanism occurs to trigger accelerated stem
cell repopulation to maintain their population necessary
for tissue regeneration. This reduces the production of effector
daughter cells, which are no longer sufficient to cover the
functional need for tissue - there is a clinical manifestation of
deterministic radiation effect in healthy tissue, acute radiotoxicity
(cf. the passage "Acute radiation sickness" in §5.2; on the side effects of radiotherapy - early and late
radiotoxicity, is briefly discussed below - " Strategic
goal of radiotherapy "). If the exposure continues
(fractional irradiation) and the tolerance dose of the tissue is
not exceeded, the proliferated stem cells can produce effector
cells in sufficient numbers to ensure the basic (albeit reduced)
functionality of the tissue; some "emergency steady
state" may occur with the reduction or disappearance of
previous acute problems in healthy critical tissue. In the case
of a tumor lesion, on the other hand, it is desirable to deliver
a sufficiently high dose to overcome the repopulation of
clonogenic tumor cells - to reduce them to a zero level, leading
to the death of tumor tissue .
× Reoxygenation -
oxygen effect
The atoms of oxygen , contained in water and other
molecules in the tissue, play a dominant role in the
radiobiological effect - oxygen- generated oxygen
radicals and peroxides effectively damage DNA in cells.
During tumor growth, as the tumor mass increases, there is often
a lack of oxygen in the cells, so-called hypoxia
. Hypoxia occurs especially when the tumor grows faster than the
capillary vascular network of tumor neoangiogenesis. In hypoxic
tumor cells, a much slower metabolism takes place (they often
remain in the G 0 phase of the cell cycle) and during irradiation there
is a lower formation of oxygen radicals - these cells therefore
have reduced radiosensitivity, they are radioresistant..
The surviving fraction of these radioresistant hypoxic cells may
be a potential risk of cancer recurrence.
Irradiation can cause some reoxygenation
(reduction of hypoxia) of tumor foci: reducing the number of
tumor cells reduces total oxygen consumption and reducing the
tumor can also reduce intratumorous pressure, loosen capillaries,
and improve blood flow and supply to the remaining cells. The
effect of reoxygenation is positive for radiotherapy -
it increases the radiosensitivity of the tumor tissue *) and thus
improves the therapeutic effect when using doses with
limited tolerances of healthy tissues. The oxygen effect is
significant especially when using sparsely ionizing radiation
(photon radiation g is most often used or X), where the indirect radical mechanism of the
radiation effect predominates. In densely ionizing radiation,
where there is an increased proportion of direct intervention
mechanism (and also increased recombination of radicals), the
effect of oxygen (oxygenation) on radiobiological effects is less
significant (see " Hadron
radiotherapy ")
*) Influence of oxygen content on
radiosensitivity - so-called oxygen effect - is
sometimes expressed by the factor OER ( oxygen
enhancement ratio ), which indicates the relative increase
in the biological efficiency of radiation in the presence of
oxygen ( normooxidation ) compared to its absence. The
ratio of OER between completely anoxic and normoxic tissue
reaches a value of about 2.5 .
The processes of
redistribution and reoxygenation vary widely between different
tumor tissues and are difficult to predict. It is therefore
difficult to introduce them into the LQ model, they are usually
considered separately. All these individual effects can result in
changes in the radiation sensitivity of cells
and tissues during irradiation , leading to further
deviations from the dependencies of the ideal LQ model . Recently, the influence of the so-called bystander
effect has also been discussed (see §5.2 " Biological effects of ionizing radiation ", passage " Bystander-Abscopal effect "), which could perhaps somewhat correct the
effect of mild inhomogeneities in tumor tissue irradiation -
increase the effect in underexposed parts target tissues.
×
Volume factor -
Radiation volume
The sixth factor is sometimes important for the final
radiobiological effects in tumor tissue and critical organs
especially, the volume of distribution of radiation
doses - the size of the irradiated volume ( Radiated volume
). At the cellular level, the biological effect is determined
primarily by the size of the dose; the same is true for local
tissue effects. Therefore, in organs with a serial
arrangement of functional parts (spinal cord, esophagus,
intestine, optic nerve), the resulting radiobiological impact is
dependent on the maximum local dose: at high local dose, the
serial organ can be radiation "disrupted" with
irreversible impairment of its function. In contrast, volume
organs with parallelby arranging functional parts
(lungs, liver, etc.) they tolerate high local irradiation well,
even above 80Gy (causing failure of only negligible functional
parts), but even relatively weaker irradiation (approx. 20Gy) of
their entire volume can significantly impair their function - the
resulting organ the effect depends on the average dose per organ.
For various radiation sensitivities of tissues and organs and
their division into serial and parallel,
see §5.2 ,
section " Local tissue and organ radiation effects ".
Irradiation
fractionation according to the LQ model
The parameters a, b, l , T 2r in the equation of the dependence of the surviving
fraction of cells on dose D and irradiation time T according to
the linear-quadratic model, as well as other biological factors
of redistribution and reoxygenation, are different for individual
tissue types, especially for healthy and tumor tissues. This
dependence can be used to optimize the resulting
radiation response of tumor tissue with respect to healthy tissue
using a suitable time schedule - fractionation -
radiation dose. The total radiation dose D is distributed
into individual fractions d i (i = 1,2, ..., n) with irradiation times t i. For a detailed
analysis, the general Lea-Catcheside dose-time integral
(derived in §5.2, " LQ
model ") can be used in the
equations of the LQ model . However, in the case of evenly
distributed fractions d i º d (D = nd), the
duration of which t i = t is short in comparison with the total duration T
of radiotherapy treatment, this equation can be used for total
therapy , substituting dose and time variables the
following values :
l In the linear a - member we substitute the
total dose D = nd, which is proportional to the number of damages
by the double a -process ( a-processes in individual fractions do not interact with
each other, they are composed linearly).
l In
the quadratic b- member it is important that the square of the dose D 2 in the LQ model
during fractionation is not D 2 = n 2 .d 2 (as would result
directly from the power of the relation D = nd), but the number
of fractions n appears in 1 .power : b .D 2 = b .nd 2 .
The exact derivation of this fact lies in the solution of the
general Lea-Catchesid integral. However, it also follows from the
physico-biological mechanism: according to the theory of dual
radiation action (see §5.2, section "Intervention and
radical theory of radiation effect"), quadratic dose
dependence refers to a single absorbed dose, in this
case to dose d of one fraction - b .d 2 ; the total effect is
formed by the sum of n independent fractions , ie
n. b .d
2 . The
individual factions do not interact with each other.
l Time
T in the Lea-Catchesid coefficient at quadratic b - we replace the member with the exposure time of the
irradiation fraction t (during which the cell repair takes
place).
l For
the time T in the additive repopulation member, we take
the total time T of the given radiotherapy (assuming that
the continuous repopulation of cells occurs during the whole
therapy at approximately constant rate). The resulting equation
of the LQ model for (regularly) fractionated irradiation with the
total dose D = nd during the total time T , divided into n
fractions with sub-doses d and exposure times t ,
will then be:
-ln (N / N o ) = a .D + n . { 2. [1- (1-e -l .t / l .t)] / l .t } . b .d - ln2.T / T 2r .
The repair mechanism may be more pronounced in LDR
brachytherapy , especially in the late stages of permanent
brachytherapy (see " Brachyradiotherapy " below). In EBRT teletherapy , the
exposure time of the individual fractions t is short
(approximately tens of seconds to minutes) due to the rate of
cell repair: t << 1 / l
, so the Lea-Catcheside factor {...} can be set
equal to 1 (there are no interactions between
the individual fractions) and the resulting effect will be: -ln
(N / N o )
= a .D
+ b . n .d 2 - ln2.T / T 2r = ( a + b .d) .D - ln2.T / T 2r . When a single short irradiation (t = T << T 2r ) again
apply additive repopulating member (ln2.T / T 2r ) ® 0.
For a basic analysis of
fractionated radiotherapy can be neglected temporal effects
reparation and repopulation - we come from the basic equation LQ
model :
E
º -ln
(N / N o )
= a .D
+ b.D 2 ,
where the logarithm of the surviving fraction of cells N / N o is denoted for
brevity by E (a kind of "irradiation
efficiency"). With regularly fractionated irradiation, D =
nd, so simple algebraic adjustments gradually give (justification of the square of n u b .D 2 was given above) :
E = a .nd + b .nd 2 = nd ( a + b .d) = D. a . [1+ ( b / a ) .d] = D. a . [1 + d / ( a / b )] .
We see that the radiobiological effect increases with increasing
dose on fraction d and also depends on the value of the a / b ratio for the
irradiated tissue. At high doses per fraction, the radiation
effect is significantly higher; at a given dose D, the effect is
highest when applied once, in one fraction (n = 1, d = D). If we
apply a larger number of fractions n with a lower dose d
to the fraction, we must increase the total dose
D to achieve the same biological effect .
Biologically effective dose BED
The logarithmic irradiation efficiency E is therefore
proportional to the total dose D with the coefficients a and [1 + d / ( a / b)]; it is this
second coefficient that expresses the relationship of the
biological effect to the fractionation of the dose and the a
/ b ratio
of a given tissue. To express the dependence of the biological
effect of radiation on dose fractionation, the derived
biophysical dose quantity is introduced as the biologically
effective dose of BED ( biological dose equivalent
) :
BED º E / a = D. [1 + d / ( a /
b )] .
It can be said that BED = (physical dose) ´
(proportionality coefficient); this proportionality factor [1 + d
/ ( a / b )] (relative efficiency) shows how the biological effect
of irradiation depends on the fractionation and the ratio a/b for a specific
irradiated tissue. Since lim d ® 0 BED = D, BED is a fictitious dose that would
lead to the same biological effect if the total dose D were
supplied in an infinitely large number of infinitesimal fractions
(or for an infinitely long time with an infinitesimally low dose
rate - if however, we neglect the time factor of cell repair and
repopulation).
Specific BED values are
expressed in dosage units [Gy] provided with an index
given by the numerical value of the a / b ratio
for a particular tissue - BED a
/ b . E.g. a dose of 60Gy, applied in
30 fractions of 2Gy, will form in the early reacting tissue
(fast-growing tumor tissue, skin) with a / b = 10 biologically effective dose of BED 10 = 60. (1 + 2/10) =
72Gy 10 ,
while in late-reacting tissue (lungs, liver, kidneys) with a / b = 3, BED 3 = 60. (1 +2/3) =
100Gy 3 .
The concept of BED is
important above all as a useful tool for comparing the
effects of different fractionation regimes : the total dose
D 1
applied in n 1 fractions d 1 gives the same (equivalent) biological effect as the
dose D 2
in n 2
fractions of size d 2 if it leads to the same BED value: D 1. [1 + d 1 / ( a / b )] = D 2. [1 + d 2 / ( a / b )]. Also, the above-mentioned therapeutic ratio of
TR radiation sensitivity of tumor tissue and surrounding
healthy tissue can be quantified as the BED ratio for tumor
tissue "TU" and normal healthy tissue "NT":
TRBED =
BED TU /
BED NT .
LQL model
In hypofractionation regimens with high doses per
fraction (d> 5, 10 or more Gy / fraction), which
allow the advanced conformational techniques of stereotactic
radiotherapy and HDR brachytherapy described below, a certain discrepancy
was shown between expected and observed effects: the classical LQ
model at these higher doses per fraction somewhat overestimates
the biological effect of radiotherapy, predicting higher damage
to normal NTCP tissue. As if the curves of the surviving fraction
of cells -ln (N / N o ) (on a log-linear scale) at higher doses actually
showed an increased proportion of the linear component than the
quadratic. To capture these clinical findings, use is sometimes
empirical model modification LQ called. LQ-L model
(linear-quadratic-linear), which for higher doses / fraction
(greater than 2. a / b , in practice> ca. 6Gy) adds additional linear
componentincreasing the surviving fraction of cells. Other
modifications of the LQ model lead to similar results -
generalized gLQ model, USC (universal survival curve), KN
(Kavahagh-Newman) model, PLQ (Pade Linear Quadratic), LQC model
(linear-quadratic-cubic), see §5.2, part " Deviations and modifications of the LQ model ".
Fractionation in practice
The same radiation dose applied in a shorter time (at a higher
dose rate) has greater biological efficiency - cf. also Fig.5.2.3
in §5.2, part " LQ
model ". From a radiobiological
point of view, the most effective would be a single
irradiation *) of a given deposit with the required
radiation dose of several tens of Gy. However, the problem here
would be the high acute radiotoxicity to the
surrounding healthy tissues, which always receive a certain
(albeit smaller) dose of radiation together with the target foci.
Therefore, it is necessary to divide the
curative radiation dose into a larger number of smaller parts - fractions
. By suitable fractionation it is possible to achieve that in the
time interval between fractions there is a partial reparation
and regenerating healthy tissue, which is then able to tolerate
the burden of the next dose. However, this also increases the
tolerance of the tumor cells (although usually less than in the
cells of healthy tissue), so that it is necessary to
increase the total dose to the tumor site.
*) However , let us consider point 2 in the
paragraph " Time fractionation of
irradiation " ..? ..
The most common fractionation,
normofractionation , consists in the
application of about 2Gy 1 ´
per day (5 days a week), for a period of
5-8 weeks ( 5w-8w ) , total dose about 60-80Gy. From a
radiobiological point of view, the optimal fractionation scheme
depends on the type of tumor, whether it is slow or fast growing.
In fast-growing tumors, the so-calledhyperfractionation
, in which more smaller doses (approx. 1.2 Gy) are applied at
shorter time intervals, eg 2-3 ´ per day, to limit the
rapid repopulation of clonogenic tumor cells. The slower dividing
cells of healthy tissues (due to the time interval between
fractions) can be regenerated, the risk of late radiotoxicity is
reduced. The whole irradiation process is often shortened and
accelerated here - so-called accelerated
radiotherapy. Are used classically fraction 2 / day. Further,
mode CHART ( Continuous Hyperfractinated Accelerated
Radiotherapy ) hyperfractionated irradiation 3 ' day, and
continuous over a weekend. The opposite procedure, so-called hypofractionation
, when only 2 ´ or 1 is irradiated´
weekly, it is used in palliative therapy,
HDR brachytherapy and sometimes also in radioresistant and
slow-growing tumors.
Single
irradiation with a high dose of tens of Gy radiation is
used in the so-called stereotactic radiotherapy ,
described below
( " Stereotactic
radiotherapy. Gamma-knife.
"); here the radiobiological efficacy is no longer precisely
described by the LQ model (in addition to apoptosis, immediate
cell death by necrosis also applies), the so-called LQL model
or other high-dose modifications described in §5.2, section
" Deviations and modifications of the LQ
model " are introduced.
In addition to the regular
doses, which are part of the used fractionation regime, certain
additional or additional doses are sometimes applied, so-called boost
( boost = additional increase ) - " saturation
of". Reasons for boost application may be radiobiological
(improvement of local tumor control with respect to individual
tumor conditions and surrounding tissues) or technical
(when for medical reasons or for irradiator failure the whole
irradiation series does not go according to schedule - additional
dose needs to compensate tumor and healthy tissues). To determine
the doses in the boost, it is appropriate to use radiobiological
modeling based on the LQ model; however, it is often based on
empirical experience. A special technique is the so-called concomitant
boost CB (Concomitant Boost;
concomitant = concurrent), in the case
of hyperfractionated radiotherapy, 2 doses are administered
sequentially daily: one for the total target volume of PTV, the
other only for the inner part of GTV, containing the macroscopic
volume of the tumor itself (see " Planning radiotherapy
" below). This increases the dose in the form of PTV in
which there is a higher risk of recurrence. Using the IMRT
technique of modulating beam intensity using an MLC collimator
(see " Modulation of irradiation beams "
below), maximum tumor dose (GTV), somewhat lower dose in the CTV
region with potential for microarray, and minimized dose in
surrounding critical tissues can be achieved relatively
accurately. The two batches of concomitant boost can then be
combined and applied simultaneously within one daily fraction.
This advanced technique, called SIB (Simultaneous
Integrated Boost ) gradually replaces sequential concomitant
boost.
Prediction of the radiotherapeutic effect -
the likelihood of curing a tumor TCP and damaging normal NTCP
tissue
Successful radiotherapy - the cure of a cancer -
involves killing as many clonogenic cells in the tumor site as
possible that would be able to regenerate the tumor (recurrence)
if they survived. To quantify this basic goal of radiotherapy and
to predict the success of treatment, the quantity TCP
( Tumor Cure / Control Probability ) was introduced -
the probability of cure the tumor . The
radiobiological effect and the behavior of cell populations have
a stochastic (probabilistic) character, according to Poisson
statistics . The probability that it will not occur
after irradiation to redistribute clonogenic cells and tumor
growth, is given by the exponential relation TCP = e - N
, where N is the number of surviving clonogenic cells in
the lesion after irradiation *). Substituting for N from
the LQ model, we get a double exponential relation for the
dependence of TCP on the dose D .:
TCP (D) = e - N o .e -
(a .D + b .D 2
) = e - N o .e -
a . BED ,
where N o
is the original number of clonogenic cells in the tumor before
irradiation (N o is on the order of 10 10 -10 12 cells). The graph of this function is S-shaped
- for low doses up to about 20-30Gy, TCP is close to zero (almost
no therapeutic effect), then increases approximately linearly,
and for doses above 80-100Gy, the "saturation state" of
TCP ® 1
(100% effect) - red TCP curve in Fig.3.6.0b; however, specific
values are different for individual types of tumor tissue, they
depend on radiosensitivity (on values a, b ).
*) This remarkably simple relationship
results from the more complex laws of mathematical statistics
. Overall cell survival is a stochastic random variable
of a binomial naturePoisson statistical distribution
. If we mean the number of clonogenic cells N, then the
probability P (n) is a random phenomenon that survives n
cells is given by P (n) = (N n /n!).e - N
. For n = 0 we obtain P (0) = (N 0 /0!).e - N
= e - N . It is the decrease in the number of
remaining clonogenic cells to n = 0 that can be considered as a guarantee
of definitive liquidation of the tumor ; Thus, the
probability is TCP = e -
N .
To express adverse biological
effects on normal healthy tissue during radiotherapy, an
analogous quantity of NTCP (Normal Tissue
Complication Probability - the probability of
complications from damage to normal NT tissue
, especially critical organs (see below). NTCP comes
from the same radiation patterns of the stochastic Poisson death
and cell survival, such as TCP, but applied to the surrounding
healthy tissue, a certain fraction of the tumor irradiated dose D
. When substituting from the LQ model, in addition to the
relevant parameters N o , a, b, l , T 2r for the given NT tissue, it is necessary to include the
volume factor , with regard to serial or parallel tissue
type :
NTCP(D,V) = e-No.V-k.e-(a.D + b.D2)
= e-No.V-k.e-a . BEDNT ,
where V [% /100] is the relative proportion of the
volume of irradiated normal tissue, the parameter k
describes the volume effect (k =
0-1; parallel organs with a large volume effect have a higher
value of k than serial organs with a small volume effect), BED NT is the biologically effective dose for normal NT
tissue. In the parameter N o (which no longer has the immediate significance of the
initial number of cells, as is the case with TCP) the requirement
for a minimum number of surviving cells (or their
percentage; these are stem clonogenic cells) in NT is implicitly
included so that their deficit does not lead to exceeding the functional
reserve competent critical authority and its necessary
function has been maintained. The dose dependence of NTCP (D) has
a similar sigmoidal shape as TCP (D), but is shifted
horizontally to higher doses of D (normal tissue
receives only a small part of the tumor dose D, or only a certain
part of the NT volume is irradiated) - NTCP green curve in
Fig.3.6.0b. In radiobiological modeling in radiotherapy, the
effort is to maximize TCP ( ®
1) and minimize NTCP ( ®0), although it is
often very difficult ....
Functional modeling of
TCP and NTCP
Instead of primary above-derived 2-exponential functions, the sigmoidal
course of dose-response curves TCP (D) and NTCP (D) is
modeled in practice using "secondary" so-called . probit-function
(from eng. probability ) of Gaussian shape
F(D,D50,m,V) = (1/Ö2p)-An[(D/D50.V-k)
- 1]/me-x2/2dx ,
where D 50 is the dose value with a 50% probability of
the studied effect (tumor elimination or complication in normal
tissue) and m is the slope parameter of the TCP
(D) or NTCP (D) curve in the linear section (maximum value of
derivation according to dose D). D 50 and m
play the role of form-factors of the sigmoidal shape of
the curves. V is the relative proportion of the volume of
irradiated tissue, k describes the volume effect. For TCP
the parameter k = 0 (so V 0 = 1 -
volume does not apply), in the case of NTCP the
value of the parameter k> 0 models the normalization
of dose Dper volume , with respect
to the serial or parallel type of critical tissue (volume effect
mentioned above, "sixth R"). In case of uneven
irradiation of critical NT tissue (as in practice) a suitable
correction is made for NTCP determination - instead of dose D the
so-called equivalent uniform dose of EUD
is introduced , recalculating the irradiation effect of
individual sub-volumes V i (total number N, ie. i
= 1 S N V i = V tot = 1) with
partial doses d i for uniform irradiation of the whole
critical organ: EUD = ( i = 1 S
N
V i .d i k
) 1 / k (weighted sum of partial
volume contributions of the given NT body with volume factor k).
Modeling of the radiotherapeutic effect using TCP and NTCP was
first introduced by J.T.Lyman, G.J.Kutcher and C.Burman in the
1980s ( LKB model ).
Methodological note: Unified concept of
TCP and NTCP
From the point of view of radiotherapy, TCP and NTCP are
independent quantities, related to different tissues with
different parameters of radiosensitivity and with conflicting
requirements of radiobiological effect. In the professional
literature, therefore, they are mostly introduced as separate
models. However, the basic ideological aspects have TCP and NTCP
in common: the same radiobiological mechanism of cell survival
and killing (quantified in the LQ model) and the probability
character with the Poisson distribution. Here we have tried to
outline a unified theory, deriving both TCP and NTCP
from the same initial "baseline principles "
as the Poisson statistical distribution and LQ model of cell
survival dose dependence. The basic approach is then exactly the
same, only with NTCP the percentage of irradiated NT volume and
the volume factor of a given NT tissue are introduced. The TCP
and NTCP models are thus unified into one concept. An open
problem in this approach, however, remains the expression of the minimum
number (percentage) of clonogenic cells in NT that must
survive to maintain long-term functionality of critical
tissues and organs - with respect to functional reserve of
relevant NT, their parallel or serial character .
![]() |
Fig.3.6.0. Some
radiobiological aspects in radiotherapy - graphical
representation (model examples). a) Basic LQ model of biological dependence on dose. b) Graphical representation of the dependence of TCP, NTCP and UTCP on dose D. c) Quantification of the success of radiotherapy with conventional irradiation (top) and conformal radiotherapy IGRT (bottom). |
TCP and NTCP are sometimes combined to
assess overall radiotherapy optimization . Introducing
the so-called. likelihood uncomplicated treatment UTCP
( Uncomplicated Tumor Cure Probability ):
UTCP = TCP. (1 - NTCP);
In the case of irradiation of several critical tissues NT 1 , NT 2 , ..., NT n , adjacent to the
target volume, the probabilities of NTCP and complications in the i-th critical organ appear in the
product of coefficients (1-NTCP i ) :
UTCP = TCP. i = 1 P n
(1 - NTCP
i ).
The curve of UTCP (D) dependence on the radiation dose has a bell
shape (blue curve in Fig.3.6.0 in the middle) - it is zero
at small (insufficient) doses, it increases to the maximum at the
optimal dose D opt and then decreases again to zero for too high doses
that damage healthy critical tissues. The dose of D opt , corresponding to
the maximum of UTPC, expresses the optimal dose in terms of the
relationship between the achieved probability of TCP tumor
eradication and the acceptable level of probability of NTCP
damage to healthy NT tissue. The position and height of this UTCP
maximum significantly depends on the precision of the
irradiation methodology : using conformal IGRT radiotherapy
or stereotactic radiotherapy (described below), the UTCP maximum
shifts to higher doses, due to reduced irradiation volume of
critical tissues ®reduction of NTCP, better tolerance of surrounding
tissues (Fig.3.6.0c).
To optimize radiotherapy, all
of the above derived dose functions are obtained by conversion
from DVH dose-volume histograms in 3D radiotherapy
planning (see " Radiotherapy Planning " below), using special computer software; the
areas under the DVH curves represent the relative "partial
volumes" of irradiated NT tissues. Also, the above-mentioned
therapeutic ratio of TR is sometimes expressed
by the ratio of these values: TR TCP = TCP / NTCP. The evaluation of all these parameters is
not always unambiguous, opinions on the "weight" of
tumor eradication and side effects on healthy tissue sometimes
differ. However, due to the danger of cancer, it should be
remembered that (with the exception of fatal damage to important
critical organs) the most serious complication is tumor
recurrence !
Time factor - the influence of cell repair and
repopulation
In principle, the influence of time factors - the influence of
cell repair and repopulation during irradiation on the resulting
biological effect can be "built into" the derived
biophysical dose quantities BED and TCP used in radiotherapy. By
replacing the simplified equation LQ of the model -ln (N / N o ) = a .D + b .D 2 general equation with
Lea-Cathesid cell repair factor and additive repopulation term we
get for BED and TCP more general expressions :
BED = D.[1 + {2.[1-(1-e-l.t/l.t)]/l.t}.d/(a/b)] - T.ln2/(a.T2r) , ® TCP = e-No.e-a . BED
.
Similarly for NTCP. However, too many parameters - and thus
degrees of freedom - complicate radiobiological modeling and
often make it ambiguous. In practice, we usually suffice with
simple laws, supplemented by empirical experience (cf. the
above-mentioned section " Fractionation in
practice ") ...
Cell repair causes that if we apply two radiation
fractions of dose d , the radiobiological effect is lower
than with one dose irradiation 2d. E.g. [N / N o ](2 ´ 2Gy) < [N / N o ](4Gy).
During irradiation, cell repair takes place in
healthy tissue and in the tumor, but at different rates. For
lower doses, more tumor cells are usually killed than normal
(late-reacting) tissue cells. At high single doses, the curves of
normal and tumor tissue may "cross", and the effect on
healthy tissue may be greater. Fractionated therapy has a higher
effect on tumor tissue and a lower effect on healthy tissue, with
this desired difference increasing with the number of fractions.
In fractionated radiotherapy, cell repopulation
of tumor cells between fractions may also occur , as the
total treatment time is relatively long. For fractionated tumor
tissue therapy with coefficients a, b and doubling half of T 2r repopulation, with
the total dose D divided into fractions d during
the total duration of treatment T , for the biologically
effective dose of BED the LQ model (without repair, but with
repopulation) is based on the relation: BED = D. [1 + d / ( a / b )] - T.ln2 / (
a .T 2r ). Thus, the
repopulation time factor reduces the biological effect of
irradiation, especially for fast-growing tumor cells (here, the
reduction in BED is estimated to be 0.5 Gy / day), which needs to
be compensated by increasing the total dose.
The model of continuous exponential repopulation with
a fixed doubling half-life T 2r during the whole irradiation is only approximate, in
fact the above-mentioned effect occurs in the irradiated tissueredistribution
of cells (fourth "R") with complex temporal
dynamics, including progressive repopulation . Its exact
inclusion is difficult, the additive term would have the shape of
an integral, model eg (ln2/T2r).0nT(1-k.e-v.t)dt,
with a time-varying rate coefficient v (t) of the repopulation
rate change. For practice, however, a simpler approach is
sufficient. The time T acc from the start of therapy, when the accelerated
repopulation of clonogenic stem cells begins (sometimes referred to as the accelerated T delay repopulation time
), is important . Reduction of the
radiobiological effectafter this time, it can be simply
written using the relation E º
-ln (N / N o ) = D. ( a + b .d) - K. (T-T acc ), where the empirical factor K (according to
the previous theoretical approach K = ln2 / ( a .T 2r )) expresses the
degree of reduction of the biological effect - at the same time
it is important the daily dose [Gy] needed to destroy the newly
formed cells on this day, ie the dose needed to compensate
for the repopulation of clonogenic cells. Using BED ( º E / a ) this relation
can be written in the form BED = D. [ a + d / ( a / b )] - K. (T-T acc ) / a. In head and neck
tumors, the time T acc is about 28 days, with prolongation of the total
duration of T therapy losing the biological effectiveness
of the radiation by about 0.8 Gy per day. This relationship is
sometimes used for shorter times T <T acc , where the equivalent dose, on the contrary, increases
relatively.
In any case, the approximate
nature of this approach must be borne in mind . The K
parameter is probably not constant during therapy, it is
small at the beginning and increases with time - progressive
repopulation. Time T accthe onset of accelerated repopulation depends on the
applied radiation dose and its timing (fractionation). And both
of these variables are, of course, different for different types
of irradiated cell population.
Combination
chemo-radiotherapy
Irradiation is sometimes appropriately combined with
chemotherapy ( concomitant
- complementary, complementary therapy, mentioned above) , which can either have an additive effect (independent
cytotoxic cell killing) or, in certain circumstances, increase
the effect of radiotherapy (so-called potentiation) - to
increase the radiation sensitivity of irradiated tissues either
by inhibiting DNA repair mechanisms or by appropriately
influencing the cell cycle to a phase more sensitive to radiation
(eg G2). Possibly. is applied before irradiation
neoadjuvant chemotherapy to reduce the extent of the
tumor so that the tumor site can be irradiated more selectively
with sufficient examination of the surrounding critical tissues
and organs.
The biological
effects of combined chemoradiotherapy can in principle also be
quantified using a suitably modified LQ model. For this purpose,
three basic mechanisms of the biological effect of simultaneous
chemo-radiotherapy need to be analyzed separately:
¨ The additive
effect is given by the sum of the radiobiological
effect of radiotherapy and the cytotoxic effect of chemotherapy,
which are independent of each other. The effect of concomitant
chemotherapy on the resulting biological effect can then be
expressed in the LQ model by adding a new independent term E ch
which expresses the efficacy of
cytotoxic cell killing in chemotherapy; the value of E ch represents the
logarithm of the surviving fraction of cells after separate
chemotherapy. The overall additive effect of chemoradiotherapy is
then: E º -ln (N / N o ) = a .D + b .D 2 + E ch .
¨ Radiosensitization
(potentiation) effect of chemotherapy, which
enhances the biological effect of ionizing radiation on cells. It
is included in the LQ model by adding a new coefficient - sensitization
factor s , which expresses the increase in radiation
sensitivity of cells due to chemotherapy. This coefficient
effectively multiplies the radiation dose in a- and b -member, so the
final effect of radiochemotherapy with sensitization is: E º -ln (N / N o ) = a .Ds + b .D 2 .s 2 .
¨ Inhibition of repopulation
by cytostatics and in particular by some targeted biologic
therapies, such as monoclonal antibodies against growth factors,
reducing the repopulation of tumor cells during fractionated
radiotherapy, leading to the elimination of a larger fraction of
tumor cells by radiation. In the LQ model with time factor -ln (N
/ N o ) = a .D + { 2. [(1-e - l .T ). (1-1 / l.T)] / l .T } . b .D 2 -
ln2.T / T 2r this slowing of cell repopulation can be captured by
modifying the additive member RP º ln2.T / T 2r - by
multiplying the doubling half-life of repopulation T 2r by a
coefficient greater than 1. At the same irradiation with
radiation dose D during time T thereby reduces Surviving
fraction of cells N / No the tumor. Inhibition of repopulation due to
appropriate chemotherapy prolongs both the half-life of
repopulation T 2r and the time T acc from the start of therapy, when accelerated
repopulation of clonogenic tumor cells begins. Thus, in
connection with the analysis of the previous paragraph, there is
less loss of biological efficacy with increasing the duration of
fractionated therapy, thus effectively increasing the effect
of therapy .
In chemosensitive tumors,
chemotherapy can also cause a reduction in the volume
, a "shrinkage", of the tumor (similar effect to neoadjuvant
chemotherapy ). Such a reduced tumor is then easier to treat
with radiotherapy, both by reducing the number of tumor cells.
improved oxygenation and thus increased radiosensitivity
due to the oxygen effect. However, these effects can no longer be
objectively included in the LQ model.
Strategic goal and methods of
radiotherapy
The "strategic goal" of
radiotherapy is therefore the selective elimination of
the tumor site with the least possible damage to the
surrounding healthy tissues - so that their functionality
is not endangered . Irradiation of the surrounding
tissues can never be completely avoided, but the so-called tolerance
dose in critical tissues and organs must be
observed *). It is necessary to introduce a sufficiently high
dose of radiation into the target area , for tumor cells
lethal - tumorous canceroletic dose
(approx. 50-150 Gy) in such a way that the surrounding healthy
tissues are not enormously damaged. The task of radiotherapy in
clinical practice is to find the optimal compromise
between these two conflicting requirements. In this chapter, from
a physical point of view, we will briefly describe how the basic
strategic goal of radiotherapy is achieved by various methods of
irradiation.
*) By critical organ or
tissue we mean such a structure in the organism, the radiation
damage of which would have serious health consequences, or in the
case of vital organs even death. Therefore, during radiotherapy,
a certain so-called tolerance dose must not be
exceeded in these critical organs in order to prevent their
irreversible damage. For various radiation sensitivities of
tissues and organs and their division into serial
and parallel, see §5.2 , section " Local tissue and organ radiation
effects ".
Theoretically, all tumors
could be locally curable by radiotherapy, but the obstacle is the
limited tolerance of healthy tissues and organs, the irradiation
of which cannot be avoided - radiotoxicity to
healthy tissues.
Side effects of radiotherapy -
radiotoxicity, secondary malignancy
As mentioned above in several places, a common limiting factor in
achieving a sufficiently high cancer dose in tumor foci is radiotoxicity
(also called radiation morbidity ) to surrounding
healthy tissues and organs, which are always partially irradiated
with tumor tissue. In terms of time, there are two types of
radiotoxicity in radiotherapy:
- Early acute radiotoxicity manifests
itself within a few days to weeks from the start of irradiation.
It is caused by the loss of stem cells in rapidly proliferating
tissues with a short cell cycle, where continuous and rapid
production of daughter effector cells is required. The loss of
these stem cells upon irradiation soon leads to depletion of
effector cells, which results in impaired function of the
affected tissue or organ. The complex time dynamics of division
of rapidly proliferating cells during prolonged irradiation
(asymmetric division, accelerated repopulation, ...) was
discussed above in the LQ model , passage " Redistribution
". Mucous membranes (esophagus or intestines), bone marrow,
epidermis are affected by early radiotoxicity. Clinical
manifestations of early radiotoxicity, if not very severe, are
usually temporaryand due to the gradual replacement of
missing cells (by dividing stem cells) they disappear within a
few weeks. Early radiation toxicity can later turn into late
toxicity (often occurring with high early toxicity) - referred to
as consequential late radiotoxicity
.
- Late radiotoxicity manifests
itself with a delay of many weeks to months (sometimes several
years) after irradiation. It is the result of tissue damage with
a slow recovery of effector cells, where therefore the
proliferation rate of stem cells is low. Damage to these stem
cells (which do not divide continuously, but only with the loss
of effector cells and the need for their replenishment) occurs
already during irradiation, but it manifests itself only when
there is a need for their division, which is unsuccessful
(mitotic death). This occurs with a longer time interval and
manifests itself in the depletion of daughter effector cells in
the affected tissue. Late radiotoxicity is manifested in
connective tissues (subcutaneous, submucosal), bone, muscle
(myocardium), eye lens, kidney or lung. The clinical consequences
of late radiotoxicity are usually permanent .
Very early radiotoxic
effects
When irradiated with high doses with radiotherapy, very early
symptoms such as fatigue, nausea, and dry mouth may appear
relatively quickly, within a few hours. These manifestations of very
early radiotoxicity are not caused by the mechanisms of
radiation killing of cells - a larger number of cells are
damaged, but this damage will appear later, only during the
mitosis of these cells. Very early radiotoxicity is caused by irritation
of regulatory centers by direct exposure to released ions,
radicals and other products of radiolysis.
By optimizing the irradiation regime,
especially by precisely directing the irradiation beams and by
appropriate fractionation of radiation doses, undesired
damage to healthy tissues can be largely minimized or reduced to
an acceptable level.
- Very
late stochastic effects. In addition to the desirable deterministic
effects on tumor tissue on which radiotherapy is based, as
well as adverse radiotoxic effects on healthy tissue, secondary
post -radiation malignancies may occur over time
due to the stochastic effects of that part of the
radiation absorbed outside the primary target tumor (including scattered radiation). ) and
irradiated other tissues and organs. Distinguish this radiation-induced
carcinogenesis since spontaneous cases it is
difficult (after all, the onset of the first cancer indicates an
increased predisposition of the individual to these diseases).
The risk or incidence of these secondary radiation-induced
malignancies is estimated at about 3% / 60Gy. It is sometimes debated whether exposure from frequent
verification imaging in IGRT-guided radiotherapy methods may also
contribute to secondary malignancies (see below).
According to the basic method
or path along which the radiation "conveys" to the
desired destination (the affected tissue or organ), the
radiotherapy methodically divided into three modalities :
n Teletherapy - irradiation "remote" bundles of radiation
from the irradiator (referred to also as EBRT
- external beam radiotherapy ).
( However, I do not use the name telotherapy
much here because of its misleading resemblance to the
charlatan methods of "teletherapy " =
"distance treatment")
n Brachytherapy - irradiation "at close" - insertion of
closed radionuclide emitters into the tumor tissue or in its
immediate vicinity.
n Radioisotope therapy - application of open radionuclides in a suitable
chemical form directly to the body (most often by metabolic
means). Radionuclides then enter the target tumor tissues via a
metabolic pathway - biologically targeted radioisotope
therapy BTRT ( biologically targeted
radionuclide therapy ).
These three basic
radiotherapeutic methods will be discussed below from a physical
point of view.
Note:
In conventional radiotherapy, it is usually required that the
target lesion (volume) be irradiated as homogeneously
as possible with a sufficiently high dose of radiation. However,
this requirement does not apply to brachytherapy
and stereotactic radiotherapy, where the dose
distribution is strongly inhomogeneous , with a
steep drop from the target site (will be described below).
External
irradiation with gamma, X and electron radiation (teleradiotherapy)
The most common method of radiotherapy is irradiation with a collimated
beam of penetrating radiation from an external
irradiator. X-rays (X) radiation of higher energies (approx. 100
keV) were used especially in the past *), now they are used, for
example, for irradiation of skin lesions. Radiotherapy with
high-energy heavy particles will be discussed below in a separate
section " Hadron Radiotherapy ". Here we will deal mainly with irradiation with
high-energy gamma radiation.
*) The main disadvantage of X-ray
therapy was the inability to achieve a sufficient dose of
radiation in the deepertumor lesion without
imposing enormous radiation on healthy shallow tissues,
especially skin. This shortcoming was largely addressed by the
use of penetrating radiation with significantly higher energies
of several MeVs, where the skin and superficial tissues ceased to
be a limiting factor as the maximum dose shifted in depth. First
it was cobalt and cesium irradiators (they were
introduced in the 50's), later hard radiation generated by betatrons
and later by linear accelerators .
Terminological note: Kilovoltage - Megavoltage
Radiation generators
are divided into two categories in radiological
"gimmicks" (in connection with historical development)
according to the radiation energies produced :
Kilovoltage - providing
energy up to 1000keV, is mostly produced by X-rays;
Megavoltage - providing energy above 1MeV, is
produced by accelerators (or radionuclides with correspondingly
high energy of radiation g ).
These slang terms are not physically appropriate and can be
misleading. We do not use them in our treatise.
The
intensity of the radiation decreases with the square of the
distance from the source. At greater distances, we obtain a more
favorable ratio between the amount of radiation that falls on the
surface of the body and the amount of radiation penetrating deep.
During deep irradiation, it is therefore irradiated from a
distance of min. 60cm from the surface of the body.
Gamma
- irradiators
Radiotherapy is currently performed mainly by penetrating
gamma radiation, produced either by radioisotope
irradiators 137 Cs ( g 662 keV) and 60 Co ( g 1173 + 1322 keV) (for
radionuclides see §1.4 " Radionuclides ") , or arising as braking
radiation (bremsstrahlung) *) under the impact
of high-energy electrons accelerated in a betatron
or linear accelerator (for
energies E e approx. 4-40MeV) to a suitable brake
target made of heavy metal (Fig.3.6.1b) - here the
radiant energies are in units up to tens of MeV (see §1.5 "Elementary particles", part "
Charged particle accelerators " ). The target is mostly
made of tungsten, on a plate about 2-3 cm thick it is thinned to
about 3 mm at the point of impact of the electron beam - it works
in "transmission" mode, braking radiation emanating
from the target in the direction of the original electron beam is
used. The robust design of the plate ensures heat dissipation (most of the kinetic energy of the electrons is
converted into heat) .
*) Terminological note: radiation
X or g ?
In §1.2 "Radioactivity", part "Radioactivity gamma
", we introduced a terminological agreement that photon
radiation emitted from atomic nuclei is called radiation g
(even if it has a low energy of a few keV), while the radiation
generated by the jumps of electrons in the atomic shell and the
bremsstrahlung of electrons is called X - rays
(X-rays - even if it has a higher energy of tens and hundreds of
keV). However, for braking radiation generated in accelerators at
energies of several MeVs, such terminology (a kind of
"megavolt X-radiation") would be misleading
, although sometimes used. This radiation lies deep in the g- region of the
classification of the electromagnetic spectrum, it has even
significantly higher energy than the usual g- radiation from
radionuclides. Therefore, we will call this high-energy
bremsstrahlung radiation gamma radiation .
At present, the betatrons have
been completely pushed out high-frequency linear
electron accelerators - LINAC , which
are smaller, more flexible and provide high radiation intensity -
Fig.3.6.1b, c (physical principles and
construction of accelerators are described in more detail in
§1.5 "Elementary particles and accelerators", part
" Charged particle accelerators " ) . For larger
accelerators for energies around 20MeV, for geometric reasons
LINAC is placed perpendicular to the gantry and the electron beam
is electromagnetically deflected in the transverse direction of
irradiation (Fig.3.6.1b). The deflection electromagnet also
serves as an energy filter of electrons, which deflects only the
electrons of the required energy (momentum) in the desired
direction - the other electrons end up on the walls of the tube(Fig. 3.6.1b shows, for simplicity, the bending of the
electron beam at an angle of 90 °, but usually 270 ° is used,
allowing a better focusing of the electron beam) . Smaller accelerators up to 6MeV can also have a
compact "rectilinear" design without deflection of the
electron beam (an indication is seen below in Fig. 3.6.4a, c).
Irradiators for radiotherapy,
equipped with linear electron accelerators with energy mostly 6
or 18MeV, are currently supplied mainly by two main
manufacturers: American Varian (Palo Alto, California, originally a manufacturer of
klystrons and accelerators) and Swedish Elekta
(Stockholm, also produces Lexell's
gamma-knife ) . They are then newly
approached by Tomotherapy and Accuray (which merged), producing special
tomotherapeutic and stereotactic robotic systems, equipped with
compact linear accelerators mostly 6MeV - see below " Tomotherapy;
Stereotactic radiotherapy ".
Left: Continuous
spectrum of braking gamma radiation generated by the impact of
electrons of energy E e 6MeV and 18MeV from a linear
accelerator on a target. In the middle: Line
spectrum of g- radiation of radionuclides 137 Cs and 60 Co. Right: Percentage depth dose
dependence for different photon energies (in the water phantom).
Braking photon radiation, caused by the impact
of electrons of energy E e on a target, has a continuous energy spectrum
with a predominance of lower energies (up to 1/3 E e ), which decreases
continuously from its flat peak (around 1/8 E e ) and then ends at
maximum energy just below the value of electron energy E e . It should be noted
that the mean energy of this radiation is significantly
lower than the original energy of the electron beam from
the accelerator. E.g. when using electrons accelerated to energy
E e= 6MeV
is the maximum in the spectrum of braking radiation around
500keV, the mean energy is about 1.5MeV, while the proportion of
photons with a maximum energy approaching 6MeV is already very
small (units%); the usual statement that "we irradiate with
6MeV energy" is therefore somewhat misleading. It is worth
noting that the depth distribution of the dose in water (and
tissue) is almost identical for g -radiation of 60 Co and
bremsstrahlung from the accelerator E e = 4MeV; and is only slightly different for an
accelerator with E e = 6MeV. These lower energy accelerators are therefore
basically interchangeable with a cobalt radiator (the cobalt source has slightly larger dimensions of the
radiator itself and therefore a larger half-shadow in the beam) .
Effective
cross section for the production of bremsstrahlung is
generally given by the rather complicated Bethe-Heitler
formula (derived from quantum
radiation theory, corrected by the Sauter and Elwert
factors of the Coulomb shielding of the electron shell) . For a not very wide range of energies of incident
electrometers E e and proton numbers Z of the target material
(medium to heavy materials), the overall efficiency of
brake radiation production h can be approximated by a
simplified formula :
h = E e [kev] . Z . 10 -6 [photons / electron]
.
Only a relatively small part (only approx. 1%)
the original kinetic energy of the incident particle changes to
braking radiation during braking in the fabric. Most of the
energy is eventually transferred to the kinetic energy of the
atoms of matter by multiple Coulomb scattering - it is converted
into heat .
It is logical that the
efficiency of brake radiation production is higher for high Z -
large electric Coulomb forces act around such nuclei, causing
abrupt changes in the velocity vector of the incident electrons
that get close to the nucleus. The efficiency of bremsstrahlung
[number of photons / electron] increases with energy E e incident electrons. However, the overall energy
efficiency - the ratio of the total energy of the emitted photons
to the energy of the incident electrons - is lower for higher
energies (due to the higher percentage of low-energy photons).
And the heat losses in the target are higher.
Contamination of the
photon beam by electrons and neutrons
The resulting beam of high-energy bremsstrahlung g is always somewhat
contaminated by electrons released during the
interaction of photons with the material of the target,
homogenization filter, screens and collimators. There is Compton
scattering, photoeffect, electron-positron pair formation. In all
these processes, fast electrons are emitted from the material. At
higher energies, above about 10MeV, photonuclear reactions and
release also occur neutrons (see below).
Secondary particles, which contaminate the photon beam, reduce
the depth effect and increase the radiation dose even outside the
direction of the primary radiation, they contribute to the
increase of the radiation dose outside the target volume.
Homogeneity of the irradiation beam
The beam of braking g- radiation, diverging conically from the interaction
point in the target, has a significantly higher intensity in the
central direction than in the peripheral parts (radiation diagram of braking radiation has a
"lobe" shape in the direction of high energy electrons
- §1.6, part " Interaction
of charged particles -
directly ionizing radiation ") .
Left: The directional radiation pattern of the
braking radiation from the target leads to an inhomogeneous
intensity distribution across the beam. Middle:
Achieve a homogeneous distribution with a suitably shaped
homogenization filter. Right : Example of
homogenization filters for different energies.
To achieve a homogeneous distribution of
radiation throughout the necessary width of the beam in the path
of the radiation following the homogenisation filter
*) - a rotationally symmetrical metal absorber disc-middle
heavily thickened shape (within a cone) that higher absorption in
the central part equalized radiation intensity across the cross
section beam (Eng. Flattening filter ). The higher the
energy of accelerated electrons E e, the more strongly the braking radiation is collimated
in the axial direction and the thicker the central part of the
homogenization filter is needed. For lower energies,
homogenization filters are usually made of aluminum, for higher
energies, heavier metals (iron, tungsten) and suitable alloys are
also used. Homogenization filters are usually replaceable and
each of them must be precisely shaped depending on the energy
used and also on the required field size and the distance in
which a homogeneous radiation intensity is to be achieved. In
addition to the homogenization of the irradiation beam, another
positive factor is the filtering out of electrons with which the
high-energy photon beam is often contaminated. Also, the spectrum
of bremsstrahlung across the beam is not exactly the same - in
the central part, the proportion of harder radiation is slightly
higher than in the peripheral parts; however, the homogenization
filter further emphasizes this difference.
*) A separate homogenization
filter is not used for cybernetic gamma knives ,
where it is irradiated with a relatively narrow central part of
the brake beam (see Fig. 3.6.4c below), the homogeneity of which
can be ensured by suitable shaping of the dot material. After
all, with stereotactic radiotherapy it is not necessary to
achieve homogeneous irradiation of the target tissue. Recently, homogenization
filters have generally been abandoned
in classical therapy, as new sophisticated computer scheduling
systems can accurately plan the dose distribution for any photon
beam dose profile profile (this profile is measured
dosimetrically and inserted into the scheduling system). Note: However, it is necessary
to take into account a slightly higher contamination of the
photon beam with an electron.
Collimation and
monitoring of the irradiation beam
The brake beam is further collimated by a system
of fixed forming orifices (primary orifice
just behind the target and secondary orifice behind the
homogenisation filter) . A part of the
irradiation head is also a radiation monitoring system
, which by means of ionization chambers indicates dose rates in
the irradiation field *). Finally, the beam is collimated
("modulated") to the desired final shape by a system of
movable screens - the most perfect collimation system is the
so-called MLC collimator (see below, Fig.3.6.3).
A light localization system is installed in the
head for visual aiming and adjustment of the irradiated field
- the light from the filament lamp is guided by optical
projection through the collimation system of the radiator so that
the agreement of the visible light field and the radiation field
is achieved. In modern isocentric irradiators, a detector is
built into the gantry opposite the irradiator (flat-panel
imaging, its principle is described in §3.2, section " Electronic
X-ray imaging "), allowing to
display the beam after passing through the patient - to create
so-called portal images - " X - ray images
of patient structures using high energy ("megavolt")
radiation. This portal display system is abbreviated EPID
( Electronic Portal Image Device ). This system also
allows operational dosimetry to be performed
operatively "", on the beam passed through the patient.
*) Radiation doses and
monitoring units
In addition to the standard units of radiation dose Gray
[Gy], in connection with phantom measurement (monitoring) of
radiation beams, so-called MU
monitoring units ( M) are often used in practical radiotherapy. onitor U nit) - 1
MU = -> 0.01 Gy (1 " centigray '). the
monitoring chamber indicates the dose of 100 MU, when in
izocentru feed delivered radiation dose of 1 Gy in water phantom (at a field size 10x10cm) .
Depth
effect of hard photon radiation
In photon radiation, the radiation dose is caused by secondary
electrons, arising from photoeffect, Compton scattering
and at higher energies also the formation of electron-positron
pairs (see §1.6 "Ionizing radiation", section " Interaction
of gamma and X-rays "). When
high-energy radiation g is used, Compton scattering predominates and the
secondary electrons have a predominantly primary beam direction
as well as high energy; they cause more and more ionization.
Thus, as high-energy radiation passes through the tissue, the
number of secondary electrons initially increases and ionization
increases . At a certain depth, the equilibrium of
charged particles is established and then the ionization begins
to decrease as the photon beam is gradually attenuated by
absorption in the tissue.
For hard photon radiation,
therefore, the maximum radiation dose is no longer on the surface
(as is the case with soft radiation), but shifts somewhat in depth
(the so-called build-up effect), depending on the
radiation energy. The depths of the maximum dose in the tissue
for different energies of photon radiation are approximately:
1MeV ... 4mm; 5MeV ... 1cm; 10MeV ... 2.5cm; 25MeV ... 5cm.
Although this effect alone can not be used for depth selective
irradiation from one direction, but has a significant impact on investigation
of the skin and the superficial tissues ( skin-sparing
effect) when izocentrické radiotherapy.
At greater depths, the
equilibrium state of ionization already occurs and the dose D
(dose rate) decreases with the depth daccording
to the standard exponential dependence D ~ e - m .d with a linear
absorption coefficient m ( r , E g ) given by the tissue density r and the radiation energy E g - the
higher the energy, the slower the decrease (it is derived in
§1.6 "Ionizing radiation", section " Radiation
absorption in substances ",
Fig.1.6.5).
High-energy hard radiation g *) therefore has
the advantage of less absorption (even in the bones) and thus a
better "geometric" ability to get the required dose of
radiation selectively to a deeper target location,
with relatively lower absorption and radiation exposure of other
tissues, especially skin.
*) From above, however, the
optimal energy of photon radiation is limited to about 20MeV,
because at higher energies frequent photonuclear
reactions occur (see §1.6, section " Interaction
of gamma and X-rays "), due to
which the beam is contaminated with neutrons
. These neutrons scatter in the tissue and cause radiation
exposure even outside the direction of the original beam, ie
outside the target volume. In general, it should be noted that at
energies higher than 10MeV g-
activation of the
irradiator materials, which are exposed to the radiation beam -
target, homogenization filters, collimators, bed and other
components are weakly radioactiveeven after the
exhibition! Short-term radionuclides ( 15 O, 11 C, 13 N, in trace amounts further 24 Na, 29 P, 34 Cl, 35 S, 38 Ca, 38,42,43 K) are also formed in the irradiated volume of the
patient , but in such a small amount that their contribution to
the radiation dose is completely negligible (<10 -5 %).
Electron irradiation
For irradiation of surface and shallow lesions, the primary
electron beam from the accelerator (energy of
the MeV unit, approx. 4-12MeV) is sometimes used . In the
arrangement according to Fig. 3.6.1b, the electrons from the
accelerator do not fall on the target, which is
displaced (of course, the homogenization
filter is also displaced) , but they are
led through a collimating tube directly into the patient's body.
The primary narrow electron beam (approx. 3 mm in diameter) is
guided, instead of on a target, on a scattering foil to scatter
the electrons over the entire irradiation field. In some
systems, the electron beam is swept to the
desired width by electromagnetic deflection coils (similar to an electron beam in a conventional screen) . Electron irradiation is suitable for surface
bearingsor at a small depth below the surface (up to about 5 cm),
which can be irradiated only from one direct direction (field)
and where at a depth below the irradiated deposit there are
tissues or organs that must not be irradiated with a higher dose
of radiation. Compared to gamma radiation, the electron beam has
a sharp decrease in dose towards the depth of the tissue: the
maximum range of electrons in the tissue in centimeters is
approximately 1/2 of the energy used in MeV, the
mean range is about 1/3 of this energy.
For high electron energies, an
analogous mechanism of the "depth build-up
effect" is manifested (cf. Fig. 3.6.5a
below), which was mentioned above for hard
photon radiation: To a certain depth, the absorbed dose increases
somewhat, then - after the equilibrium of charged particles has
been established - it begins to decrease rapidly as the electron
beam is inhibited and attenuated by interaction with tissue. If
high-energy electrons need to irradiate the surface layers of the
skin, the build-up effect is undesirable and tissue-equivalent boluses
(also mentioned below) are used to suppress it , which leads to
an increase in the surface dose and a reduction in the depth
dose.
" Visibility of the invisible "
- display of radiation beams
Ionizing radiation used in radiotherapy is invisible to
our eyes , we can register them only using special methods of detection
and spectrometry (Chapter
2 " Detection and spectrometry of ionizing radiation ") . For better clarity,
however, it would be appropriate to somehow directly " make
visible " this radiation, respectively. its
interaction with the substance. One of the methods was described
in §2.2 - 3-D gel dosimeters ; however, it is a relatively complicated and demanding
method, it is used very rarely ... There are two other ways to
directly and easily "make visible" the passage of
ionizing radiation through a substance: Cherenkov
radiation in an optically transparent medium (also in water ) and
scintillation radiation (preferably
in a liquid scintillator ) .
We used these methods experimentally for electron and photon
beams at our workplace and for proton beams at PTC .
.Cherenkov
radiation
During the passage of fast electrons - whether primary or
secondary - through the medium, a weak visible so-called Cherenkov
radiation is emitted (§1.6, passage
" Cherenkov
radiation ") . The following figure shows an example of the
"visibility" of an irradiating electron and photon beam
in water using this Cherenkov radiation :
![]() |
Cherenkov radiation generated in an
aqueous phantom during irradiation with electron and
photon radiation beams. Left: A cylindrical phantom (diameter 20 cm and height 18 cm) filled with water was irradiated with a wide (magnetically scattered) beam of 9MeV energy electrons from a linear accelerator. Middle: . During passing through the upper part of the phantom, fast electrons generated Cherenkov radiation to a depth of about 4.5 cm, when the energy of the electrons fell below the threshold level of 260 kV. Right: When irradiating the same phantom with a beam of photon radiation (max. Energy 6MeV, beam with a diameter of 4cm)form secondary electrons along the g beam Cherenkov radiation - with a deep decrease in intensity as the primary photon beam weakens as it passes through water (just below the surface, a slight increase in intensity is initially seen - build-up effect to a depth of about 1 cm, discussed below) " Secondary radiation generated by X and g interactions ") . Note: In the upper and lower part, optical reflections of light from the cover and from the bottom of the phantom are visible. Due to the relatively weaker intensity of the images, the images contain a higher amount of disturbing noise. .. Acknowledgments: Irradiation of the water phantom on TrueBeam and CyberKnife deviceswas performed in cooperation with colleagues: Ing.L.Knybel, Ing.L.Molenda and Ing.B.Otáhal. |
Display of radiation beams
in a liquid scintillator
Another option for displaying the passage of beams of ionizing
radiation through a substance in a suitable phantom is the use of
a liquid scintillator (liquid
scintillators and their use for internal measurement of
beta-radioactive samples are discussed in §2.6, section " Detection of beta radiation by liquid
scintillators ") .
At our departmwnt, we used a liquid
scintillator (in a very unconventional way)
to map and visualize the radiation
beams - electron, photon, proton - used in radiotherapy.
We filled a glass measuring cylinder with a
diameter of 6 cm and a height of 44 cm with 1 liter of liquid
scintillator (we useddioxane
scintillator with a density of 0.95 g / ml) and
placed it under the irradiation head of the respective irradiator
- electron Varian , photon CyberKnife , proton IBA
. From the side, we observed and photographed the
scintillation radiation generated in the scintillator along the
passage of the irradiation beam :
![]() |
Fig .... Scintillation radiation
generated in a cylinder (diameter 6 cm and
height 44 cm) filled with a liquid scintillator
during irradiation with electron, photon and proton
radiation beams. a), b): A cylindrical phantom filled with a liquid scintillator was irradiated with a wide electron beam of 6 MeV and 18 MeV from a linear accelerator. c), d): When irradiating the same phantom with a photon beam - max. energy 6MeV, beam 1.5 cm and 3.5 cm in diameter - secondary electrons along the g beam generate scintillation radiation - with a deep decrease in intensity as the primary photon beam weakens when passing through a liquid. Acknowledgments: Irradiation of the scintillation phantom on TrueBeam and CyberKnife devices was performed in cooperation with colleagues: Ing.L.Knybel, Ing.L.Molenda and Ing.B.Otáhal. e), f), g): When irradiated with narrow(" pencil beam ")proton beams of energy 100, 170 and 226 MeV, the protons penetrate to different depths depending on the energy, with a significant Bragg maximum. Acknowledgments: Irradiation with proton beams from the IBA cyclotron was performed in cooperation with colleagues: Ing.P.Máca,Ing.M.Andrlík,Mgr.L.Zámeèník, Ph.D. , Ing.M.Navrátil, Ph.D.(and consultations with colleagues Ing.V.Vondráèek and MUDr. MUDr. J.Kube, Ph.D.) from the PTC proton center in Prague. |
Analysis and
discussion of the image:
¨ When irradiated with a wide
electron beam of energy 6MeV (
a ), a bright blue glowing trace to a depth of about 26
mm can be seen in the scintillator, where the electrons are
already braked.
¨ Electrons of energy
18MeV ( b ) continue to a depth of
about 78mm, under scintillation radiation. However, the
interaction of these high-energy electrons with the scintillator
atoms also produces intense photon bremsstrahlung
radiation , which is penetrating and continues to depth.
The angular distribution of the emitted
photons of bremsstrahlung depends on the energy of the primary
charged particles. At low energies, the bremsstrahlung is emitted
practically isotropically in all directions from the point of
interaction. As the energy of the electrons exciting the
bremsstrahlung increases, the mean angle of the emitted quanta
becomes smaller and smaller - at high energies of the incident
charged particles, the bremsstrahlung is preferentially emitted
in a narrow cone " forward " in
the direction of impact of the primary particles. The directional
radiation pattern of high-energy bremsstrahlung has the shape of
a sharp "lobe" in the direction of the primary beam.
Thus, in addition to a clear
scintillation pattern of electrons in the upper part, we also
observe a weaker narrow beam of bremsstrahlung ,
continuing to the bottom of the phantom.
¨ When
irradiated with a photon beam from CyberKnife
(narrow and wide - c, d ) with a continuous
spectrum with a maximum energy of 6MeV, we see a
significant scintillation trace from secondary electrons across
the entire cylinder - the photon beam penetrates deep
to the bottom (and would reach even deeper)
, with a slight depth drop in intensity as
the photons are gradually absorbed as they pass through the
liquid.
It is interesting to compare these images
with the above representation of the same irradiation beams using
Cherenkov radiation in an aqueous phantom.
¨ When irradiated with proton
beams ( e, f, g ), we see a significant
scintillation trace, which amplifies and ends
with a clear Bragg maximum ; the radiation no
longer continues to a greater depth . The depth
of the Bragg maximum increases with proton energy
.
The blue " halo
" around the proton beam is caused by secondary electrons
ejected from the matter as the protons pass. With lower proton
energy, this "halo" is wider - electrons are less
collimated in the direction of the primary beam; this is
especially evident at the end of the orbit around the Bragg peak,
where the protons are already considerably slowed down.
Irradiation
field
From a geometric point of view, radiation for radiotherapy can be
divided into one or more areas of certain shapes and intensities
and from different directions - the so-called irradiation fields
. For surface lesions, one irradiation field of softer photon
radiation (or electrons) is usually sufficient; for lesions
deposited in depth, a larger number of suitably shaped
irradiation fields are used (converging or
opposite fields, "crossfire" of four fields and many
other combinations) . Various absorption
filters, screens , wedges (Fig. 3.6.1b ') or special collimators (see below) are often used to
form the shape of the radiation beam (and thus also the isodose curves) . , suitable filters are used to
influence the energy spectrum of the radiation .
To compensate for the irregular shape of the surface, or to
adjust the dose on the surface and in depth, the so-called compensatory
bolus (Greek bolos = lump,
wad, piece ) is sometimes used - a
suitably shaped tissue-equivalent material of a certain
thickness, which is applied to a suitable place on skin, or
inserted off-surface into the radiation beam.
Note: A more
detailed description of irradiation techniques of this kind lies
outside the scope of our physical treatise. From a physical point
of view, they are not very interesting and, moreover, they are
gradually being pushed out more and more by more advanced and
accurate IMRT and IGRT techniques - see below.
The most perfect deep irradiation
technique is isocentric irradiation with
high-energy radiation with suitable shaping and modulation
of the irradiation beam - IMRT , with
or. IGRT imaging navigation - and stereotactic
irradiation with narrow sharply collimated beams of
radiation (with radiation navigation); the most complicated is hadron
radiotherapy . These methods are described in detail
below.
Isocentric
radiotherapy
The main strategic goal of radiotherapy - effective selective
irradiation of the tumor site with the least possible
damage to surrounding tissues - is achieved by irradiating the
tumor site with a collimated beam from multiple
directions *) so that the intersection of beams
, ie focus or isocenter , where
doses add up, it was localized to the tumor site - Fig.3.6.1a.
The surrounding healthy tissues then receive a reasonably lower
dose , divided into a larger area. Simply put, healthy
tissue (its individual sites) is irradiated only once, while the
tumor is irradiated each time.
*) For this purpose, the radiator is
mounted on a special round stand, the so-called gantry
(gantry - portal, continuous supporting structure ),
enabling controlled rotation of the radiation
source around the patient by means of electric motors .
Fig.3.6.1. Movement isocentric radiotherapy with a
collimated beam of gamma radiation.
a) Basic idea scheme of irradiation with a
rotating irradiator. b) Arrangement of the
radiator with a linear accelerator. c) Example
of a modern IGRT radiator.
Collimated
fields and radiation beams for radiotherapy
From a general physical point of view, the properties
of ionizing radiation were described in §1.6 "Ionizing
radiation" (fields and beams were then
mentioned in the section " Fields and beam, radiation intensity ") . The primary radiation
from the accelerator (electron radiation or proton radiation for
hadron therapy) usually emits in a precisely defined direction,
in a narrow beam (which is then further modified, filtered and
shaped). However, the radiation g (and possibly X), arising
in radionuclides (cesium or cobalt), or excited as secondary
braking radiation after the impact of the primary electron beam
from the accelerator on the target (Fig.3.6.1b), is emitted in
practically all directions(high-energy
braking radiation has only a higher intensity in the central
direction, which is corrected by a homogenization filter) . In order to create an irradiation beam for targeted
(tele) radiotherapy, it is necessary to shield the
vast majority of this diffuse radiation and transmit only the
radiation in the required direction - to perform the collimation
of the radiation . The simplest collimation is roughly
shown in Fig.3.6.1a - tube -shaped collimator .
More complex collimation systems are used to accurately shape the
irradiation beam, the most advanced of which are the
electronically formable MLC collimators
described below ("Irradiation beam
modulation") .
In the middle part of the
(homogenized) beam of radiation defined by the collimator, there
is an approximately homogeneous intensity distribution. At the
edges, the intensity does not suddenly decrease to zero, as would
follow from an idealized geometric configuration, but decreases
continuously. Absolutely sharp collimation cannot be achieved in
practice for two reasons :
- Geometric
blurring due to the non-zero size of the primary source (manifests itself especially in radioisotope sources) .
- In
the case of penetrating high-energy radiation g , partial radiation
occurs at the edges of the collimator .
In the marginal parts of the
collimated beam, a kind of " half shadow
" is created . Next to this geometric penumbra
the scattering of the radiation beam in the
tissue also applies (this scattering is significant especially in
the electron beam). At higher energies, the photon beam in the
tissue is sharper, there is less scattering penumbra
. These two effects - geometric and scattering - create in the
dose distribution in the tissue the resulting dose
half-shadow in the marginal parts of the radiation
beam, which must be taken into account when planning
radiotherapy, can significantly affect the isodose curves
.
Technical Note:
For the sake of simplicity, the irradiation beams are shown
in Figures 3.6.1 and 3.6.2d by lines (arrows) of constant width.
In reality, however, the radiation beams have a diverging
geometry - with distance from the radiation source
expand .
Radiotherapy planning
The combination of physical and biological factors in most cases
enables sufficiently effective and selective
irradiation of the pathological lesion. In clinical radiotherapy,
the patient's own irradiation is always preceded by a very
important and demanding process of radiotherapy planning
, the result of which is the so-called irradiation plan
, containing all the specific details of the irradiation process
for the patient. A properly designed radiation plan is a basic
prerequisite for successful radiotherapy.
The main basis for creating an
irradiation plan are detailed diagnostic images of the
irradiated area. At present, it is mainly the X-ray
images tomographic( CT ), or on nuclear magnetic resonance ( MRI ) and scintigraphy imaging , in
particular positron emission tomography ( PET ). These images serve both for the precise
localization of the tumor site together
with the determination of its size and shape, as well as as a
detailed anatomical-density map of the distribution of
tissue densities and the location of organs .
Radiotherapy
simulator
In exact radiotherapy planning, a so-called simulator
is used - a device that mimics the entire irradiation process and
allows its optimization. The classic simulator is a diagnostic X-ray
device with an image intensifier, the X-ray tube of
which is mounted on a rotating isocentric arm and is equipped
with a system of adjustable apertures, enabling the imitation of
a beam of radiation as it will then be used on its own
therapeutic irradiator. The simulator enables localization
of the target volume and topometry of tumor deposits, aiming
of the beam and modeling of field geometry
and irradiation parameters, drawing of orientation and reference
points and markers on the patient's body.
Instead of the classic simulator, the
so-called virtual simulator - X-ray imaging
device CT is now often used for advanced
irradiation technologies (IMRT, IGRT). equipped with a aiming
system and special software for batch planning. The planning
software first converts the Hounsfield units of the CT image to
the electron density of the individual tissues.
Furthermore, the target volumes and critical
organs are marked on the pictures . Then the images are
overlaid with the characteristics of the radiation beams (energy,
dose distribution - isodose curves). The marked structures are
then displayed in the transformed BEV (
Beam's Eye View ) mode - from the
point of view of the radiation beam. In conventional planningthese
overlapping images are then sought to find the most favorable
irradiation conditions for delivering the desired dose to the
target volume. The number of irradiation fields and their shape,
dose rate, angles and other parameters for optimizing the
irradiation plan are set. The so-called inverse planning
will be mentioned below in connection with the IMRT and IGRT
techniques.
Images from CT examinations
are thus directly included in the planning of
therapy - 3D-planning, which is followed by the so-called 3D
conformal radiotherapy (3D CRT), or even more advanced therapy
with modulated IMRT-IGRT beams. The transfer of data from the CT,
via the planning computer to the computer controlling the
irradiator, provides the possibility of shaping the
irradiation fields based on accurate spatial knowledge
of the internal anatomy around the target tissue of the patient;
the radiation beams are thus adapted to the target volume and
protection of the surrounding critical tissues.
From these data and the
required radiation dose in the target tissue
(this dose depends on the tumor type - its radiosensitivity
), as well as the maximum tolerance dose in the surrounding critical
organs , the intensity, energy and geometric parameters of
the radiation beam are calculated, including precise radiation
positions. angles. Batch fractionation is further
determined . The whole process of planning and subsequent
radiotherapy is now largely automated using
computer software that works in several basic stages (Fig.3.6.2)
:
Fig.3.6.2. Some basic stages of computer radiotherapy planning.
a) Diagnostic X-ray (CT) image of the irradiated
area. b) Drawing of areas of interest of the
target volume and critical tissues, selection of the irradiation
procedure, number and shapes of beams and radiation intensities
(fields). c) Optimization of the irradiation
plan using dose-volume histograms of DVH. d)
Control of the function and movements of the irradiator by the
resulting irradiation regulation.
l Analysis
of diagnostic data , choice of treatment strategy -
curative or palliative therapy, combination with surgery and
chemotherapy, localization of the target tumor volume.
l Processing of initial X-ray
images from CT (Fig.3.6.2a). Tissue density (expressed
on CT in Hounstfield units) is converted to electron
density . This takes into account the inhomogeneity of
the tissues (different electron densities of soft tissues, water,
air, bones) during the passage and interaction of the irradiation
beam. The electron density of the substance is directly
proportional to the linear energy transfer LET (the
amount of energy loss per unit path) and thus the local
ionization in the tissue and the absorption of radiation - radiation
dose distribution. To refine the irradiation plan, it is
also appropriate to take into account gammagraphic images of PET
(eg by computer fusion of CT + PET images), which map the viability
of tumor tissue - it was discussed above in the section
" Diagnosis of cancer ".
l Drawing
the regions of interest ROI into the picture -
especially the target volume of the tumor
lesion, then the risk critical tissues and
organs (Fig.3.6.2b). These areas of interest are drawn in
individual transverse sections, the program combines them (using
interpolation) into a three-dimensional volume .
Perpendicular frontal and sagittal sections can also be used when
drawing ROI.
Target
volumes irradiation
Target irradiation volume ( Target Volume ) means the
corresponding region of tissue localization and size (volume), to
which must target canceroletal desired dose. For successful curative
radiotherapy, it is necessary to apply a lethal dose of
radiation not only to the actual volume of the macroscopically
detected tumor deposit, but also to some neighboring areas - the
so-called safety margins (margins),
reducing the risk of insufficient irradiation of structures that
could be affected by cancer and subsequently cause recurrence of
the disease. In connection with this, we have three or four
consecutive target volumes in radiotherapy:
¨ Basic target volume GTV
( Gross Tumor Volume) represents the intrinsic volume of
a macroscopically detected tumor lesion, imaged using an
appropriate image (mostly CT). Some other neighboring areas - lem
- margin - are then added to this initial, basic or gross
volume .
¨ Clinical
target volume of CTV
To safely ensure local control of the irradiated
lesion, it is necessary to apply a lethal dose of radiation not
only to the actual volume of the macroscopically detected GTV
tumor site, but also to those neighboring areas where clinical
experience could already hide hidden microscopic spread of tumor
cells. Therefore, we increase the irradiated target volume of GTV
by a clinical safety margin - the so-called clinical
target volume of CTV is created
(Clinical Target Volume ). It is analogous to the safety
margin in the surgical removal of visible tumors.
¨ Internal target volume of ITV
Due to internal physiological changes in the position of the
target volume within the organism (eg due to respiration *,
variable filling of the bladder and intestines, peristalsis,
swallowing, heart pulsation), further expansion to the internal
target volume of ITV (Internal Target
Volume) is needed . which includes the entire path of
internal movement of the target tissue.
*) Tumor tracking Advanced methods of
stereotactic radiotherapy use the so-called tumor tracking
- monitoring the movement of the tumor due to respiration, its
consideration and correction, which allows to reduce ITV
and thus minimize the exposure of the surrounding healthy tissue,
or. escalate the dose to the tumor site. These
"tracking" methods of respiratory gating or respiratory
synchronization are discussed below in the " Stereotactic Radiotherapy " section.
¨ Resulting planned target volume
of PTV
Due to the expected reproducibility of the position of the
patient and the irradiator during fractional irradiation, it is
sometimes necessary to further expand the target volume by the
so-called position hem . This creates the resulting Planning
Target Volume ( PTV), which is drawn in the
irradiation plan. PTV includes CTV and an expanding rim for ITV
organ and tissue movement, as well as for expected irregularities
in irradiation settings. The resulting PTV is thus a unification
(outer envelope) of all partial target volumes: PTV =
GTV È CTV È ITV È
[position lem].
l Enter
the required radiation dose in the target tissue and the
maximum allowable dose in critical tissues. This is based mainly
on empirical experience, which results in the coefficients a, b of radiosensitivity
of a given type of tumor tissue and tolerance doses for healthy
critical tissues (discussed above in the
section " Physical and radiobiological
factors"). "Passage" Prediction
of therapeutic effect ") .
l Selecting the
basic irradiation method - the number and
geometric configuration of the radiation fields, energy and
intensity of the beam - its eventually. Modulation, the number of
fractions.
l Calculation
of the distribution of local dose in the thus mapped
tissue - construct is called. isodos curves (touch is seen on obr.3.6.2d) .The radiation beam in practice, is never homogeneous, as
well as the absorption of radiation in tissue, so that the
spatial distribution of radiation intensity and the radiation
dose is usually a complex waveform (highest
dose is usually in the central part of the bundle, The spatial distribution of the radiation dose is often
mapped using the so-called isodose curves - imaginary lines
representing the connection of points with the same dose.
Usually, isodose curves are plotted for certain percentages from
the site with the maximum dose, e.g., isodoses of 80%, 50%, 20%,
and the like. (reminiscent of contours on
the map) .
l Optimization
of the irradiation plan. Dose Volume
Histograms are often constructed for this purpose
(Fig.3.2.6c). These histograms provide an illustration of the 3-D
dose distribution using a clear 2-D curve display. Each marked
area of ??interest has its own DVH curve. On the horizontal axis
is the dose (in Gy or in% of the max. Dose), on the vertical axis
is the volume (in% of the volume of the marked structure). DVHs
show the dose exposure of the target volume (PTV) and individual
identified critical organs (NT).
DVH
dose-volume histograms
Dose-volume histograms indicate how much of
the volume of the target or critical tissue receives a particular
dose. From the point of view of the basic radiotherapy strategy,
it is desirable that the largest possible volume of the target
(tumor) PTV tissue receives the highest possible percentage of
the required dose (ideally 100%). At the same time, the smallest
possible volume of critical healthy tissue NT received the lowest
possible part of the dose. This dosage exposure target volume and
critical organs indicated schematically shown in a dose-volume
histogram DVH . The optimization of radiotherapy
here consists in optimizing the areas under the
DVH curves - the largest possible area under the target PTV
volume curve and the smallest possible area under the histograms
of NT critical organs (NT / PTV area shares under DVH curves
represent relative "partial volumes" of irradiated NT
tissues).
In a more detailed analysis, we
can further improve radiotherapy optimization by converting dose
and dose distribution values from standard DVH to BED
, or to TCP + NTCP and derived UTCP
(these values were defined and discussed above in " Physical
and radiobiological factors in radiotherapy ", passage " Prediction
of radiotherapeutic effect - TCP, NTCP ").
l Transfer data to the irradiator coordinate
system .
l Creation of an irradiation prescription
, according to which the functions and movements of the
irradiator are controlled during the actual
irradiation (symbolically in Fig.3.6.2d) - mainly angular
positions of the irradiator, exposure times, geometry of the
radiation beam by means of modulation by the MLC collimator.
Current planning calculation
systems are also able to implement so-called inverse
planning (see below), in which the planning system
calculates the parameters and movements of the irradiator so as
to achieve the primarily required dose distribution in the target
volume (bearing) and do not exceed tolerance doses in surrounding
tissues.
Dosimetry
and verification in radiotherapy
To ensure the necessary accuracy of radiotherapy, a so-called verification
system is also needed . For dosimetric
verification ionization chambers or diode detectors are
most often used. These detection elements can be individual (with
mechanical shift), in a linear or two-dimensional matrix
arrangement, or in a cylindrical structure for measuring
isocentric irradiation. They are placed in the irradiation beam
either directly ("in the air") to map the intensity of
the beam, or they are inserted into suitable water or plastic phantoms
, modeling typical anatomical structures for irradiation. Dose
monitoring is also performed " in vivo ",
directly when irradiating a patient to whose body dosimeters are
applied to the appropriate sites. An elegant method of
verification and at the same time in vivo
dosimetry is the use of images from the portal
flat-panel of the irradiator(flat-panel
principle is described in §3.2, passage " Electronic display X-rays ") , their calibration and
quantification - called. portal dosimetry EPID (
Electronic Portal Dosimetry image ).
Rarely, 3-D gel
dosimetry systems are also used , allowing to determine
the spatial distribution of the dose in the irradiated volume
(the gel is filled in a phantom modeling the irradiated
structure). This method is quite demanding both in the stage of
phantom creation and in terms of evaluation (a more detailed
description is in §2.1, section " 3-D gel dosimeters "), it is used only for research and development
work.
For the quantitative
assessment of the consent of irradiation plans and dose
distributions, the so-called gamma-analysis ,
whose output parameter g
-index (0 <g£ 1) is closer
to 1, the better the agreement.
In modern irradiation systems,
the irradiation and verification technology is integrated
into one irradiation device. High demands are placed on the accuracy
and reproducibility of the geometric position
of the patient relative to the radiation beam - so that
the irradiated target volume is precisely set in the coordinate
system of the irradiator. Various markers (markers) drawn or
placed on the surface of the body and laser sights
are used for this. Opposite the irradiator, detectors (display
flat-panels) are built into the gantry, enabling the creation of
so-called portal images during irradiation ; even more
perfect is the X-ray system con-beam CT . These IGRT
-guided radiotherapy methods are described in the following
section. In classical stereotactic radiotherapy of
intracranial lesions, a stereotactic frame is used for
precise targeting of the target lesion , in cyber irradiators
special stereoscopic X-ray imaging and aiming systems -
see the section " Stereotactic
radiotherapy. Gamma-knife
" below.
The proper interplay of this
complex "technological chain" requires the cooperation
of an experienced radiological physicist .
Uncertainties in
radiotherapy
Every physical or technical, diagnostic and therapeutic method is
burdened with greater or lesser inaccuracies, errors,
uncertainties. Naturally, even during the complex chain of
radiotherapy, we encounter a number of uncertainties. The
"input" primary uncertainties are :
¨ Location
and extent of the disease , the uncertainty of which is
given by the accuracy and sensitivity of diagnostic methods, or.
it can be affected by artefacts of imaging methods, inaccuracies
in the patient's settings, his general movements and the
movements of organs inside the body.
¨ Radiobiological factors
- radiosensitivity of tumor and healthy tissues (parameters a, b in the LQ
model, the rate of cell repair and repopulation) is known only
approximately and in a lump sum, it can vary considerably from
individual to individual. This leads to uncertainties in the
basic regulation of the radiation dose and its fractionation.
During the process of planning and implementation of
radiotherapy, this is followed by other uncertainties :
¨ Inaccuracies in plotting ROI
- defining target volumes and critical structures in planning
images. This process is highly dependent on the experience of the
relevant expert
¨ Uncertainties in irradiation
technology - accuracy and stability of energy and
intensity of the primary irradiation beam, uncertainties in the
monitoring system, accuracy of the collimation system, geometric
setting of distances and isocenters, accuracy of transfer of
irradiation plan parameters to the irradiator control system.
¨ Inaccuracies
and disturbances during the patient's own irradiation -
variability in the positioning of patients under the irradiator,
fixation and movement of the patient, movement of tissues and
organs inside the patient during irradiation.
New knowledge in the field of
radiobiology, together with advances in diagnostic methods and
technical improvements in irradiation technologies, especially
their integration with imaging modalities, make it possible to
gradually reduce or eliminate these numerous uncertainties. This
increases the radiobiological, dosimetric, geometric and overall
accuracy of radiotherapy .
Modulation of radiation beams
Radiotherapy with modulated beam intensity - IMRT
In order to perform sufficiently intense and
homogeneous irradiation of the tumor and investigation of
surrounding tissues, it is necessary to shape the beam
to achieve maximum irradiation of the target volume of the given
geometry (size and shape) and the dose in the environment lower,
the surrounding tissues and organs were shielded against
radiation. For this purpose, suitably shaped filters
(masking blocks of various shapes) and screens
or collimators defining the field size are
inserted into the radiation beams . This used to be done manually
for each irradiation field and was very laborious(The workplace was equipped with a mechanical workshop,
where the covering blocks were cast, cut and machined) . With technical development, therefore, we proceeded to
create more universal mechanically movable screens. By dividing
these screens into independently moving segments, a very flexible
multi-lamellar collimator MLC ( Multi Leaf
Collimator) was constructed , mounted on the output of the photon
beam of braking radiation from the accelerator - Fig.3.6.3. MLC
collimators have a larger number of lamellae (approx. 60-120
sheets) 5-10 cm thick, which can be moved independently
by means of electric motors . This makes it possible to create an
opening of any shape for the radiation beam , or
several openings dividing the bundle into several parts. The
edges of the lamellae are suitably shaped to mimic a diverging
irradiation beam to reduce "half-shadow". The entire
collimator can continue to rotate. The electric motors driving
the blades are computer controlled - the MLC collimator is electronically
formable .
Irradiation is performed from
several directions, while during irradiation with the help of
electric motors the position of individual lamellas of the
collimator changes - the intensity is modulated
across the radiation beam and thus the dose is regulated.in
individual parts of the irradiated volume. The beam of radiation
is as if divided into individual rays with different intensities.
By combining several fields modulated in this way from different
directions, a more optimal dose distribution, selective
irradiation of the target tissue with better investigation of the
surrounding tissues and critical organs (which is obscured by
appropriate MLC shaping) is achieved. This makes it possible to
irradiate even irregular tumors with maximum examination of
healthy tissues in the vicinity of the tumor. The method is
called IMRT ( Intensity Modulated Radio
Therapy ) - radiotherapy with controlled (modulated)
beam intensity . This is ensured by the construction of
special MLC collimators, which modify - shape, modulate-
radiation beam at the output of the radiator (linear
accelerator). Dose intensity modulation is achieved by
superposition of overlapping radiation fields during rotation of
the irradiator with different positions of the MLC lamellae. The
edges of the lamellae projectively "copy" the shape of
the irradiated target volume, transmit an intense beam into the
tumor bed and shield the surrounding tissues and critical organs.
![]() |
Fig.3.6.3. Electronically adjustable
collimators for precision radiotherapy with modulated
IMRT beam. a) The multi-lamellar collimator MLC with the help of motor-shifted shielding lamellae allows to flexibly shape (modulate) the radiation beam from the accelerator for radiotherapy with modulated beam IMRT. b) Micro-MLC (mMLC) - miniaturized MLC as an extension to a standard irradiation head with MLC, for therapy with narrow sharply collimated beams. c) Binary (bipolar) MLC for tomotherapy. d) An iris-collimator with an electronically (motorized) controlled hole size - aperture - can replace a whole set of fixed collimators with circular holes of different diameters in a cybernetic gamma knife. |
From the point of view of time control, the modulation of the
IMRT irradiation beam can take place in two modes :
l Intermittent
mode ( step-and-shoot ), where the collimator
lamellae are in motion only during pauses between irradiations.
The MLC collimator forms the desired aperture through which
irradiation is performed. Then the irradiation is stopped, the
lamellae are moved to the next position (or the collimator is
rotated), the angle changes to gantry and another dose of
irradiation takes place. It is basically an improved technique
for a large number of static fields.
l Continuous mode
( dynamic, sliding windows- sliding window) - the
collimator lamellas move smoothly, move and modulate the beam
into the desired shape during irradiation. The movement of the
collimator blades in synchronization with the rotation of the
collimator and the entire irradiator on the gantry is
electronically controlled by the appropriate software. According
to the irradiation plan, when the irradiator is rotated on the
gantry (gradually by up to 360 °), the dose rate changes and is
irradiated with a modulated beam. This process is sometimes
referred to as Intensity Modulated Arc Therapy (IMAT)
- intensity-modulated radiotherapy angle .
Another
improvement of this system is called AMCBT ( Arc-Modulated
Cone Beam Therapy ) - angularly modulated therapy with
conical beams , or VMAT
(Volumetric Modulated Arc Therapy) - volume modulated arc therapy
, or RapidArc. It contains an irradiation beam
controlled by a modulated MLC collimator and a controlled
rotation of the irradiator around the patient. In some systems, the
primary intensity of the beam is also continuously modulated
by regulating the flow of electrons in a linear irradiator.
Controlled movement of the bed, rotation of the collimator with
the patient and rotation of the irradiator gantry are also
possible.
The VMAT
technique therefore allows the dynamic change of
some parameters during irradiation: - The gantry can move at a
variable speed; - the position of the individual lamellae of the
MLC collimator is variable during rotation; - The collimator can
rotate. The dose and geometry of the beam is thus continuously
modulatableduring the rotation of the radiator on the
gantra.
Thanks to another, angular-intensity
degree of freedom (a number of finely adjustable
irradiation beam angles with individually set beam shape and
intensity are available), the selectivity of the radiation dose
delivered to the target tissue is further improved and the irradiation
time is shortened . By modulating the dose rate during
irradiation, healthy tissues and critical organs are better
protected, and the whole-body dose is reduced
.
In
addition to the standard MLC collimator, two modifications are
used :
Micro-MLC (mMLC) - a miniaturized multi-lamellar
collimator for irradiation with narrow sharply collimated beams
in so-called stereotactic radiotherapy (see
below). It is mostly used as an attachment mounted on a standard
irradiation head with MLC for radiotherapy with modulated IMRT
beam (Fig.3.6.3b).
Slit -shaped binary or bipolar
MLC with a plurality (64) of linearly arranged lamellae
that open and close, thereby modulating the beam in the plane of
the transverse section (Fig. 3.6.3c). It is used in so-called tomotherapy
(see below, Fig.3.6.4a). The slats of binary MLCs are driven
electromagnetically or pneumatically, which achieves a very fast
response of opening and closing of slats (tenths of a second).
The method of
intensity modulated radiotherapy, analogous to IMRT, has recently
been introduced in proton radiotherapy - the so-called IMPT
(Intensity Modulated Proton Radiotherapy ), see " Hadron
Radiotherapy " below.
Image-guided
radiotherapy - IGRT
The high potential for accuracy,
flexibility and conformity of IMRT technology (as well
as gamma-knives , see below) can only be used
effectively in co-production with a very precise method of
verifying the targeting of the irradiation beam to the
target volume. Such verification of the target volume can be
performed by displaying the area of ??the
irradiated lesion and surrounding structures before each
irradiation or fraction, followed by computer comparison with
initial planning images, evaluation and transfer of results to
the irradiator coordinate system. In this case, it is
online image management. According to the current images
obtained immediately before each individual irradiation, the
position of the patient and the targeting of the tumor site can
be adjusted as required. This achieves a precise setting
that is updated accordingly each day of treatment. Only after the
patient's position has been verified in this way is the
self-irradiation triggered.
Such
additions and improvements irradiation technology is referred to
as IGRT ( Image-Guided Radiation Therapy
) - Radiotherapy controlled ( navigated
) by image *), controlling the patient's
position (target volume and surrounding structures) during the
treatment process using radiological imaging methods. It combines
the IMRT irradiation technique with the imaging verification
technique (Fig.3.6.1b, c). It allows the display of the target
volume and surrounding structures using a display device
connected to the irradiator. A simpler method is the
above-mentioned portal imaging (lower flat-panel in Fig.
3.6.1b, c), which displays bone structures well, but often does
not provide sufficient contrast for imaging soft tissues,
including the lesion itself. For quality imaging, the irradiator
can be further equipped with an additional X-ray imaging
system (sometimes called In Room CT - CT in the irradiation room , Synergy ,
orOBI - On-Board Imager System - an
imaging system mounted directly on the irradiator ), which
is used to accurately control the position of the patient and
target tissue before irradiation; it can be performed before each
irradiation fraction. The OBI imaging system is mounted on the
radiator gantry (linear accelerator) perpendicular to the
radiator's central axis. The X-ray imaging system rotates with
the gantry and is positioned to have the same isocenter as the
high-energy beam of the radiator. Prior to irradiation, an X-ray
planar or CT image is performed on the
irradiator with a widely collimated cone-beam CT , which
irradiates the patient and impinges on the opposite flat-panel
imaging (its principle is described in §3.2,
passage "Electronic X-ray imaging "). The X-ray machine and the detector
rotate around the patient on a common radiator gantry. The
resultingcurrent imagesare compared withreference
images- initial CT or planar images from the simulator
and, if necessary, appropriateposition correctionor
beam shape modification by collimator. MLC, with larger
differences and variation in radiation plan, there-optimization.
it allows eliminating errors in patient positioning among
different factions irradiation, Conn. and change the position and
size of the target tissue and surrounding anatomical conditions
during radiotherapy. X-ray display providescurrent imagesstructures
and organs before and on the basis of the irradiation procedure,
the accuracy of radiotherapy is optimized by
controlled IMRT . The new systems enable verification not only
between individual fractions, but also interfacial
CT imaging during the rotation of the irradiator with IMRT.
Very
precise localization of the tumor and surrounding structures
helps to improve the therapeutic ratio - to
irradiate the tumor site with a sufficiently high dose and to a
large extent eliminate the harmful radiobiological effect on the
surrounding healthy tissues and organs. In principle, ultrasound
imaging can also be used for IGRT , but the recognition of
structures in these images is more difficult and is practically
not used in telotherapy. Ultrasound navigation is used in some
methods of brachytherapyas
described below and shown in Fig. 3.6.7 on the right.
*) IGRT is sometimes considered
in the narrower sense only as a verification method
; however, see the section " Hybrid integration
of imaging and irradiation technologies "
below.
The IGRT
verification method is most often used in connection with
irradiators with a modulated IMRT beam according to Fig. 3.6.1b,
c *), so it is IMRT + IGRT . The high-precision tomotherapy
and stereotactic
gamma-knife , Leksell, and especially cybernetic radiotherapy
methods described below are further based on IGRT image
navigation . IGRT can be supplemented by a system of correction
for respiratory movement , the so-calledRespiratory
Motion Technology or Real-Time Position Management
( RPM ), enabling monitoring of the change in the
position of the target volume depending on the patient's
respiratory cycle - this is used for selective irradiation of the
target volume only in the selected part of the respiratory cycle,
so-called respiratory gating . when synchronizing the
movements of the irradiator with the respiratory
synchronization . All these procedures are now integrated
into the DART ( Dynamic Adaptive
Radiotherapy ) system, which makes it possible to evaluate
the results obtained during IGRT and, based on them, to operatively
adapt the parameters of the irradiation procedure so
that the dose distribution is optimal.
*) Occasionally used with a linear
integration of the CT in the embodiment irradiator CT-on-Rails
( CT on rails ). A CT scanner, mounted on rails, is
installed in the irradiation room together with the irradiator
itself. In the opposite end of the room, it can be used for basic
CT imaging. On the rails, the CT scanner can then be moved to the
radiotherapy position, where the deviations of the target volume
and other structures are checked in comparison with the planning
images, with subsequent correction of the patient's position.
This system has again been used in some new carbon-12 hadron
radiotherapy systems (see " Hadron
radiotherapy " below), where it is
problematic to mount an On-Board imaging system on very
robust and complicated gantry .
Biologically guided
radiotherapy - BGRT
Anatomical and functional-biological multimodality imaging
methods are increasingly included in the irradiation process,
together with modeling of molecular-cell radiation response of
tumor and healthy tissue (molecular imaging, monitoring of
radiotherapeutic effect including early detection of apoptosis,
discussed above). section " Diagnosis of cancer "). The sum of
these approaches makes it possible to gradually achieve
"biologically guided" radiotherapy BGRT
( Biologically Guided Radiation Therapy ), adapted to
individual conditions specific to the patient and tissue -
radiotherapy controlled (guided) molecular imaging .
This area mainly
includes the biologically targeted radioisotope therapy
discussed by open emitters, where the complex teranostic
approach discussed in §4.9, section " Combination of diagnostics and therapy -
teranostics " is being developed
.
Hybrid integration
of imaging and irradiation technologies
The accuracy of the localization of anatomical
structures in CT and NMRI imaging, as well as the targeting of
the isocentre in the irradiators, is already very high, approx. 1
millimeter. However, the use of this accuracy to actually target
the dose to the desired site may be hindered by variability
in patient position and organ
mobility within, as well as changes in their size and
anatomical proportions (see " Conformal radiotherapy
" below). It is therefore desirable to monitor
online on an ongoing basis the position of the patient
and internal anatomical structures by means of an imaging system
directly on the irradiator. This creates images of organs and
anatomical structures in the irradiator coordinate system, to
which the modulated irradiation beam can respond in feedback by
modifying and correcting irradiation conditions to achieve the
exact desired dose distribution in the target volume and
surrounding tissues. Image-guided radiotherapy ( IGRT )
and tomotherapy therefore require the merging of
the imaging and irradiation device into a single hybrid
system - Fig.3.6.1c and Fig.3.6.4a, c. Daily
images can then be taken before each
irradiation"target tissues and surroundings, according to
which it is possible to perform position correction, operative
updating of irradiation prescription, or correction of
irradiation plan.
In IGRT systems, hybrid
combination [ LINAC + CT ] is already standard.
Hybrid combinations of irradiator with imaging system are under
development NMRI nuclear magnetic resonance (the
NMRI principle has been described above - " Nuclear magnetic
resonance ") This combination is expected to better map
structures (target tumor as well as surrounding tissues and
critical organs) - especially soft tissues - on NMRI, which would
allow to make a more perfect adjustment and targeting of the
radiation dose from the radiator, so it is a two-mode MR-IGRT
technology.The system has already been tested [60
Co + NMRI] - two or three cobalt irradiators (equipped
with MLC collimators) combined with simultaneous magnetic
resonance imaging. For the highly desirable combination [LINAC
+ NMRI], a significant technical problem so far is the
mutual negative influence of both modalities - influencing the
operation of a linear accelerator by a strong magnetic field of a
NMRI superconducting electromagnet and interfering with NMRI
display by strong electromagnetic signals generated during
accelerator operation. Also fast secondary electrons generated in
tissue by the interaction of the primaryg-radiation,
will have their paths deviated from the original direction in a
strong magnetic field (they are acted upon by a Lorentz force in
the direction perpendicular to the movement and perpendicular to
the transverse magnetic field), which may disrupt the
directionality of the resulting radiation effect of the radiation
beam tissue required radiation dose).
The
scintigraphic method of PET positron emission tomography
is very suitable for primary tumor diagnosis (see Chapter 4
"Scintigraphy", part " PET cameras "),
especially with the use of radiopharmaceutical 18
FDG. The metabolic cellular activity of the tissues is displayed.
However, this method is also suitable for monitoring the
response tumor tissue for radiotherapy, as it displays
metabolically active tumor tissue, as opposed to inactivated
cells. Among other things, it is able to recognize tumor
recurrence from other processes (eg from the consequences of
previous tumor treatment). This monitoring of the success of
radiotherapy can be performed off-line, but a hybrid combination
of [ LINAC + PET ] radiotherapy irradiator with
PET imaging is also possible.
Another
interesting hybrid combination that may be implemented in the
future is the combination [ hadron 12
C-irradiator + PET ], where the dose distribution from
accelerated carbon core beams is monitored by annular positron
emission tomography (PET) camera detectors displaying
annihilation photons generated in areas of Bragg maxima from
positronsb +
-radioactive 11 C - see below
" Hadron
radiotherapy ", passage " Radiotherapy
with heavier ions ", fig.3.6.6. And in the distant
future a possible hybrid combination [ antiproton
irradiator + PET ], where a PET camera mounted on
antiproton irradiator gantry could monitor the dose distribution
in the tissue by detecting annihilation radiation from positrons
arising secondarily from antiproton interactions in the tissue
(see "Antiproton radiotherapy" below) ).
Conformal radiotherapy, inverse
planning
All these gradually evolving methods
lead to better irradiation selectivity - a
higher dose in the target tissue and a reduction in the
dose to the surrounding healthy tissues. They allow better dose
distribution in the target volume - so-called conformal
radiotherapy ( conform = adapt ), also referred
to as three-dimensional conformal radiotherapy (
3DCRT). In this technique, a three-dimensionally defined
target volume is selectively and homogeneously irradiated with
the desired high radiation dose, which drops sharply outside the
target volume, so that the surrounding healthy tissues are
irradiated with a substantially lower dose. The size and shape of
the irradiated area is adapted to the irregular volume of the
tumor bed. The dose distribution can be adapted for tumor foci of
various shapes, including the situation where the tumor foci are
closely adjacent, or partially surrounds critical organs and
tissues. IMRT uses a number of irradiation fields at different
angles, which adapt to the shape of the bearing and
"copy" its contour. The modulation of the irradiation
beam makes it possible to partially cover itcertain
portions of the target volume that interfere with a critical
organ that the tumor may press (or partially surround). The
radiation dose in the target tissue is compensated by stronger
irradiation from other fields. As a result, sufficient and almost
homogeneous irradiation of the tumor site can be achieved with
significant investigation of adjacent critical organs (isodose
curves can be concavely "curved" around the critical
organ). This result is achieved in IMRT by inhomogeneous
transport of partial radiation doses to the lesion, adapted to
the irregular shape of the tumor and the anatomical situation in
the environment.
Conformal
radiotherapy techniques make it possible to selectively
increase (escalate) applied radiation doses in target
tissue by reducing the dose in critical organs . The sum of these
IMRT + IGRT methods is also sometimes calledadaptive
radiotherapy (ART) - irradiation is adapted to
each patient individually, it changes with specific anatomical
conditions, even over time in the same patient *). Surgical
continuous IGRT includes, in addition to the three
dimensions of spatial imaging, a time factor
- sometimes referred to as 4D-radiotherapy .
*) The irradiated patient is
not immobile and unchangeableobject! There are a number
of events that can change the patient's internal anatomical
proportions somewhat. Respiratory movements, intestinal
peristalsis, changes in tissue volumes due to the dynamics of the
disease and due to the therapy itself take place. This can lead
to differences in the storage of target volumes of up to units of
centimeters. This can have a significant effect on the accuracy
of selective radiotherapy; without correction for these facts,
the target lesion could be partially "missed" during
irradiation and healthy tissue could be irradiated instead. Correction for respiratory
movements is especially important
when irradiating tumors in the lungs and chest area. There are
basically two modifications of the method for eliminating the
disturbing effect of respiratory movements on irradiation :
- Respiratory gating, when the
irradiation beam is switched off and on so that the irradiation
takes place only in the selected defined phase of the respiratory
cycle (eg in the expiration period).
- Tumor tracking , where the sensed
breathing movements are electronically transmitted via a computer
to the radiator control system, which "shifts" the beam
in the rhythm of the breath so that it is still directed to the
target bearing.
Said
complex method of radiotherapy planning, the initial requirement
is the distribution of radiation dose and computerized scheduling
system determines the optimal shapes, intensity and irradiation
time of each modulated radiation fields, sometimes referred to as
" inverse planning ":
Inverse Planning
This "inverse" comes from the fact that some stages are
"reversed" compared with previous conventional planning
procedures (Conventional planning is sometimes
referred to as "forward" - forward ) .
First, the target volumes and structures of critical tissues and
organs on individual CT sections are accurately marked. After
entering the required dose into the target tissue and the maximum
permissible dose for the surrounding healthy tissues and critical
organs, a 3D-model of the dose is created. The
planning system then designs the number and shape of the
irradiation fields, the dose rates, the times, the angles of the
gantry radiator; this was done manually in conventional planning.
Each partial radiation field (from a given angle) is virtually
decomposed into individual surface elements - pixels,
the distribution of which is governed by the positions of the
lamellae of the multi - leaf collimator MLC; this distribution is
computer-optimized so that the spatial distribution of the batch
corresponds to the required values. An important output part of
the computer irradiation plan is therefore the data on the
position of the lamellae and the rotation of the MLC collimator.
All this data is transferred to the irradiation computer, which
according to them electronically controls all
movements of the gantry, collimator blades, accelerator power and
other irradiation parameters. The adjective "inverse"
is likely to become unnecessary in the future ,
as no other type of planning will exist ...
In addition to the high
purchase price (and higher operating costs), a certain disadvantage
of all these advanced radiotherapy methods is greatertime-consuming
irradiation process and a slightly higher whole-body dose
of radiation (even outside the directly irradiated
area), arising as a result of more frequent diagnostic
and monitoring irradiation .
Paradoxical
note: Accurate irradiation of a defined tumor site with a
rapid decrease in the radiation dose to the environment is
certainly very desirable and leads to a better investigation of
healthy surrounding tissues. On the other hand, it can sometimes
paradoxically have a certain disadvantage: in the case of
micro-seeding of tumor cells into the vicinity of the defined
lesion, recurrence of the disease may occur more easily after
radiotherapy than with previous methods, where the target volume
was relatively strongly irradiated. It is therefore necessary to
pay increased attention to the definition of a sufficient area of
??the flange around the bearing itself and its incorporation into
the target volume.
Tomotherapy
A special modern variant of IGRT-radiotherapy modulated by CT
image is the so-called tomoradiotherapy . The prefix " tomo " expresses the
fact that the irradiation takes place gradually in a series of
narrow transverse sections perpendicular to the
longitudinal axis of the patient, defined by a beam from the
orbiting accelerator (Fig . 3.6.4a)
. Diagnostic imaging and therapeutic irradiation technology is
integrated into one system. CT imaging provides
up-to-date images of the target tissue and surrounding
structures before each irradiation procedure and, based on them,
optimizes the accuracy of radoiotherapy with controlled
modulation of beam intensity.
An
interesting variant is the tomotherapy apparatus employing the
same linear accelerator as a source of radiation for imaging and
therapeutic irradiation :
¨ CT
imaging is realized as a transmission g
-CT , where instead of the X-ray linear
accelerator with dots, producing Rezina in " low
dose " (reduced energy and especially with many times
lower beam intensity) photon radiation
("megavolt X-radiation") fan-shaped collimated
("Cone Beam"), which illuminates the
patient and is registered in the opposite direction by a system
of detectors(arranged in a circular section, most often
it is a multipixel single-row xenon ionization chamber) similar
to classical CT. As with CT diagnostics, along with the rotation
of the accelerator and detectors, the bed is moved
with the patient (helical or spiral scanning), followed by the
reconstruction of the density images.
¨ After switching
to the high-dose power mode (without
using a homogenization filter), the same linear
accelerator rotates around the patient and irradiates
the target tissue located in the previous diagnostic CT
step. This irradiation can take place with a modulated
beam using an MLC collimator *): for different angles,
the intensity g can be-beam larger or
smaller (or radiation completely switched off), or the beam
suitably shaped so that the radiation dose avoids critical
tissues. As in the previous step, together with the rotation of
the accelerator and detectors, the bed and the patient are moved
in a controlled manner - helical or spiral tomotherapy
is performed . Modulation of the dose intensity is achieved by
superposition during the rotation of the irradiator with
different positions of the lamellae of the binary MLC, modulation
in the longitudinal direction by means of superposition during
the overlap of the individual sections.
*) Since tomotherapeutic irradiation
takes place only in a narrow beam rotating in a plane
perpendicular to the translation axis, it is sufficient to
modulate the irradiation beam intensively only in one direction
(plane). Therefore, a special somewhat simpler multi-lamellar
collimator MLC is used here, sometimes called binary
(bipolar) MLC., which, however, has a faster
response of opening and closing of the slats (Fig.3.6.3c). It
typically consists of 64 blades with a pneumatic drive mechanism.
For the
time being, CT detectors must be switched off or removed during
power irradiation, as high radiation flux would overwhelm them
and could damage them (in further development, the detectors are
expected to be switched on during irradiation and to continuously
modulate feedback intensity). This elegant, accurate, and highly
integrated system is sometimes referred to as "HI-ART"
(" Highly Integrated Adaptive Radiation Therapy
").
The first prototype
of a tomotherapeutic irradiator ( Corvus system) were
constructed in 1993 by M. Carol (Nomos Corp.), TRMackie, P.
Reckwerdt et al. (Univ. Of Wisconsin). For further development
and production of these devices, the company Tomotherapy
Inc. was founded in 2002 . based in Madison, Wisconsin, USA,
which supplies these systems commercially.
Tomotherapy with 60
Co
In principle, a radionuclide emitter 60-cobalt ( g 1173 + 1322 keV)
can be used as a source of photon radiation for tomotherapy , as
a replacement for LINAC (as discussed above in the
section " External irradiation with
gamma, X and electron radiation - teleradiotherapy ", dose distribution for g- radiation 60 Co is very similar
to LINAC 4 or 6MeV). The classic cobalt irradiator is
equipped with a binary multi-leaf collimator and an opposite
imaging detector (flat-panel). It can operate in the same
configuration as in Fig. 3.6.4a, or using two or three 60 Co sources - one for flat-panel
imaging ("daily CT"), the other for self-therapy.
However, such systems are used only very rarely, because
radionuclide sources in radiotherapy are generally abandoned
(with the exception of Leksell's gamma knife).
Fig.3.6.4. Some special gamma irradiation techniques (top
principle, bottom device). a) Tomotherapy. b)
Lexell's gamma knife. c) Cybernetic gamma-knife.
Stereotactic
radiotherapy - SBRT. Gamma - knife.
Stereotactic Body Radio Therapy (SBRT )
is a very accurate high-dose irradiation of a
small target volume, usually a large number of targeted thin
beams of intense ionizing radiation, with a sharp
decrease in radiation dose outside the target volume (sometimes referred to as the " zone effect
") . Each individual beam is
relatively weak and does not cause significant radiobiological
effects on its tissue path. However, if these rays are directed
to a common focus- target tissues, their
summation results in a high effective dose capable of damaging
and inactivating tumor cells. Outside the focus, the radiation
dose decreases sharply, so that already at a distance of a few
millimeters from the focus, the dose already corresponds
practically to the dose from one beam. Using the so-called stereotactic
focus , the target volume is precisely spatially defined
by transferring the diagnostic image to a 3-dimensional coordinate
system (without direct visual inspection). Based on the
coordinates that locate the site, it is possible to achieve
highly selective irradiation of even a small target deposit with
a high dose of radiation, with relatively low damage to
surrounding tissues. Due to its high accuracy, the method is
sometimes referred to as stereotactic radiosurgery SRS
( sterotactic radiosurgery) *) - allows a single ablation
irradiation with a high dose, which eliminates the
lesion (tumor or malformation). This method is suitable where
classical surgery is difficult or unsolvable (eg fine structures
in the brain). This targeted irradiation with a
"gamma-knife" can then replace the classic surgical
intervention - without surgical burden and surgical complications
(bleeding, infection). High accuracy (1-2 mm) enables effective
treatment of even small tumors near important centers or in areas
with a complex anatomical structure. Irradiation is usually
performed once or with a small number of
fractions (2-3).
*) After all, this method is used not only
for cancer therapy, but also for " radiosurgery"removal
of vascular malformations or neuropathological (eg epileptic)
foci in the brain - single focal intracranial irradiation
. Stereotactic radiosurgery is a non-invasive alternative
to" bloody "surgery.
Terminological note: The term stereotaxy
was created by combining the words: stereo = spatial and
taxe right place (lat. tactio = touch, touch ).
it is also used for accurate surgical procedures.
In classical
radiotherapy used the standard single doses of about 20
to 40 applied at 2Gy fractions radiobiologickým mechanism of the
cell apoptosis to reproductive sterilizationclonogenic
tumor cells; the resulting effect is described by the LQ model.
In stereotactic radiotherapy , a high single
dose (in the order of tens of Gy) is applied to a small target
lesion either once or in a few fractions (1-5 fractions). With a
single dose of tens of Gy, in addition to apoptosis, immediate
cell death in interphase - necrosis is already
partially applied (radiobiological effect
is no longer precisely described by the LQ model, its high-dose
modifications are sometimes used - LQL model, gLQ model,
USC (universal survival curve), KN (Kavahagh-Newman) model, PLQ
(Padé Linear Quadratic), see §5.2, passage " Deviations from the LQ model and its
modifications ". Tumor cells are affected by such a large radiation
dose (with high dose rate) that nitrocellular repair does not
take place and cell repopulation does not take place, all cells
are "killed" - the tumor sterilization effect becomes
ablative . Therefore, in addition to the name stereotactic
radiotherapy SBRT, the term stereotactic ablative
radiotherapy SABR , SABRT ( Stereotactic
Ablative Body RadioTherapy ) is also used; sometimes the association with the English word saber
= saber is mentioned with a bit of exaggeration - it is an
effective and elegant weapon against tumors .
It is interesting to note that high-dose SABRT is more pronounced
(otherwise rare)the abscopic effect of the
antitumor immune response (§5.2, passage
" Bystander-Abscopal effect ") .
Stereotactic radiotherapy
makes it possible to precisely target a high radiation dose to
the tumor focus, while maximally saving healthy tissues. This can
achieve high local control - effective destruction of the
tumor site - even near important critical organs and
complex anatomical structures, with a lower risk of side effects
and complications (lower radiotoxicity,
less risk of secondary radiation-induced malignancies) . Stereotactic irradiators - Lexell's gamma knife
and CyberKnife - irradiate with about 10-30 times higher
spatial accuracy than conventional linear accelerators.
Note: Similar
objectives are achieved by somewhat other means - beams
of heavy particles - the hadron
radiotherapy below .
Leksell Gamma-Knife (LGK - Leksell
Gamma Knife )
Now conventional device for high-precision radiotherapy is
izocentrické Leksell Gamma-Knife (first prototype developed in 1967, and neurosurgeon
L.Leksell radiologist B.Larsson coworkers at Karolinska Institute
in Stocholmu) . Radiotherapy takes
place by precisely targeted irradiation of a pathological site in
the brain with gamma radiation from a large number of solid radioactive
sources 60
Co ( g 1.173 + 1.332 MeV),
whose narrow collimated rays from different directions intersect
in a common focus , into which a pathological
district of brain tissue is positioned by stereotactic
localization. Large total radiation doses from all intersecting
rays act in the focus, outside this focus the dose decreases
darkly and is already 100 times smaller in the vicinity of a few
millimeters from the focus; corresponds to the dose from a single
beam. The emitters are arranged on a hemispherical surface and
are equipped with collimators directing
(transmitting) the beams of radiation g
to the center (Fig. 3.6.4b above). In the basic type of devicethere are 201 small encapsulated cobalt sources with
assets of about 1GBq, evenly distributed on a hemisphere with a
diameter of 400mm, which gives a dose rate of about 3 Gy / min in
the isocenter.
Definitive
precise collimation is performed by secondary collimators in
special collimation helmets (there are several
types of them in the accessories of the instruments, or their
segments can be moved by motor). Prior to the actual
radiotherapy, a coordinating stereotactic aiming frame is
attached to the patient's head with four screws(Fig.3.6.4b
below), enabling to mark on the X-ray or MRI image the position
of the pathological lesion, contrast markers and displayed
structures to relate to the three-dimensional coordinate system
of the irradiator. More preferred here is magnetic resonance
imaging, which provides a more contrast imaging of the soft
tissues of brain structures. The tomographic image of the brain,
which also shows the marks of the stereotactic frame ( fiducial
markers ), is transferred to the planning system and serves
to precisely set the target volume to the focus of the gamma
knife. Rays from some 60 Co
sources can be discarded as needed by a shielding
"plug" in the helmet if they pass through critical
structures that should not be exposed to radiation (such
as the optic nerve, ocular lens, brainstem). Irradiation
time depends on the size and type of lesion, it is on the order
of tens of minutes. Tumors are irradiated with a single dose of
about 20-25 Gy, up to 100 Gy (necrotizing ablation
dose) is used in malformation radiosurgery . If the target
volume is larger or irregular in shape, the bed is moved with the
patient so that the focus moves in the lesion and there is a
gradual irradiation of the entire target volume - multiisocentric
irradiation. Brain tumors for LKG therapy should not be larger
than 3 cm and their number should not be greater than 5. However,
in some workplaces 20 lesions are irradiated, mostly with
palliative intent. The therapy is basically one-time
, but in case of recurrence or appearance of new metastases, the
treatment is repeated, even 3 times.
It was
for new types of gamma knivesincreased irradiation space (using 192 cobalt emitters with cylindrical geometry,
without collimator helmets - these are replaced by a
motor-controlled conical collimator with 8 independently moving
segments with 576 holes) , which allows irradiation of
other target volumes in the head and neck ( up to vertebrae C1,
C2).
The gamma knife is used to treat mainly brain tumors and
metastases, meningiomas, auditory nerve neurinoma, ocular uveal
melanoma, vascular and neurological malformations, and pituitary
adenoma.
Leksell's
g- knife has two disadvantages :
¨ Its construction is
basically single-purpose - adapted for the
therapy of brain lesions (the innovated model also
allows irradiation of lesions in the neck area) .
¨ Radioactive emitters 60 What have a half-life of 5.27
years, they gradually weaken and need to be replaced
. This is a very complicated and expensive matter.
Nevertheless, Leksell's gamma-knife is intensively used in larger
workplaces specializing in diseases of the central nervous
system. It is the most accurate device for tumors in the head
area.
Universal and cybernetic gamma-knife
With the technical improvement of the "classic" IGRT
isocentric radiotherapy using g-
radiation, precise irradiation with narrow beams
with millimeter accuracy is also possible here . This gradually
achieves the properties of a gamma knife for universal
use, for various irradiated localizations, not just the
brain *). In addition to precisely working IGRT irradiators with
an MLC collimator, resp. mMLC (micro-multileaf collimator - Fig.
3.6.3b) - in the classical, VMAT, or tomotherapeutic arrangement,
"cybernetic (robotic)" stereotactic irradiators
with a sharply collimated beam were also developed .
*) For accurate stereotactic irradiation, however,
the brain is the most suitable object, as it is enclosed in the
skull, which can be well fixed and thus ensure sufficient
accuracy (<1mm) of targeting the beams to the target bearing.
In other locations, the problem is the mobility of
structures due to respiratory movements, peristalsis,
filling and emptying of cavities, muscle mobility, etc. Some of
these movements are corrected with advanced irradiation
technologies (eg.respiratory gating in respiratory
movements).
Cybernetic gamma-knife
is a precisely functioning cybernetic image-guided irradiator - a
complex computer-controlled system, consisting of several basic
components (Fig.3.6.4c) :
¨ Radiation source g
- compact linear accelerator (LINAC) of electrons with
an energy of about 6MeV, equipped with a target converting energy
of electrons for braking g- radiation.
A homogenization filter is not used here. ¨ Narrow collimators
for setting different diameters of the irradiation beam. Either a
set of mechanically interchangeable collimators
with different aperture sizes is used, or the collimator can be
equipped with a variable iris diaphragm, whose
electrically moving segments allow automatic on - line setting of
various apertures - diameters of the irradiation beam during irradiation (Fig.3.6.3d). Some new types
of devices are also equipped with a multi-lamellar
collimator MLC.
¨ Cybernetic
arm on which the radiator is mounted: the movements of
the radiator are ensured by a special stand - "cybernetic
(robotic) arm" with servomotors controlled by a computer
(Fig.3.6.4c), with a large range of possibilities of movement of
the irradiator. With these servomotors, the irradiator flexibly
moves around the patient with all degrees of freedom - it can
move, rotate, rotate around the bed - and purposefully irradiates
the tumor bed with a large number of narrow beams, at various
angles, with appropriate doses of radiation. In some new systems,
not only the irradiation head moves "robotically", but
also the bed with the patient, which takes over part of the
movements ("degrees of freedom") of the irradiator
(Fig. 3.6.4c below).
¨ Stereotactic
X-ray imaging system , equipped with two orthogonally
placed X-rays (one of which can be seen in Fig.3.6.4c) and
flat-panel imaging (located either on stands under
the lounger or recessed in the floor) , scans the irradiated area, and
stereoscopic X - rays of significant structures in the patient 's
body can be used as a stereotactic base
(reference system). Thus, a fixed external stereotactic frame is
not necessary as in classical stereotactic radiotherapy, as a
"stereotactic frame" serve certain significant
structures in the body of the irradiated patient :
- Some parts of the skeleton - vertebrae
(spinal, lumbar, thoracic, cervical), skull structure;
- Directly irradiated tumor
- if the difference in density between the lesion and the
background is shown clearly enough on X-rays;
- For reliable navigation of stereotaxy (especially in the
area of soft tissues), special so-called fiducial markers
("reliable" - lat. Fiduacia
= faith, trust, reliance, coverage ) are sometimes
implanted in the vicinity of the tumor - easily recognizable
reference location orientation markings in the
number of 3- 6, implanted around the target tissue. Usually gold
grains of about 2x5mm size are used.
Note: Gold as a
material for fiducial marks has two advantages: 1.
It is an inert metal, well tolerated by tissues. 2.
Due to the high density, gold grains appear in high contrast on
navigation X-rays.
On-line tumor tracking
These locating "reference
points" or structures are marked on the irradiation plan and
the X-ray navigation system on the irradiator then constantly
monitors them and controls the movements of the irradiator or
robotic bed with the patient accordingly. Before each sub-dose
from a certain direction, a stereotactic image is taken, which is
compared on a computer with the initial images that were used to
create the irradiation plan. If the position of the target tissue
deviates (due to movement of the patient or movement of target
structures within the body) from the planned position, the
computer system calculates the appropriate beam alignment
correction and the cybernetic arm is adjusted to the new correct
position to emit the next dose. Continuous shooting and
comparison of current images with default ones allows you to
operatively correct the position of the irradiator, so that even
when changing the position (e.g.the integration of the
irradiator with the X-ray imaging device into one system
thus ensures optimal on-line image-controlled
angular-dose modulation of the irradiation beams
(IGRT-SBRT). The above-described technique of image-guided
(navigated) IGRT radiotherapy is brought to
complete perfection here!
Correction for respiratory movements
For accurate irradiation of target volumes in the lungs, chest
and partly also the abdomen, it is useful to equip the system
equipped with a device for synchronization and correction
for respiratory movements . It is usually performed
using an optical laser system with sensors attached to the
patient's chest, which electronically monitors breathing
movements. There are two basic ways to eliminate the effect of
respiratory movements on the geometric accuracy of irradiation :
- Respiratory gating - is a simpler way in which
the irradiation beam is switched off and on so that the
irradiation takes place only in a selected defined phase of the
respiratory cycle (eg in expiration).
- Respiratory synchronization -
opto-electronically monitored breathing movements are transmitted
to a computer, which first creates a "breathing curve".
With the help of this curve, the sensed signals of respiratory
movements are then electronically transmitted to the servomotors
of the irradiator arm, which "sways" in the rhythm of
the breath, so that the irradiation beam is still directed to the
target bearing - respiratory tracking .
Note: A
certain problem of the whole process of "respiratory tumor
tracking" may be the positional relationship between the
monitored markers (optical reflectors or metal fiducials) and the
target tumor during the whole respiratory cycle. A planning CT
scan for SBRT in the chest and abdomen is commonly taken with
breath holding and represents the target volume, fiducial
markers, and surrounding anatomical structures only when exhaling
or inhaling; does not provide information on possible changes in
position between the tumor (or its deformation) and markers in
other phases of respiration. To solve this problem, it is
desirable to take two CT images - during exhalation and
during inhalation, on which changes in the distance between
individual markers and defined parts of the tumor on both images
are then evaluated.
In
general, tumor tracking allows for more accurate
targetingradiotherapy using individual and reduced margin
in ITV, which can be used to better save healthy tissue or to
escalate the dose in the tumor itself.
Large number of beams, high accuracy
and selectivity
Even with cyber irradiators, their integration with the
CT imaging device into one system ( "In-Room
CT" ) is sometimes (occasionally) used for accurate
imaging and targeting of the target bearing and surrounding
critical tissues immediately prior to exposure (but this is not
necessary if there is a planning CT nearby).
Flexibility
of the irradiator's movements allows you to irradiate the target
volume with a large number of thin beams from
various directions, in an angular range of almost 360 ° (except for the
direction from below under the lounger) . This achieves
higher accuracy and selectivity of the radiation dose delivered
to the target tissue (with a high dose gradient outside the
target volume), with the possibility of respecting shape and
anatomical anomalies - well avoiding critical tissues. In
general, all these precise stereotactic techniques are suitable
for radiotherapy of small tumor foci , up to
about 3-5 cm, in areas with a complex anatomical structure. It is
worth noting that, unlike the other telotherapeutic methods
mentioned above, the cybernetic gamma knife is not an
isocentric technique : the irradiator does not have
a rotating gantry and its beam can be directed at any angle..
However, the isocentric mode can be achieved, if necessary, by
suitably controlled movements of the radiator by means of the
servomotors of the cybernetic arm. It can be said that the
cybernetic irradiator can operate in 6D positioning mode: classic
movement in the x, y axes, for movement in three further
rotations.
For
precise irradiation with on-line tumor tracking, we can talk
about 4D radiotherapy - 3 spatial dimensions and
1 temporal dimensions. The inclusion of radiobiological
processes then represents a new 5th dimension - in a way it
is 5D radiotherapy .
A proton
beam , or a heavier ion beam , can also
be used for stereotactic radiotherapy , using the effect of the
Bragg maximum depth dose (see below).
CyberKnife
The first prototypes of cybernetic irradiators have been
developed since the late 1980s, mainly in the laboratories of
Stanford University (JRAdler et al., Inspired by
the first type of Leksell gamma knife and an effort to improve
it) , using an industrial robot Fanuc (Japanese Fanuc developed within the electromechanical
company Fujitsu) . On this basis, Accuray (based
in Sunyvale, California) was founded in 1991 , which
significantly improved this robotic radiotherapy stereotactic
system and has been supplying it under the name CyberKnife
since 2001 (Fig. 3.6.4c below). A similar type of stereotactic
irradiation system is Novalis (manufactured by Brainlab),
which also has continuous X-ray scanning, but uses a special
Micro-Multi Leaf collimator (mMLC, mentioned above, Fig. 3.6.3b)
to collimate the photon beam, which can flexibly shape the
irradiation beam using computer control.
Hadron
radiotherapy
Hard electromagnetic radiation - gamma or X - is the most common
type of radiation used in the treatment of cancer. A number of
precise techniques have been developed to selectively
direct this radiation to tumor foci (discussed above) . However, a
disadvantage here is the not very advantageous depth
profile of the radiation dose :
In conventional irradiation of
deeper lesions with photon beams , most energy
is transferred to the tissues located on the surface and at shallow
depths in the body *), before they hit the tumor itself.
With increasing depth of penetration into the tissue there is a
slow exponential decrease - black curve in Fig.3.6.5a(It would be similar in the case of irradiation with
electron beams - a red curve, the intensity of which decreases
rapidly with depth; it is not suitable for deep irradiation) . Thus, in a deeper-placed tumor, the photon beam
transmits the largest dose of radiation to the tissues in front
of the tumor, then only (partially attenuated) radiation passes
through the tumor and continues through the healthy tissues
behind the tumor. So healthy tissues and organs receive a
relatively large radiation dose before and after the tumor ...
This leads to the risk of damaging important tissues and organs
in the areas of radiation application. In anatomically more
complex places, it is often difficult to decide which lowest
radiation dose to use in order to ensure a therapeutic effect
without permanent damage to important tissues and organs.
*) "Depth effect" of high-energy g-radiation
(mentioned above in the introduction to the section
"External irradiation with radiation g and X") is relatively
small and is no longer dealt with here.
Thus, in each individual photon beam from
a given direction, the sites in front of the
target tissue are irradiated even slightly more than the bearing
itself, and the sites behind the target area are
also exposed to only a slightly smaller radiation load . Although
irradiation from multiple directions outweighs the total
radiation dose at the target site, the gradient and dose
selectivity may not always be sufficient, especially when
irradiating tumors in close proximity to important tissues and
organs. However, there are physical mechanisms *) that allow this
selectivity of the irradiation to be increased by
achieving a more favorable balance in the depth distribution of
the dose: it is irradiation heavy charged particles
, often referred to as " hadron therapy
".
*) Radiobiological factors
also apply here . The biological effect of radiation is related
to the ionization density given by the loss of
radiation energy per unit path, the so-called linear
energy transfer LET (§5.1 " Effects of radiation on matter. Basic quantities of
dosimetry . ") . Electron and photon
radiation has a low LET, it is sparsely ionizing
radiation . In contrast, fast protons, heavier ions,
pions, neutrons, as well as products of nuclear reactions in the
tissue, have a high LET - they show "dense" ionization
and strong radiobiological effects., even for
hypoxic tumors. The oxygen effect is significant especially when
using sparsely ionizing radiation (photon radiation g or X is most often
used ), where the indirect radical mechanism of the radiation
effect predominates. In densely ionizing radiation, where there
is an increased proportion of the direct intervention mechanism
(and also increased radical recombination), the effect of oxygen
(oxygenation) on the radiobiological effects is less significant.
There is more frequent damage to the affected
cells - the cells are inactivated, stop dividing and die by
apoptosis. In addition, this higher radiation efficiency is
accompanied by the possibility of its better depth
"targeting" to the desired location.
By hadron radiotherapy we
mean irradiation with heavier particles-
protons, heavier nuclei (ions), p - mesons or neutrons (possibly
antiprotons in the future) , which
collectively belong to the category of hadrons
- particles showing strong interaction (see §1.5, passage " Systematics of elementary particles " and " Elementary particles and their properties ") . However, proton
irradiation and heavier nuclei do not use strong interactions,
but electromagnetic interactions, which intensely ionize these
heavy positively charged particles with irradiated tissue (see the section " Common aspects of hadron radiotherapy " below) . First, let's
describe proton radiotherapy .
Fig.3.6.5. Hadron radiotherapy with proton
beams.
a) Bragg curves of the depth dependence of the
effective dose of radiation in the tissue when irradiated with
gamma radiation, high-energy electrons and accelerated protons. b)
Selective irradiation of the tumor site with a beam of protons of
such energy that the Bragg maximum lies in the depth of the tumor
localization. c) Principle schematic
representation of a proton radiotherapy workplace.
Proton
radiotherapy
If we irradiate tissue with a beam of accelerated protons
(with an energy of about 100-200MeV and a speed of about 1/2 the
speed of light), the dose-dependence curve has a so-called Bragg
curve (see §1.6 " Ionizing
radiation ", section " Interaction of charged particles ") , a completely different
shape than for gamma radiation, as seen in Fig.3.6.5a (blue
curve). During their flight, fast protons interact with matter in
three ways :
¨ Coulomb interactions with electrons
in atoms
The main mechanism by which fast-flying charged protons lose
their energy is the inelastic interaction with the atomic shells
of matter - ejection of electrons
of atoms (Fig.1.6.1 top center). These secondary
electrons are then a major factor in the radiobiological
effect in the tissue. Due to the fact that protons are almost
2000 times heavier than electrons, interactions with individual
electrons practically do not affect the movement of protons - the
path of protons remains straight and the loss of
energy of protons in matter is almost continuous
.
The secondary electrons of the
proton beam have significantly lower energy than
the photon beams (where the energy of the
secondary electrons can approach the energy of the primary
photons, ie several MeVs) . Protons with an
energy of the order of 100 MeV are relatively " slow
" (speed max. C / 2) - and only for thismax.
velocities are able to accelerate the secondary
electrons. A simple kinematic consideration shows that the
maximum energy of the secondary electrons here can then be about
50keV. In reality, however, the energy of most electrons is much
lower (protons in their rapid
passage through the atomic shell suffice Coulombovsky to transfer
only a small amount of energy to electrons) - usually only tens
of eV (see spectrum in
Bethe-Bloch. Formula in §1.6 " Ionizing radiation
", passage " Charged particle interactions ") .
¨ Coulomb interactions with atomic
nuclei
For protons flying very close to the atomic nucleus (with a small impact parameter)
there is a repulsive Coulomb force which, due to the large mass
of the nucleus, elastically deflects the proton
from its original linear path. According to the law of
conservation of momentum, the reflected core
moves to the opposite side . In light materials, a reflected
nucleus (eg a hydrogen nucleus - a proton) can gain considerable energy. These effects may
contribute to the partial lateral scattering of the
proton beam.
¨ Nuclear reactions
Upon direct "intervention" of the nucleus (with almost zero impact parameter), the proton enters the nucleus, where it can trigger a nuclear
reaction (§1.3 " Nuclear reactions and nuclear energy ", passage " Types of nuclear
reactions "). The
nucleus can emit a secondary proton, a deuteron,
an alpha particle or a heavier ion, one or more neutrons, gamma
photons. From the resulting secondary radiation from nuclear
reactions, its penetrating component can be negatively
applied in proton therapy - gamma photons and "stray"
neutrons, which fly to greater distances and can cause unwanted
radiation exposure of surrounding tissues outside the
target volume. An interesting use of nuclear reactions for
imaging is mentioned below in the section " Nuclear reactions in hadron
therapy and the possibility of gamma monitoring ", for a possible increase in the effectiveness
and selectivity of proton therapy in the section " Proton-boron therapy ".
¨ Braking radiation protons in light materials
is practically negligible , in contrast to
electrons (§1.6, section " Interaction of charged particles ").
To illustrate the
interpretation of the interaction of proton radiation with
tissue, in comparison with other types of radiation, we will
duplicate the important figure 1.6.1 from §1.6 (we will be particularly interested in the image of
" Protons 200MeV " at the top center
and the corresponding curves on the right) :
![]() |
Fig.1.6.1. Interaction
of fast charged particles with matter. Top left: Schematic representation of ionization mechanisms in the passage of beta - and alpha particles . Top middle: Three basic mechanisms of proton radiation interaction with matter. Bottom: Interaction of positron beta + radiation with a substance ending in annihilation of a positron with an electron. Right: Bragg curves of depth dependence of absorption and specific ionization along the path of gamma photons, accelerated electrons and protons. |
When a charged particle passes through a
substance, the linear transfer of (ionizing) energy is directly
proportional to the electron density of the substance (which increases with density r and the proton number Z of
the substance) and indirectly proportional
to the square of the velocity of the charged particle, here the
proton. Therefore, rapid protons ionize relatively little when
entering tissue. As protons slow down and their
velocity decreases, the ionizing effects increase
- as the proton moves more slowly, the effective time of
the electrical Coulomb effect on the electrons in the
atoms increases , so it is enough to transfer more energy and
pull out more electrons.
The dose-dependent
distribution of the dose thus has a characteristic shape: as fast
protons pass through the tissues, the initially absorbed dose is
relatively low and almost constant, up to the end of the proton's
range in the tissue. Towards the end of the range, the dose
increases sharply, reaches a maximum and then follows a very
rapid decrease to zero. Accelerated protons transfer most of
their energy in a narrow depth region of the
so-called Bragg peak, just before their maximum
decay; here the densest ionization and the
largest radiation dose occur . About 70% of the
energy of the proton enters the region of the Bragg maximum.
Tissues lying in front of this maximum are
irradiated with a significantly smaller dose (only about 30% of energy is transferred here) , tissues lying beyond this maximum
they even get almost no radiation dose, because
the protons do not reach there at all; after braking, the proton
is neutralized by electron capture (hydrogen
is formed) and further ionization no longer
continues. With this specific depth dose dependence of the Bragg
peak can be applied to the target volume higher dose
compared with standard photon radiotherapy and radiation at the
same time saving the surrounding healthy tissue,
especially those lying deeper behind target volume.
Note: Absence of Cherenkov radiation
Unfortunately, the proton beam of the used energy of approx.
200MeV can not be displayed using
Cherenkov radiation in water as well as an electron or
photon beam (picture above in the passage
" Cherenkov
radiation ") . The basic reason is that these protons are relatively
" slow ". A threshold energy of
approx. 460 MeV is required for the emission of Cherenkov proton
radiation. And the secondary electrons ejected from the atoms
along the proton beam in the tissue usually have a very
small energy of tens of eV or a small part of the keV
unit (discussed above, see also the
spectrum of the Bethe-Bloch formula in §1.6 " Ionizing
Radiation ", passage " Interactions charged particles ") , much lower than the
threshold energy of 260keV for the formation of Cherenkov.
electron radiation in water ... However, it can be very well
displayed in a liquid scintillator (picture
in passage "Visualized invisible ").
The
depth that occurs Bragg peak of the substance, is given by the
energy of the proton; proton energy 200MeV makes this
depth in the tissue of about 25 cm. Changing energy proton beam
can adjust the depth in which there is a
maximum radiation dose. This can sensitively
modulate the dose distribution within the body :
Proton beam modulation
The proton beam from the
accelerator is relatively narrow and has a certain fixed energy,
so the Bragg maximum is relatively sharp, so
that the protons would transmit a sufficient radiation dose only
at a narrowly defined location at a certain depth. The width of
the Bragg peak for monoenergetic protons is only about 2 cm,
which is often much less than the size of the tumor, which is
also usually irregular in shape. Therefore, in order to
sufficiently irradiate the entire tumor volume, it is necessary
to shape and expand the proton beam, both in the
transverse direction and in depth. There are basically two ways
to proceed :
Passive modulation
By using suitable "deceleration" filters (wedge or
stepped thickness) we dissipate energetically
bundle so that we reach the extension of the Bragg peak to the
required dimensions. Depending on the thickness of the filter,
the energy of the protons in certain parts of the beam is reduced
so as to achieve the required irradiation of the tumor throughout
its depth. Deceleration filters are mechanically made often in
the form of modulating disks , which rotate in a
controlled manner in a beam of proton radiation.
Forming screens and compensators are used to
cross-shape the beam, either fixed or turned individually for the
patient according to the shape of the tumor and the irradiation
plan.
A certain undesirable side effect of filters and screens is the
formation of secondary neutrons, which are formed during the
interaction of high-energy protons with the atomic nuclei of the
materials used. These parasitic neutrons contaminate the proton
beam.
Active scanning
We irradiate the target area from each direction
with a suitable meandering "scan", changing the
energy of the particle beam and moving the maximum dose
to different depths; gradually, the entire target volume is
irradiated. However, most of the accelerators used -
cyclotrons - do not have the ability to continuously change
the energy of the beam, they have a fixed energy. The energy of
protons is changed (reduced) externally by means of
deceleration filters , mostly graphite degraders at the
output. Synchrotrons have variable energy, but they are
rarely used due to their greater complexity and cost.
New systems have developed magnetic deflection and
narrow proton beam scanning ("pencil
beam "), which is very flexible: no laborious
individual screens and compensators are required and no secondary
neutrons are produced. Only this technique is the future of
proton therapy ...
A combination of hadron irradiation with
conventional photon irradiation is also used to irradiate larger
volumes of tissues.
Secondary particles in
proton therapy
In addition to Coulomb interactions with electron shells (in
which electrons causing radiobiological effects are ejected), a
small part of protons undergo nuclear reactions
in the material - other secondary particles
are formedprotons, photons, neutrons, deuterons, a-particles (Fig.1.6. 1 top middle). Secondary
neutrons and photons can "travel" outside the target
tissues and radiate more distant tissues and
organs (with a possible risk of secondary
malignancies) . Measurements have shown
that the total fraction of energy escaping through secondary
radiation is about 1-2% of the primary energy of protons. An
interesting use of secondary radiation is mentioned below in the
sections " Nuclear reactions in hadron therapy and the
possibility of gamma monitoring " and " Proton-boron therapy ".
Construction of the proton irradiator
The source of the proton beam - and thus the most important part
of the hadron therapeutic system (Fig.3.6.5c) - is the accelerator
. It is most often a cyclotron or synchrotron (for accelerators, see §1.5, section " Charged particle accelerators ") , the use of powerful linear
proton accelerators can be expected in the future .
Although according to the classification in §1.5. it is a
"small accelerator" *), the accelerator laboratory
occupies relatively large spaces - one large room (hall) with its
own vacuum accelerator tube surrounded by strong electromagnets,
shielding, as well as several smaller rooms with air
conditioning, power and control electronics.
*) Cyclotrons for proton energies of 250MeV tend to have a
diameter of about 4-5m, synchrotrons about 6-8m. Significantly
smaller compact accelerators are also being
developed, cyclotrons with superconducting electromagnets
, which could be mounted directly into the radiator gantry.
Combinations [ cyclotron
- > linear accelerator
], sometimes called " cyclinac " , are also tested
. Behind the smaller cyclotron , which provides
protons or heavier ions of fixed energy (approx. 30 MeV), there
is a linear accelerator ( linac ) with
a high gradient, which further increases the energy of particles
to a value to reach the Bragg maximum at the required depth of
the tumor lesion. This technology would allow easy, fast and
flexible electronic beam energy regulation - active 4D
scanning for moving organ therapy.
Experiments with laser
acceleration of protons are promising - §1.5, passage
" Laser accelerators LWFA". The intensity is, however, still very low,
perhaps they can improve and apply in the more distant future ..?
..
Accelerated protons using
electromagnets raging with out- of accelerators
and vacuum conveying tube is fed into the
treatment room. On one accelerator may be connected to several
irradiation facilities , where the individual sub-beams
are led by transport tubes equipped with deflection electromagnets
- Fig.3.6.5c (only the main tube is drawn
here, branching transport tubes to the irradiation facilities are
not drawn due to space) In the end irradiation
head *), "nozzle", in irradiation, the proton
beam is shaped by means of other precisely
controlled electromagnets (as mentioned
above in the passage " Proton beam modulation
") and enters the irradiated tissue.
Proton beam can be focused by a strong magnetic field to a narrow
"pencil" beam ( pencil beam
).
*) The irradiation head is often mounted on
a special stand, the so-called gantry , enabling
controlled rotation around the patient's body
for isocentric radiotherapy (cf. Fig. 3.6.1
above). The rotation of the proton radiation beam can be
performed using a combination of mechanical movement of the
gantry and controlled magnetic fields of electromagnets - it is a
very robust and complex device (whose
purchase price is close to the price of the primary cyclotron!) .
As in conventional photon
radiation therapy is often used here fractionated
radiation from multiple directions , intensity modulated
beam ( IMPT - Intensity Modulated Proton
Therapy) in analogy to the above modulation for IMRT photon beams
( " modulated radiotherapy intensity
") . An additional advantage of
hadron radiotherapy is the ability to depth-adjust the
area of ??maximum energy transferred to the tumor site for each
beam . At a given energy, all heavy charged particles (both for protons and heavier accelerated nuclei) reach roughly the same place (depth) in the tissue,
where they stop and transfer the maximum of their energy. Thanks
to this increased selectivity, it is possibleincrease
the focal dose (and thus increase
the likelihood of effective destruction of tumor cells) without more serious damage to surrounding tissues.
In special cases, stereotactic
single therapy is also performed for benign
malformations or therapy for eye tumors.
One of the other favorable
physical properties of heavy particle beams is their minimal
lateral scattering . A proton, whose mass is 1836 times
larger than an electron, is only minimally deflected when
interacting with the electron shells of atoms, it flies in one
direction "forward" *). This feature also contributes
to better targeting of the radiation dose to the
desired location.
*) A larger part is directed in this
direction of the primary beamsecondary electrons
released during the interaction of heavy fast particles with
matter.
Advantages of proton
and ionic radiotherapy
In summary, proton radiotherapy has three basic advantages :
× A well-defined pathway
and radiation dose during the movement of protons in the
tissue, which can be regulated by proton energy.
× The area of maximum
dose distribution is narrowly localized and can be
precisely adjusted by the energy of the particles. In the path
before the Bragg maximum (at a smaller depth) the radiation dose
and ionization density are relatively low Þ
relatively small radiobiological effect. In the area of ??the
Bragg maximum (located inside the tumor) the dose is high, the
radiation densely ionizes and has a high radiobiological
effect .
× At greater depths than the proton
range, beyond the Bragg maximum (behind the tumor), the radiation
dose is practically zero - healthy tissues behind the
tumor are not affected by protons.
This leads to a better
opportunity to precisely target a high radiation
dose to the tumor focus, while maximally conserving the
surrounding healthy tissues. This can achieve high local control
- effective destruction of the tumor site -
especially in deeper tumors near important critical organs and
complex anatomical structures, with lower risk of side effects
and complications (lower radiotoxicity) , lower scattered radiation, lower risk of secondary
radiation-induced malignancies .
In summary:
Radiotherapy with
heavy charged particles allows maximizing the radiation dose in
the target tumor volume and minimizing radiotoxicity in the
surrounding healthy tissues.
Radiotherapy with heavier
nuclei (ions) and, in theory, pions also have these advantages.
In some cases, this is approached by the possibility of
monitoring the radiation dose along the beam, eg by PET imaging
of secondary radioactive nuclei emerging along the beam of
high-energy carbon nuclei(see the section
" Nuclear reactions in hadron therapy and
gamma monitoring options
" below). Other physically interesting
aspects of hadron radiotherapy are discussed below.
Note: Similar
goals are achieved bysomewhat other means - a gamma knife
- the above stereotactic radiotherapy SBRT .
Bragg curves dependence of the dose depth
distribution in the tissue (water phantom) for different kinetic
energies of protons ( left ) and 12 C nuclei ( middle
). Right: Example of the depth dependence of the
radiobiological effect (surviving fraction of cells) on tissue
irradiation (with radiosensitivity a ~ 0.35) with a 150MeV
proton beam.
Radiotherapy
with heavier nuclei (ions)
Accelerated protons (energies up to 250MeV) are
currently the most commonly used for hadron therapy . However, heavier
accelerated particles *) - alpha particles or lithium,
beryllium, boron, carbon, etc. nuclei, whose wider use can be
expected in the future , also have a similar and somewhat greater
effect ; is referred to as hadron radiotherapy with heavy
ions (" heavy ions
" are considered to be atoms heavier than hydrogen, deprived
of all or part of their electrons) . The
arrangement is basically similar to Fig. 3.6.5c, the technology
is even more demanding than with proton radiotherapy (synchrotron for 12 C has a diameter of 20-25 meters!) .
*) The Bragg curve of the depth
distribution of the radiation dose has a slightly different shape
for heavier ions than for protons. Bragg's peak has a slightly
sharper increase before the maximum (lower irradiation of the
tissue before the tumor). However, beyond the Bragg maximum, the
dose does not drop as sharply to zero as for protons: the curve
here has a kind of "tail" (representing about 10% of
the dose in the input plateau), stretching about 2 cm to greater
depth - the interaction of heavy ions with tissue atoms occurs
fragmentation and sharply reflected lighter ions (mostly protons)
are formed, which at high energy have a longer range
than primary heavier ions.
Of the heavier nuclei, accelerated
12
C carbon nuclei (carbon ions) are particularly
suitable for radiotherapy . They are relatively easy to obtain(by ionizing carbon dioxide gas with electrons) in an ion source to accelerate and show a high radiation
contrast in the region of the Bragg maximum. In addition, nuclear
reactions of 12 C nuclei in tissue produce 11 C nuclei that exhibit b + -radioactivity, allowing scintigraphic
monitoring of dose distribution in irradiated tissue by
PET (see the section " Nuclear reactions in hadron therapy and
gamma monitoring options
" below) . Accelerated oxygen
nuclei 16 O have similar properties , including the formation of b + -radioactive nuclei 15O, also suitable for PET monitoring of dose
distribution.
Radiotherapy of mesons p -
Mesons p - - negative pions have a particularly significant
radiation maximum at the end of their decay in the
substance (for their origin and properties
see chapter 1.5, section " Properties and interactions of elementary
particles ", passage
" Mesons p and K ") . In
addition to the usual mechanism of the Bragg peak (longer effective time of interaction of a slower
charged particle with the atomic envelope of the substance), this contributes to this effect by the fact that at the
end of its path the p - mesons
are trapped in the nuclei of atoms (in tissue eg
in cores of carbon 12 C, oxygen 16 O, nitrogen 14 N). In this capture p
- -mezonu ring in reaction with proton ( p - + p + ® n a + 140MeV) releases
about 140MeV energy that is higher than the binding energy, so
that the excited core is cut usually to and particles
capable, deuterons, neutrons and protons (in the case of heavier
nuclei, 6
Li or 12 C
are also present among the fragments ). E.g. for carbon the
reaction p - + 12 C ® 2 a + 3n + p, whereby
particles a carry a kinetic energy of about 30MeV and neutrons about
70MeV (the remaining 40MeV is used to overcome the binding energy
of the nucleus). By inhibiting these fragments, considerable
ionization energy is transferred at a given site, i.e. a dose of
radiation that effectively kills the tumor cells.
Mesons p - are obtained by bombarding target nuclei (eg carbon or
beryllium) with protons accelerated to high energies, greater
than about 500 MeV, in a large accelerator (eg
synchrocyclotron). A certain problem is the very short
lifetime of these particles, about 10 -8seconds, so they
cannot be distributed to more distant irradiation facilities. The
range of pions with energies of 50-100MeV in the tissue is about
10-25cm. The decay of pions at the end of their path causes some
undesirable scattering of the radiation dose; also, fast neutrons
flying away from the point of interaction of the pions cause a
certain radiation dose outside the target volume. Due to its high
technical complexity and cost , this method is still
only in the stage of experimental testing in a few of the largest
accelerator centers.
Antiproton radiotherapy
Other unusual particles that could potentially be beneficial for
targeted radiotherapy are antiprotons p 'or
negative protons p -
(their properties have been described in §1.5, part "The properties and interactions of
elementary particles "). Accelerated antiprotons after entry into tissue ionize
similar to normal protons - initially low ionization density
slowly increases and just before braking is a significant
increase of ionization in the Bragg peak . After
the braking, but in addition, the annihilation
antiproton proton or neutron in the atomic nucleus of the
irradiated substance (tissue) to formp-mesons, typically: p '+ p®2p
+ +2p - +p o .
Secondary mesonsp -they
can behave as described in the previous paragraph; in general,
positive and negative pions decay rapidly into muons and
neutrinos, the neutral pion into two quantum gamma (these
particles usually escape from the site of interaction).
Additional quanta can be emitted from "affected" nuclei
(unless they are hydrogen nuclei) by the mechanism of nuclear reactions. Antiproton annihilation
thus releases additional energy up to several
hundred MeV at the site of the Bragg peak , which significantly increases
the radiation effect at the site of the Bragg maximum -
about 3 times compared to protons. An accompanying phenomenon
during interactions are also positrons, whose annihilation
gamma-photons of energy 511keV can be detected using a PET
camera and thus monitor the actual distribution of the
radiation dose in the tissue.(similar to
that mentioned below for radiotherapy with 12 C carbon nuclei ) - Fig.3.6.6. A
certain disadvantage of antiproton therapy is the
slightly higher radiation dose outside the target volume
(including the whole body dose) , caused by penetrating pions, neutrons and g , flying in all
directions from the site of antiproton interaction.
Antiprotons p- can
be prepared by bombarding target nuclei with accelerated protons
in reactions p + p ® 2p + p + p 'and p + n ®2p + n + p '. The kinetic
energy of the protons must be at least 5.6 GeV, but to achieve a
higher yield over 20 GeV, which can only be achieved on large
accelerators. The resulting antiprotons fly out with rather high
kinetic energies of several GeV for radiotherapeutic purposes, so
they must be slow at about 100-200MeV energy in deceleration
. This resulting energy determines the range of
antiprotons in the tissue and thus the depth of
the Bragg maximum of the radiation dose. The method is
in the stage of laboratory testing in the largest nuclear
laboratories (CERN, FERMILAB); Due to the extraordinary
complexity and cost , the introduction of this
interesting method into clinical practice cannot be expected in
the foreseeable future ...
Neutron therapy
In principle, neutron beams can also be used for
radiotherapy . Either they are fast neutrons ,
which collide with nuclei in the tissue, especially hydrogen
nuclei, to form accelerated protons that have strong ionizing
effects. Fast neutrons have high LET and radiobiological
efficiency, but depth dose distribution in the tissue is not more
advantageous than with gamma radiation. In addition, the neutron
beam is difficult to collimate and modulate, and exhibits
considerable scattering "to the sides" of the original
direction in the tissue.
An interesting unconventional method for increasing
the selectivity of neutron irradiation of tumor bearing is
called. Neutron capture therapy (NCT - Neutron
Capture Therapy ) by means of slow neutrons.
In this therapeutic procedure, suitable atoms whose nuclei have a
high effective neutron capture cross section (see §1.3., 1.6)
are bound to the tumor site by means of a suitable compound,
which is preferentially taken up and accumulated in the tumor
tissue (see §1.3., 1.6) - boron enriched in
isotope 10B
is used. Special boron compounds (BSH-mercaptododecarborate,
or BPA-dihydroxyboralfenylalanine) have
been developed for brain tumors , which penetrate only marginally
into healthy brain tissue, but are selectively taken up
in tumor tissue cells that have a disrupted blood-brain barrier.
. Bor-Deoxy-Glucose can be used
for metabolically active tumors elsewhere in the body .
The tumor deposit prepared in this way is then
irradiated with a beam of low-energy neutrons
(with energies of about 1eV-10keV), which slow down (moderate) to
thermal energy as the tissue passes and are then trapped
in the boron nuclei, occurring by reactions (n, a ): 1 n + 10 B ® 11 B * ® 7 Li + 4 He for the decay of
the boron core and the emission of helium (ie alpha particles)
and lithium nuclei. The resulting alpha particles and lithium
nuclei, carrying away considerable energy
released in the reaction, have a very small range
in the tissue , it stops about 10 µm from the reaction site, so
that the ionization energy is transferred practically directly
inside the respective tumor cells, which can be effectively
destroyed , without radiation damage to the surrounding
tissues. The described method is currently experimentally tested
in brain tumors of glioblastomas (and also brain metastases of
cutaneous melanoblastoma).
The source of neutrons for
radiotherapy can be either a nuclear reactor (§1.3, part " Nuclear reactors ") , but in laboratory
conditions neutron generators , special small
charged particle accelerators, mostly deuterons, with a tritium
target, (§1.5, part " Charged
accelerators " are more advantageous. particles "passage" Neutron Generators ") , or radioisotope source consisting of a
mixture and -záøièe with light element (such as mixtures of
americium beryllium, reacting a
, n), or severe transuranovým radionuclide
(typically californium 252) during the spontaneous fission
neutrons are released ( §1.3, " TRU ") . For neutron capture
therapy to retard the first moderator .
Neutron capture therapy dot not exceed the
framework certain experimental studies (in
practice not worked too) and is now used
only sporadically ... Regarding the use of boron
, on the contrary, promising " Proton-boron therapy " below.
Nuclear reactions in hadron
radiotherapy and the possibility of "in-beam"
gammagraphic monitoring
When irradiated with high-energy hadrons (protons, pions, fast
neutrons, antiprotons), most of these particles interact with the
atomic shells of the irradiated substance (tissue); this gives
their ionizing and radiobiological effect. However, a small part
of these particles also undergo a number of nuclear
reactions with the nuclei of atoms in the tissue, during
which various secondary particles and fragments of nuclei are
formed. In these nuclear reactions, secondary (or tertiary)
radiation is emitted, which can in principle be detected and used
to monitor the dose distribution in the tissue.
This is a hadron activation analysis using the
resulting gamma radiation (only
this high-energy photon radiation is penetrating
, can fly out of the irradiated tissue and be detected) . The principle of activation analysis was given in
§3.4, part " Neutron activation
analysis " (where it was mainly neutron activation, but similar
principles apply to irradiation with protons and heavier ions) . Gamma radiation in nuclear reactions is basically
created by two mechanisms :
× Deexcitation of the
excited levels of target nuclei formed after the reaction. This
radiation has a line spectrum with a number of energies (in a wide range of about 100keV-10MeV) and can be analyzed using gamma
spectrometers with scintillation or semiconductor detectors
(HPGe) - see section "" below. Gammagraphic imaging for
such high energies is difficult with standard scintigraphic
collimators, special slit collimators are tested, experimentally
also high energy cameras with electronic collimation, using
Compton scattering kinematics (§4.2, part
" Alternative physical principles of
scintillation cameras ",
passage " Compton camera ") .
× Positron emissions from positron
radionuclides formed during nuclear reactions. These positrons in
the tissue annihilate with electrons to form pairs of annihilation
radiation quantities gamma energy
511keV. The distribution of positron radionuclides can be imaged using a PET gamma camera .
In terms of time, it is a secondary
radiation of two types :
¨ Prompt
gamma radiation, emitted immediately during the reaction or
immediately after the reaction due to deexcitation of the excited
nuclear levels in the irradiated substance. This radiation must
be measured "online" directly during irradiation.
¨ Subsequent - delayed
- gamma radiation, emitted by radionuclides generated after the
reaction, which have a certain shorter or longer half-life. Here
we can also measure and display "off-line" with a
certain time interval, with respect to the half-life of the
analyzed radionuclide.
In-beam
PET monitoring
From the point of view of gammagraphic monitoring of the passage
of a radiation beam through a substance (tissues), such reactions
that lead to the formation of positrons are of
particular interest : either e + are emitted directly or nuclei showing positron b + -radioactivity are formed. Annihilation of positrons
with electrons is accompanied by the emission of pairs of
opposite quanta of annihilation radiation g
of energy 511keV. These photons can then be detected by the positron
emission tomography method of PET (see
" PET cameras "
in Chapter 4 "Radionuclide scintigraphy") - Fig. 3.6.6a. The most common positron radionuclides
generated by the high-energy irradiation tissue, are: 11C (T 1/2 = 20.3 min.), 15 O (T 1/2 = 122 s.) And to a
lesser extent 10 C (T 1/2 = 19.3 s.). As there is some correlation
*) between radiation dose and induced positron radioactivity (or
direct positron emission and annihilation radiation), this allows
scintigraphic monitoring of dose distribution in
irradiated tissue using PET - " making the invisible
visible " online, in situ , or off-line with
the use of emerging positron radionuclides with a not too short
half-life (lower parts of Fig. 3.6.6b, c).
*) This correlation can be negative
or positive, as shown by the curves in Fig.
3.6.6b, c. It depends on the mechanism of reactions and the kinetic
balance of the irradiating particles and the induced
radioactive nuclei. In proton therapy , the
three radionuclides are formed by the ejection of neutrons from
carbon and oxygen nuclei in the region of high proton energy,
before the Bragg maximum; the correlation is negative - the
greatest activity is induced in the region of low LET, in the
region of Bragg's maximum there is none (Fig.3.6.6b). During
irradiation of the 12 C nucleus , two kinds of strip
reactions take place: 1. A neutron is entrained
from the 12
C nucleus, which produces b + -radioactive 11C, which continues in
flight and stops at the site of the Bragg maximum - a positive
correlation between the dose of 12 C and the induced b
+
-radioactivity (Fig. 3.6.6c). 2. The fast-flying
12 C
nucleus ejects a neutron from the carbon or oxygen nucleus in the
tissue, creating 11 C, 15 O or 10 C, which remains at the site of its origin (ie outside
the Bragg maximum) - again a negative correlation. There is also
a positive correlation between the dose distribution and the
intensity of annihilation g- radiation in the case of a nuclear reaction of antiprotons
or pions p - at the
point of their cessation (Bragg maximum).
For PET monitoring of dose distribution, a case of
positive correlation is more suitable, even under conditions of
sufficiently high induced b + -activity. With a
negative dose-activity correlation, the PET images are of poor
quality, only the passage of the tissue bundle outside the target
volume can be monitored (Fig. 3.6.6b below); is briefly discussed
below.
Note:
b + -radioactive isotopes
are induced even in classical irradiation with g- beams with an
energy higher than about 10 MeV, but the activities are very
small, insufficient for gamma imaging.
Fig.3.6.6. a) Possibility of gammagraphic
"in-beam" monitoring of hadron radiotherapy using
positron emission tomography. b) Negative
correlation between dose distribution D and induced b + -radioactivity in the proton beam. c)
Positive correlation between dose distribution D and induced b + -radioactivity in irradiation with accelerated carbon
nuclei.
A typical example of
nuclear reactions enabling PET-monitoring with a positive
dose correlation is radiotherapy with accelerated carbon
nuclei (ions) , where during nuclear reactions *) in the tissue
from the part of the 12 C nuclei b + -radioactive 11 C nuclei are formed
, which continue to fly a it stops, as well as
the basic nuclei 12 C, at the place of the Bragg maxima (Fig.3.6.6a, c). By
gammagraphic PET-imaging of the positron radioactivity thus
induced, we obtain an image of the distribution of the sites in
which the 12 C + 11 C nuclei stopped and delivered the maximum radiation
dose. With a PET camera installed on the radiator, we canmonitor
the distribution of the dose in the target tissue and in
the environment - thus control the course of radiotherapy
similarly to the IGRT method (mentioned
above) . This method is called in-beam
PET monitoring - monitoring directly in the
irradiation beam using PET - Fig.3.6.6a.
*) "Peripheral" nuclear
reactions, so-called strip reactions (see the section
" Mechanisms of nuclear reactions " in
§1.3 " Nuclear reactions "), in which a neutron is detached from the flying
nucleus 12
C during interaction with the nucleus in the tissue , are mainly
used here. 12 C ® 11 C + n. This creates
a neutron-deficient carbon nucleus 11 C (continuing in motion), which is b + -radioactive: 11 C ® 11 B + e + + n with half-life T 1/2 = 20.3min .; it disintegrates
only after stopping at the site of Bragg's maximum. Subsequently,
the positron e + is annihilated with the electron: e + + e - ® 2 g , while these two
oppositely scattering quantum g
with energies of 511 kV can be used for PET
scintigraphy . This displays the distribution of 12 C + 11 core stop
points C, which are also the sites of the largest
radiation dose in the Bragg maximum. Due to the short
half-life of 11 C, PET imaging must be performed immediately after
hadron irradiation - either directly with a PET camera installed
in an irradiation facility, or within a few minutes on a camera
in another room in the workplace.
In proton
radiotherapy , radionuclides 11 C and 15 O are formed by the ejection of neutrons from carbon
and oxygen nuclei in areas where protons have high energy, ie in
the input beam to a distance of about 1-2 cm before the Bragg
maximum. Activated nuclei remain "standing" in their
original places in the tissue (or are
reflected only at short distances). In the
region of the highest dose, the activation is zero (the energy of
the slowed-down protons is subthreshold, not enough for the
reaction). Here, too, PET images may provide some information on
dose distribution, but there is a negative correlation
between the absorbed dose and the induced activity on the PET
image .
Scintigraphic imaging of PET
is also very suitable for monitoring the biological
response of tumor tissue to radiotherapy in general
(both hadron and conventional g
radiation ), as it is able to monitor the
cellular activity of the tissue - to distinguish the remaining
(or recurrent) viable tumor cells. Positron
radionuclides ( 11 C, 15 O, 13 N, ...) , thus
produced along the path of the hadron beam, can thus be measured
by means of a PET camera. Although this technique is suitable for
post-treatment and correction of the irradiation beam, it does
not allow real-time online monitoring. It may be effective for
less perfused structures (such as a scaffold), but in
well-perfused tissues, rapid biological leaching and movement of
induced radioactivity occurs. Due to the generally low induced
activity, longer PET acquisition times are needed.
Hadron-gamma-activation
analysis - prompt gamma monitoring of the irradiation beam
During the passage of the hadron beam through the irradiated
tissue, there are a small percentage of interactions with the
nuclei of the irradiated substance to form excited nuclei
, which then deexcite by emission of prompt gamma
radiation. Thus, another possibility of in-beam
monitoring is the analysis of this deexcitation g- radiation
generated along the hadron beam. Scintillation gamma cameras with
slit collimators that provide 1-D projection of prompt gamma
radiation along the path of proton rays are tested. This method
is suitable for monitoring in pencil beam mode , but is
not applicable to irregularly shaped fields in scattering mode,
where different parts of the field reach different penetration
depths. .... ..........
Proton-boron capture therapy
Recently, the possibilities of further increasing the
effectiveness of proton therapy for the selective
killing of tumor cells using nuclear reactions of
protons with appropriate substances incorporated into tumor
tissue have been explored . Most promising one is the
proton-boron capture therapy PBCT ( Proton-Boron
Capture Therapy ). Therapy of this kind is
performed in two steps :
1 . A suitable compound containing boron atoms
, isotope 11B , is first trapped in the tumor bed.
Increased metabolism of tumor cells compared to normal cells can
be used for this. If we also apply, for example, glucose with
chemically attached boron atoms - Bor-Deoxy-Glucose (it is analogous to the well-known Fluordeoxyglucose 18 FDG, used in PET
scintigraphy) , it will accumulate more in
tumor cells. Other such compounds are mercaptododecarborate
(BSH) or dihydroxyboralfenylalanine (BPA). For chemical
coupling it is sufficient to use natural boron, which contains
80% of the isotope 11 B and 20% of the isotope 10 B.
2 . The tumor deposit prepared in this way, in the cells of
which boron is contained, is then irradiated with a proton beam.
During the interaction of protons with boron nuclei, nuclear
reactions p +
11 B ®
3 a
*) occur, in which three alpha-particles with an
average energy around 3MeV are emitted , the total released
energy has the value Q = 8.7MeV. These alpha particles are
immediately braked about 10 µm from the reaction site, so that
high ionization energy is transferred practically directly inside
the respective tumor cells, which can be effectively
eliminated by DNA birefringence , without radiation
damage to surrounding tissues.
*) This reaction proceeds in 3
stages: first the capture occurs - the fusion of the proton with
the boron nucleus 11 B to form the excited carbon nucleus 12 C *, which
immediately decays into beryllium 8 Be and alpha particle 4 He, after which 8 Be is immediately cleaved to 2 alpha particles: p + 11 B ® 12 C * ® 8 Be + 4 He (3.8MeV); 8 Be ® 4 He + 4 He (2.4 + 2.4MeV). The overall result is the emission
of three alpha particles: p + 11 B ® 3 a . The reaction has an increased effective cross section
of 1.2 barn for proton energies around 700keV, which corresponds
well to the slowed protons in the region of the Bragg maximum.
The proton-boron reaction also emits gamma photons with a main
peak of 718keV, which could in principle be used for " in
beam " gamma monitoring of the distribution of the
alpha-particle dose along the proton beam in and around the
target tissue; however, due to the low concentration of boron,
this weak radiation will be difficult to detect against a much
stronger background of secondary radiation arising from nuclear
reactions of protons with carbon and oxygen nuclei in the tissue,
especially the annihilation gamma 511keV (Fig. 3.6.6).
The
result of such combined proton therapy, "enhanced" by
secondary alpha-particles from nuclear reactions, is selectively higher
radiobiological efficacy compared to the protom beam
itself. It is a molecular- biologically
targeted proton therapy . A significant improvement
in the therapeutic effect can be expected, especially due to
densely ionizing alpha particles, especially in hypoxic and
radioresistant tumors. However, the basic condition for the
success of this method is a sufficiently efficient and selective
uptake of boron in the target tumor tissue.
Common
aspects of hadron radiotherapy
Somewhat unusual name " hadron therapy
" originated because particles that interact with a strong
interaction - so-called hadrons - are used here(see §1.5, passage " Systematics of elementary particles ", " Elementary particles and their properties " and 1.6 ). However, in the
case of its own therapeutic effect, the electromagnetic
interaction leading to the ionization of the substanceis
used here in particular; a strong interaction is seen withp, antiproton and
neutron or proton capture therapy. What is important for a given
application is that, in the end, the particles are heavy
and electrically charged, with high
radiobiological effects and specific depth distribution of
radiation dose. In p - ,
neutron or antiproton therapy , it is a bit of an exaggeration to
say that at the end of the particle path, inside the target tumor
tissue, there is a kind of miniature " nuclear
explosion " whose energy effectively kills
tumor cells, with minimized radiation damage to surrounding
tissues. Even with proton or ion therapy, it can be said that the
radiation dose in a sense "explodes" at the site of the
Bragg peak, which should be located inside the tumor.
The relationship between dose
and biological effect is also basically given by the standard linear-quadratic
(LQ) model mentioned above (it is analyzed in detail in
§5.2, part " LQ model "),
from which, however, there are some deviations. In addition to
the square, minor corrections should be included, including higher
powers of the dose , originating in multiple interactions of
densely ionizing radiation with the DNA structure.
All" hadron "methods
outlined above - proton therapy (+ ion, muon or
antiproton) and neutron capture therapy , we
present here mainly because they are very interesting in
terms of nuclear and radiation physics.Only proton
therapy has so far developed into the wider therapeutic practice,
the others are still in the laboratory testing stage.
Brachyradiotherapy
For irradiation of smaller volumes of target tissue, it is
sometimes possible to use the so-called brachytherapy
*) - a method of local radiotherapy , in which
the radiation source is in close contact with
the tumor site. The condition for the usability of brachytherapy
is the mechanical availability of the lesion. In
organs affected by cancer, the radionuclide radiation source is introduced
(by puncture or implantation) either directly into the tumor bed
( interstitially ), or is introduced intracavitatively
into body cavities (eg into the uterus), or intraluminally
into tubes, or. is applied to the surface of the tumor (so-called
mulch ).
*) Greek brachys
= short - this is radiation from a short distance, "at
close range", in contrast to teletherapy as
radiation "at a distance". From this point of view, we
can compare it with open radionuclide therapy
, which is "completely close" - at the cellular level;
see the discussion below Radioisotope
therapy with open emitters - the closest possible
brachytherapy .
Selective
irradiation of the tumor bed is achieved here by the
highest radiation intensity in the immediate vicinity of
the emitter , while decreasing sharply
at greater distances- in vacuum it would be approximately
squared distance , in tissue it is even faster due
to the exponential absorption of radiation. It is therefore
possible to concentrate a very high dose of
radiation on the tumor site , usually without the risk of more
serious damage to the surrounding healthy tissues.
If we have a radionuclide
gamma emitter - radiophore - of radius r 0 with activity A
[GBq], located in the tissue with the absorption coefficient m for the emitted
energy of gamma radiation, then the resulting intensity I
of gamma radiation (and thus the dose
rate D ') in the surrounding tissue at a
distance r (> r 0 ) will be given by the product of the geometric inverse
quadratic dependence r -
2 and absorption exponential
dependency :
D '(r) ~ I (r) = G . A / r 2 . e -m . r , r> r 0 .
Left: Dependence of gamma radiation
intensity on the distance from a point or spherical radionuclide
source of activity A in the material environment.
Right: Scintillation radiation of a 192Ir brachytherapy
radiophore (400 GBq activity )immersed in a liquid scintillator flask.
For r <r 0 - inside the source - the course of radiation
intensity is different, depending on the construction, material
and distribution of radioactivity within the radiophore (however, this does not apply in brachytherapy) . Initially, for close distances outside the source, a
quadratic decrease predominates, at greater distances the
decrease is more pronounced exponential (attenuation
of radiation in the tissue) .
In terms of time,
brachytherapy is divided into temporary and permanent
(permanent) brachytherapy :
Temporary
brachytherapy
Closed radionuclide emitters of a longer half-life - radiophores
- are introduced into the target tissue for a specified
period of time T. This application time is then
proportional to the radiation dose D - simply put: D ~ G .AT, where G is the radiation
dose constant for a given type of radiation resp. radionuclide, A
is the activity of the radiophore (which
due to the long half-life of the radionuclide can be considered
constant during a relatively short exposure) .
As a radiation source for brachyradiotherapy, radium
226 Ra (a - decay, T 1/2 1602 years) has long been used , whose decay products
(such as 214 Pb, 214 Bi, 214Po , ...) they are gamma emitters. Radium had some
disadvantages, eg radon is formed during its decay, as well as
low intensity of g- radiation leading to long exposure times (approx. 2
days) - it was LDR brachytherapy ( Low Dose
Rate - low dose rate , <2 Gy / hour). . Therefore, radium
was gradually replaced by some other artificial radioisotopes:
cobalt 60 Co , cesium 137
Cs and especially iridium 192 Ir . With
sufficiently high radifor activities (approx. 400GBq, mostly 192 Ir), the exposure
time is reduced to tens of minutes - HDR
brachytherapy ( High Dose Rate - high dose rate,>
10Gy / hour). Rarely is used the so-called pulsed
brachytherapy PDR ( Pulsed Dose Rate
), in which the radiation dose is delivered fractionally
during one brachytherapy application: the radiophore moves in a
sequence of repetitive steps - in "pulses". Neutron
radiophores are also used experimentally
(especially with a 252 Cf Californium ), where neutron radiation has a high
LET - higher ionization density and a stronger radiobilogical
effect (even on hypoxic tumors).
Fig.3.6.7. Two basic techniques of brachyradiotherapy.
Left: During temporary brachytherapy, from the
openings of the head of the shielded box afterloading, the
emitters are led through hoses to the target area and returned to
the container after exposure. Right: During
permanent interstitial brachytherapy, small radiophores are
permanently implanted into the target tissue using applicators.
Emitters, or radiophores
, for brachytherapy are closed encapsulated
radioisotopes, the envelopes of which are in the shape of
needles, tubes, wires or rollers. A significant improvement of
the brachytherapy technique is the so-called afterloading
( afterloading - addtional
load,introduction ) : an
inactive tube or tube - applicator is
first inserted into the target area or body cavity , which is
precisely set (using a brand or
"mock-up" of the radiophore, introduced to the end of
the application tube) . Navigation
is performed for precise settings as well as for batch
distribution planning X-ray imaging (most often C-arm, at least 2
perpendicular projections to obtain a spatial-volume image), or
CT, ultrasonography or NMRI. A separate radiator - a radiophore
- in the shape of a small cylinder (mounted on a guide wire) is
then introduced into this tube for a specified period of time ,
which is returned to the shielded box after the end of the
exposure. The former manual afterloading has now been
replaced by automatic afterloading , in which radiators
are inserted and returned using electronically controlled motors.
The shielded container can contain a large
number of radioforms *), which can be introduced either gradually
or simultaneously into different transport paths - Fig.3.6.7 on
the left.
*) On the idea diagram in the
left part of Fig.3.6.7, all possibilities are shown for
generality. However, current HDR afterloading devices usually
contain only one more powerful 192 Ir source
. This is for economic and technical reasons: radiators are
expensive and decay (need to be replaced); the mechanism for
simultaneous introduction of multiple emitters is technically
complicated. This intensive radiophore is gradually
introduced into the various transport pathways , if
necessary , to achieve the desired dose
distribution in the target volume into which the individual
applicators are introduced; this implementation is fast enough.
For precise uniform implementation applicators in the desired
geometry by irradiation plan is sometimes used special grid
template ( template), similar to the one
schematically shown in the right part of Fig.3.6.7.
Compared to the manual
application of radiophores, automatic afterloading has two main
advantages :
- It significantly reduces (or even completely eliminates) the
radiation exposure of workers when performing brachyradiotherapy.
- By moving the sources in the applicator, we control the time
for which the source is in certain positions ,
thus achieving the required distribution of the radiation
dose in the target volume. With this controlled
modulation of the dose distribution, the automatic afterloading
significantly clarifies the therapeutic effect.
Miniature electronic
X-ray sources could be promising emitters for
brachytherapy (we are working on the development of laser
micro-X-rays) with adjustable dose rate and selectable effective
X-ray energy. They would also have the advantage of better
radiation safety and the absence of radioactive waste.
The radiobiological effect of
brachytherapy can be described by a general linear-quadratic
(LQ) model (given above in the section " Dependence
of radiation biological effect on dose and its timing
"), but including specific factors of spatial and temporal
dose distribution in different types of brachytherapy :
l HDR brachytherapy , in
which individual applications last several minutes (up to tens of
minutes), in terms of time distribution of the dose is similar to
fractionated external radiotherapy EBRT
. Reparation during the fraction is not applied, the dose rate
factor is negligible. However, cellular repopulation of
tumor cells between fractions may occur , with a total treatment
duration of relatively long. For HDR therapy of tumor tissue with
coefficients a, b and doubling half-life of T 2r repopulation , with total dose D divided into
fractions d during total treatment time T , for biologically
effective dose of BED the LQ model (without repair but with
repopulation) is based on: BED = D. [1 + D / ( a / b )] - T.ln2 / (
a .T 2r ).
l LDR
brachytherapy, in which there is a continuous exposure
with a low dose rate with a relatively short total treatment
time, the repopulation of tumor cells is significantly limited
(a constant dose rate to the target volume takes place). For LDR
exposure of tumor tissue with coefficients a, b and repair rate constant
l ,
with dose rate R and time T , for the biologically
effective dose of BED the LQ model (with repair but without
repopulation) is based on a simplified relation: BED = R.T [1+ 2R
/ ( l .
(a / b )]. (1-1/l.T). The case of permanent LDR brachytherapy is
discussed below:
Permanent brachytherapy
In this method, emitters with a shorter half-life (days to tens
of days) are introduced into the target tissue permanently
and have a long-term effect until their disintegration and
radiation. Dose rate R decreases exponentially with a
half-life T 1/2 of the radionuclide used: R (t) ~ G .A (t) = G .A about .e - (ln
2 / T 1/2 ) .t , the total radiation dose is given time
integral D ~ G . 0 ò ¥ A (t) dt = G . 0 ò ¥ A o .e - (ln2 / T 1/2 ) .t dt ~
G .A o .T 1/2 . The total radiation dose is thus given by the initial
applied activity A of
the implanted emitters.
The
radiobiological effect is generally expressed by the equation of
the LQ model (given above in the section " Dependence of the
radiation-biological effect on the dose and its time schedule ") containing the time factors of cell repair and
repopulation. In the initial stages of permanent brachytherapy,
there is practically no cellular repopulation due to the
constantly supplied sufficiently high dose rate. From the thus
reduced equation of the LQ model (with repair, but without
repopulation) it follows for the biologically effective dose
of BED
in permanent brachytherapy of
tumor tissue with coefficients a, b and repair rate constant
l ,
using a radiophore with half-life T 1/2 and initial dose rate R o , simplified relation: BED = R o . (T 1/2 / ln2). { 1 + R o / [( l + ln2 / T 1/2 ). (A / b )] } . The initial dose rate here is proportional to the
initial applied activity: R o ~ G .A o .
Due to the exponential
decrease of the dose rate with time, the radiation effect is
highest in the initial phase. After about 3 to 4 half-dose rate
decreases so that the sufficient cell repair mechanisms
appropriate changes to eliminate - deterministic radiation
effects disappear , continuing (and increasingly
weakening) the radiation dose is therapeutically ineffective *),
and "unnecessary" ( "Wasted
dose" - "waste" or "reactive" dose
) - cf. with a discussion of the effect of dose rate in
§5.2., part " LQ model
" .
*) The proportion of ineffective (unnecessary) dose may be
somewhat lower (and the therapeutic effect thus reasonably
higher) than would result from the LQ model, due to two
circumstances :
1. If tumor
regression occurs during irradiation , the tumor tissue may
"shrink" and the remaining tumor cells may become closer
to the radiophores, increasing their dose rate.
2. If there is hypersensitivity to low
doses (see §5.2, section " LQ
model ", section "Deviations
from the LQ model", Fig. 5.2.4c), deterministic radiation
effects can continue secretly even at low doses.
Permanent
interstitial brachytherapy consists in the implantation
of a large number (several dozen) of small radiophores using
suitable needle applicators of manual
afterloading (under X-ray or ultrasound control), or using a template the shape of a regular grid
( template ), directly into the target tissue -
Fig.3.6.7 on the right. For example, grains *) containing radioiodine
125
I ( g 35keV, X 27keV) are used,
each with an activity of approx. 10-20MBq, or 103 Pd (X 21keV), or 131 Cs (X 33keV). Gold 198 Au has a short half-life of 2.7 days, but too high an
energy of g 412keV, so it is no longer used. Irradiation
is relatively long-term (half-life 125 I is 60 days, 103 Pd has T 1/2 = 17 days, 131 Cs is T 1/29.7 days), in terms of dose
rate, it is LDR (or even VLDR - Very Low Dose Rate
) brachytherapy, while due to the low energy of photon radiation,
the radiation exposure of the environment is minimal, virtually
all radiation is absorbed in the tissue. The method is suitable
for slow-growing tumors, it is mainly used for prostate
cancer . In addition to 125 I, beta emitters such as 106 Ru ( ® 106 Rh, half-life 174
days, max. Energy 3.5 MeV) are also used to irradiate small
deposits in more complex structures, eg in ophthalmology
.
*) Several grains of the radiophore can be
joined together using a special fiber (so - called strand).
As they are gradually ejected from the needle applicator, the
grains are arranged linearly at the same distance, which ensures
a more homogeneous irradiation of the target area and also
prevents individual shifts (migration) of individual grains in
the target tissue or even their escape from the target tissue.
Computer
planning systems (although not as complicated as IGRT)
are currently used for brachytherapy , which determine the dose
distribution in the target tissue based on images of the source
position (simulated by markers in the afterloading applicator)
and determine the source times and movements of the source
afterloading control system. (or activities and positions of
continuously applied radiophores) such that the required dose
distribution is achieved in the irradiated target volume
.
The
so-called bystander effect (see §5.2 " Biological effects of ionizing radiation ", passage " Bystander-Abscopal effect ") could also partially contribute to a more
effective irradiation of tumor tissue , which could perhaps
somewhat correct the effect of mild inhomogeneities in tumor
tissue irradiation - increase the effect in underexposed portions
of the target tissue.
Cancer therapy: ionizing radiation - or chemistry? |
At present, the therapeutic use of ionizing radiation is very important and beneficial. However, this method only affects the consequences , but does not address the causes of the disease. It is hoped that the future of cancer treatment will lie more in advanced chemical, biochemical and immunological methods - at the cellular and molecular level . |
Radioisotope therapy with open emitters - the tightest
possible "brachytherapy"
When we apply a radioactive substance to the body, it enters the metabolic
process in a way that is determined by the chemical
form of the substance - its pharmacokinetics. If we
manage to label with a suitable radionuclide a substance that is selectively
taken up and accumulated in the tumor
tissue, we can get a very effective way of radiation elimination
of the tumor "from the inside". From the point of view
of the above-mentioned division of radiotherapy methods (according to the method of "targeting" the
radiation dose to the affected tissue) ,
radiotherapy using open radionuclides can be
described as the closest possible brachytherapy
(permanent) - at the cellular level. However, due to its
physical, chemical and biological specifics, this targeted
therapy with open radionuclide emitters forms a separate
radiotherapy category and is mostly performed in nuclear
medicine workplaces . It is called biologically
targeted radionuclide therapy ( BTRT ) or molecular
radiotherapy , sometimes endoradiotherapy .
Unfortunately , we do not have such a suitable
substance for most cancer processes ; it will be shown
below when such a radioactive substance "at least
partially" has"and how it can be used
for effective radionuclide therapy. The application of open
radionuclides is also used for non-tumor therapy
in hyperthyroidism and in radionuclide synovectomy (see below).
The methodical approach is
completely different from external therapy and brachytherapy. In
classical radiotherapy accurately know the localization
and extent of the tumor bed which then Irradiate precisely
directed radiation beams, or placed in the vicinity of the lesion
brachytherapy radiofor (obr.3.6.8 left) . When the radioisotope therapy need to know the biological
(biochemical, pharmacokinetic) properties of the
tumor tissue, which is applied by suitable for the metabolic
environment of the organismradiopharmaceutical (Fig. 3.6.8 on the left) , which
gets inside the tumor deposit (it is picked
up there biologically) and by its radiation
destroys the tumor cells " from the inside
" (Fig . 3.6.8 on the right) . We basically
don't need to know the location of the tumor site, the
radiopharmaceutical can be taken up even in sites we don't know
about yet (eg micrometastases) . Thus, this targeted therapy uses radionuclides to kill
tumor cells, which are bound to a suitable " transporter
", whose task is to selectivelytransported
to target tissues a sufficient amount of a radionuclide to the
dose of radiation emitted killed tumor cells, while surrounding
healthy tissues and organs should be damaged as little as
possible - not be irreparably compromising functionality (in accordance with the above stated general
"strategic goal" radiotherapy " strategic goal and
methods of radiotherapy
") .
Fig.3.6.8. Biologically targeted radionuclide
therapy ("molecular radiotherapy").
Left: Comparison of
the methodological approach of external radiotherapy and
radioisotope therapy. Middle: Time
dependence of the surviving fraction of cells in the tumor during
radioisotope therapy. Right: The
"crossfire" effect of hard radiation b on tumor cells.
Physical and biological
factors
Similar to external radiotherapy, radionuclide therapy is
achieved by co-production of two basic factors :
×
Physical factors
- type of radionuclide, type of emitted radiation ( a, b, g ) and its
energy, half-life.
× Biological and
radiobiological factors - radiosensitivity of
pathological cells in comparison with cells of healthy tissues
and organs, pharmacokinetics of therapeutic radiopharmaceuticals
(their uptake in target tissues and other tissues).
The basic requirement is high
accumulation in target tissues and low
accumulation in healthy tissues. The biokinetics of
therapeutic radiopharmaceuticals can be influenced
pharmacologically to some extent (eg by
discontinuation of TSH or thyrogen in the thyroid gland, or
rituximab in lymphomas) .
For therapy with open
radionuclides, only radiation with low penetration
(short range) is suitable , especially beta
radiation (the range of which in the tissue
is usually less than 5 mm) , or Auger
electrons (with a very short range of
the order of nanometers) , or alpha
radiation (also a short range of tens of
micrometers) . The short range of this
radiation in the tissue ensures that virtually all the energy is
deposited in the target volume and the effect of the radiation is
thus localizedto the organ or area of tissue in
which the radioactive substance has been taken up *), with
minimal damage to surrounding healthy tissues.
*) However, radiation exposure to other
tissues and organs may occur due to partial undesired
uptake of the used radiopharmaceutical in these tissues
and during metabolic processing and clearance of the
radiopharmaceutical (blood, urinary tract or GIT).
Therapeutic beta or alpha
radionuclides should meet several criteria :
l The nuclide
should have a high proportion of corpuscular beta or alpha
emission and a low gamma component.
l The half-life
should correspond to the biological kinetics of the target
ligand. The effective half-life of the radiopharmaceutical, which
is the result of the physical half-life of the nuclide and the
half-life of the biological elimination of the ligand, then
determines the duration of therapy.(or its
faction) .
l If the
daughter nuclide is also radioactive - the radionuclide decays by
the conversion series ( "In vivo generators"
in nuclear medicine ) , the decay chain should not contain intermediates with
a long half-life (which could be released
from the target lesion and cause radiation exposure to healthy
tissues - more details) is discussed below in the section " Alpha and beta radionuclides for
therapy ") .
l Radionuclide
atoms should be able to form stable compounds or conjugates
with the necessary biomolecules - radioligands (Fig . 3.6.10
a ) .
Physico-radiobiological effects
For large and heterogeneous tumor lesions, it is appropriate to
use a radionuclide with high energy b radiation (such
as 90 Y
with a maximum energy of 2.3 MeV and a range in the tissue of
about 5 mm, which represents about 100-200 cell diameters) for
the so-called "crossfire effect" :
this radiation can destroy even those tumor cells that are not in
direct contact with the bound radiopharmaceutical (cells that do not have the appropriate receptors, or
that the radiopharmaceutical does not penetrate them inside the
tumor) . These cells come under
"crossfire" of hard radiation from a radionuclide bound
to surrounding cells (shown in Fig . 3.6.8 on the right) .
However, for the eradication
of smaller tumor foci, or tumors infiltrating normal tissues in a
diffuse form, this effect could cause increased radiation
exposure to surrounding healthy cells. Here, on the other hand,
radionuclides with a lower energy of radiation b , such as 177 Lu with a maximum
reach in the tissue of about 2 mm, or alpha-radionuclides are
suitable . Shorter penetration of 177 Lu radiation captured in tumor cells into surrounding
tissues may lead to a more favorable tumor / healthy tissue
effect ratio.
For cancer diseases involving
larger and smaller tumors, the so-called tandem therapy 90 Y - 177 Lu, or " cocktail"co-administered
radiopharmaceuticals labeled with high- and low-energy beta
radionuclides.
The effect of radioisotope
therapy may be further contributed by the radiation-induced
biological bystander effect (described in §5.2, section" Effect of radiation on cells
", passage" Bystander-Abscopal effect ") . In late stages of
radionuclide therapy, when radiation doses are already low,
biological efficacy may increase the effect of hyper-
irradiation. -radiosensitivity to low doses of
radiation (§5.2, part " LQ
model"Passage" Deviation from
the LQ model "obr.5.2.4c) . This
reduces the proportion of "unnecessary waste batch " ( Wasted dose ) in the
later stages of therapy.
Alpha and beta
radionuclides for therapy
So far, beta-radionuclides
are mainly used for radioisotope therapy (middle
and lower part Tab.3.6.1) - discussed
above. Recently, however, alpha radionuclides
have been increasingly used here (upper
part of Table 3.6.1) , whose radiation has
a high LET - high ionization density - to create
double DNA breaks , which leads to high
radiobiological efficiency of cell killing. In the case of alpha
radiopharmaceuticals, high radiation energy is released in a very
small volume, which leads to a lower radiation exposure of the
surrounding tissues. Comparing the a - and b- emitting radionuclides in
terms of use for biologically targeted therapy, we can emphasize
the following differences :
¨ The weight of a -particles is
about 7000 times greater than b
-particles.
¨ Energy a particles capable
is » 10
to 30 times greater than b particles capable of: a typically 4-8MeV, b approx
0,2-2,25MeV.
¨ The electric charge of a -particles is 2
times larger than b -particles ( a : +2, b: -1 of elementary charge |
e |) .
¨ Ionization density
(linear energy transfer LET) a-particles is about 100 times larger than b -particles. For
alpha particles with energies of 4-8 MeV, the LET in the tissue
is about 100 keV / micrometer, at the end of the path in the
Bragg maximum it can increase locally up to 300 keV / m m. For beta
particles with typical energies of hundreds of keV, LET is only
about 0.2 keV /micrometer.
¨ Effective range a particles capable of
tissue is substantially shorter than b particles capable.
In a range
is about 2-5 cell diameters, in b hundred cell diameters.
This comparison shows that alpha radionuclides have locally
higher radiobiological efficacy than beta, but due to the
short range, in a -radiation hardly applies the
"crossfire effect". However, low penetration (short
range in the tissue, approx. 50-90 m m) and high ionization
density (LET tens to hundreds of keV / m m) allow effective
destruction of tumor cells with minimal collateral damage
to the surrounding healthy tissue.
Radiobiological
effects of reflected cores
when the emission of alpha particles - helium heavy nuclei with
high kinetic energy - occurs due to action and reaction, the back
reflection daughter nuclei with kinetic energy of about
100keV (§1.2 passage " Backward reflection cores ") . The nuclei reflected in
this way brake very quickly in the tissue on a path of about 500
nm, along which they cause dense ionization of the
substance
with high LET (of the order of
hundreds of keV / m m). If this occurs inside the cell, it can cause double
DNA breaks or damage to the mitochondria, which can result in
apoptosis. The reflected nuclei thus contribute
somewhat to the radiobiological effect , which,
however, is located here in the very close vicinity
of the alpha-decay site, only 0.5 micrometers.
In vivo radionuclide generators
Most alpha-radionuclides used in nuclear medicine are converted
by the whole decay series
(§1.4, passage " Decay
series ") and after their application to the organism they behave
as "in vivo radionuclide generators" ( "In vivo
generators" in nuclear medicine ) - (fig.3.6.10b, c ) . The advantage here is the emission of several
alpha-particles (typically 4alpha
/ decay, see eg 227
Th - where is 5alpha ) with high energies of about 4-8
MeV, which leads to high radiobiological efficiency.
A
certain problem with in vivo generators is the
redistribution of daughter radionuclides - release -
dissociation - of daughter atoms from
chemical bonding in radiopharmaceutical molecules due to
nuclear reflection during alpha-particle emission (§1.2, passage " Nuclear reflection ") and differences in
chemical properties of daughter atom (oxidation number). Already
at the first a-conversely, the chelation of the radionuclide with the
ligand is disrupted by the back reflection of the nucleus (and thus the daughter atom) and
the chemical transformation of the original atom. Subsequent and -emitting
daughter atoms are then free. When this occurs on the cell
surface, the lymphatic and bloodstream can transmit the
radioactivity thus released to non-tumor tissues (Fig . 3.6.10 b
). If the daughter atom escapes from the target tissue during its
transformation, the effectiveness of the therapy is reduced
by a few subsequent energy alpha-particles from the decay series.
These released radioactive atoms can then migrate and be taken up
in other tissues (eg bone marrow) and cause unwanted radiation exposure there.This
side effect will be alleviated if the radiolabeled ligand
penetrates the cells quickly enough and is internalized
therein (Fig. 3.6.10 c )
; then nascent charged daughter atoms, which are highly
reactive, can remain bound in the cytoplasm inside the cells long
enough to be able to repeatedly decay and transfer all their
radiation energy. This internalization of the daughter
radionuclides in the generator in vivo can also reduce or
prevent undesired redistribution of radioactivity outside the
tumor tissue.
Fig.3.6.10. Radiolabeled biomolecules as radiopharmaceuticals for
diagnostics and therapy in nuclear medicine.
a) Chemical binding of a radionuclide to a
biomolecule (eg a monoclonal antibody)
using a bifunctional chelating molecule (eg DOTA). b)
Release - dissociation - of the daughter atom from the chelating
bond in the depth of the backscattering of the nucleus and
transformation of the oxidation number of the daughter atom
during radioactive transformation (eg alpha). When a radionuclide
is bound to the cell surface, the released daughter radionuclide
can metabolize to healthy tissues (and cause
unwanted radiation exposure) . d)
Prevention of this leakage by internalization of the
radiopharmaceutical inside the cell.
For these reasons, it is also desirable that the decay chain
of the radionuclide used does not contain daughter intermediates
with a longer half-life that could be released
from the target lesion and cause radiation exposure to healthy
tissues. E.g. actinium 225 Ac ( 225
Ac (10d .; a ) ® 221
Fr (4,8m .; a ) ® 2 17
At (32ms .; a ) ® 213
Bi (46m .; b - ) ® 213 Po (4 m s .; a ) ® 209 Pb (3.3h .; b - ) ® 209
Bi (stab.) ) is more advantageous
in this respect than the otherwise promising thorium 227 Th ( 227 Th (18.7d .; a ) ® 223 Ra (11.4d .; a ) ® 219 Rn (4s .; a ) ® 215 Po (1.8ms .; a ) ® 211 Pb (36.1min .; b - ) ® 211
Bi (2.2min .; a ) ® 207
Tl (4.8min .; b - ) ® 207 Pb (stab.)),
Where 223U
problematic with a half-life only slightly shorter than the basic 227 Th.
In general, however, all
radiopharmaceuticals, including daughter radionuclides in an in
vivo generator, are taken up not only in tumor cells, but more or
less in other tissues, where they cause undesired
radiation exposure .
Tab.3.6.1. Some radionuclides suitable for biologically targeted
therapy (their properties and uses will be described below).
The range (range) of radiation in the tissue depends on the type
and energy of the respective quanta. For radiation b ,
the maximum range is given by the maximum energy
in the continuous spectrum; however, only a small percentage of
electrons have this energy b . More important here is the mean range
, which represents about 1/3 of the maximum range - it is given
by the mean energy in the spectrum b (§1.2, part " Radioactivity beta "). For radiation a,
if it is "monochromatic", there is practically no
difference between the maximum and medium range (the difference
is only when two or more alpha lines with significantly different
energies are emitted).
The radionuclides are listed in the table
according to the range of the respective radiobiologically most
effective quantum, alpha or beta.
Radionuclide therapy: beta- yes , beta+ no !
Positrons b + have
essentially the same radiobiological effects as electrons b -
of the same energy. However,
positrons are annihilated with electrons after braking in the
tissue, which generates a penetrating annihilation g- radiation with an
energy of 511 kV, which places a strong radiation load on
surrounding and more distant tissues and organs. Positron b + radionuclides are therefore unsuitable and unusable
for therapy !
Radionuclide therapy
with Auger electrons
In addition to radiation a,
b, g, some radionuclides emit conversion
and Auger electrons (+
Coster-Kronig electrons) . They are formed
by the internal conversion of (virtual) photons of g -radiation and
characteristic X-rays inside the atomic shell (§1.2, passage
" Internal conversion of gamma and
X-rays "). In contrast to the
continuous spectrum of electrons b- radiation from the
nucleus, the conversion and Auger electrons have a discrete
spectrum consisting of several monoenergetic lines. Auger
electrons have significantly lower energies than
b- rays,
usually keV units or less. Auger electron emitting radionuclides
have the following specific properties in terms of biologically
targeted therapy :
× It is emitted several
(approx. 5-20) electrons per decay.
× Very short d
touch Auger electron - water or tissue is of the order of
nanometers .
×
Their LET is locally » > 20 times higher
than beta (energy » 100keV).
× In the immediate vicinity of »5 nm from the radionuclide,
a locally high micro-dose arises from Auger
electrons (according to a fictitious theoretical conversion » 10 4 -10 7 Gy).
These properties result in
locally high radiobiological (cytotoxic) efficiency
killing of cells in the range of a few nanometers, which,
however, can only be applied if the Auger electron-emitting
radionuclide decays directly inside the DNA molecule of
the cell, in particular between the DNA strands. So far, two ways
to bind the appropriate radionuclide to DNA molecules in vivo
are being tested : 1. Labeling of pyrimidine
derivatives that are incorporated into DNA in vivo. 2
. Labeling of DNA dyes that bind to DNA via hydrogen
bonds.
Intensive sources of Auger
electrons are mainly radionuclides decaying by electron capture,
such as 125
I, 77 Br, 123 I, 124 I,111 In, 67 Ga, 201 Tl, ...; they are
also emitted by some "pure", metastable g- radionuclides
(including 99m Tc).
Effect of gamma
radiation
Radiation gamma in radionuclide therapy
have virtually no therapeutic effect, and its presence may even
cause undesired irradiation of other organs and tissues than the
target lesion. However, in the case of mixed beta-gamma emitters,
gamma radiation can be advantageously used for scintigraphic
imaging of the distribution of the radiopharmaceutical
in the organism ( Chapter 4 " Radioisotope
scintigraphy " ) and for monitoring the course of therapy..
Such mixed therapeutic radionuclides with a useful component of
radiation g are mainly 131 I [ g 364keV (81%)] , then 153 Sm [ g 70keV (5%) and 103 keV
(28%)] , 186 Re [ g 137keV (9%) ] , 177 Lu [ g 113keV (3%) and 208keV
(6%)] , 166 Ho [ g 48-58keV (9%) and 81keV
(6%)] , or 223 Ra [row of lines g 0.15-1 MeV] . Detailed
gamma spectra of these and other radionuclides are given in
§1.4, section " The
most important radionuclides
".
For pure higher energy
radionuclides b , such as 90 Y, bremsstrahlung may be used for
detection (gammagraphy) , but the accuracy of localization and
determination of organ activity is significantly worse (for yttrium-90, however, there is a possibility to use
very weak annihilation radiation for PET scintigraphy with better
resolution than bremsstrahlung - is analyzed in §1.4, passage
" Ytrium 90 Y ") .
Note:
It is worth noting that the basic requirement of " as
much beta as possible, as little gamma as possible
" for radionuclides for therapy is exactly opposite
to radionuclides for diagnostics (scintigraphy), where the main
component must be gamma radiation, while beta radiation, which
increases the radiation exposure, should be represented as little
or not at all (as is ideal for 99m Tc) - see Chapter 4. " Radioisotope
scintigraphy ".
Radiopharmaceutical
application
Therapeutic radiopharmaceuticals are usually administered
intravenously , sometimes orally ,
further into the cavities and joint capsule. Carriers
(" transporters ") in radiopharmaceuticals
have a wide chemical range - from simple inorganic compounds (such as chlorides or iodides) ,
through more complex organic substances (..,
peptides, ...), to very complex labeled
monoclonal antibodies.
The optimal dosage of
[MBq] activity of a therapeutic radionuclide is
based on a trade-off between the maximum desired radiation
effect in the target tissue and the radiotoxicity
of the preparation, which is often inadvertently taken
up and radiated by other tissues and organs.
Based on thorough laboratory and clinical trials, the recommended
applied activity [MBq] is determined for each
therapeutic radiopharmaceutical , usually calculated on the
patient's weight (or on the body surface
area - an empirical formula from the patient's height and weight)
; individual refinement can be done on the
basis of an MIRD analysis ( Determination of radiation dose from internal
contamination. MIRD method. ).
For application to the joints(radionuclide
synovectomy - see below), the values of the
recommended applied activity are derived from the size of the
joint.
Radiation dose and its distribution in
radionuclide therapy
In radionuclide therapy, the distribution of the dose, as well as
its time variability, in tumor and healthy tissue is usually more
complicated than in external radiotherapy. This is due to time-varying
biological processes of uptake (accumulation) and
leaching (clearance-loss) of radioactive substances in different
types of tissues; the physical half-life of the
radionuclide used also approaches this . The basic relation for
the radiation dose from the homogeneous distribution of
radioactivity in the substance was derived in §5.1, passage
" Radiation dose from radioactivity "; here we will modify it appropriately. The
radiopharmaceutical with A inj activity is usually partially absorbed
after administration (within a few hours)in target tissues; the
rest leaves the body mainly through the urinary tract.
In the simplest case, the
activity A o = a .A inj , given the accumulation capacity a the given tissue,
accumulated evenly in
the target mass deposit m
(accumulation is often expressed in%) .
This activity A o causes with its emitted particles in the given deposit
a dose rate R o [Gy / s] = A o . <E> .6.10 -12 / m, where <E> [MeV] is the mean energy of the
short-range particles (mostly beta , or alpha), which is absorbed
in the investigated deposit (coefficient
6.10 -9is
the energy conversion factor between MeV ® Joule units , including
also the weight conversion g ®
kg) . Then, this
activity will be accumulated with time t to
decrease approximately exponentially: A (t) = A o .e - k .t
with an effective rate k = ln2 / T 1/2 phys + ln2 / T 1/2 biol , the physical half-life T 1/2 physics
of the radionuclide used and the biological half-life of the
radiopharmaceutical T 1/2 biol of tissue. The dose rate in the bearing will decrease
at the same rate. The total cumulative dose D
received in the target tissue after the time T has elapsed
is then D(T) = 0nTR(t)dt
= (Ro/k).[1- e-k.T]
. This radiation dose, together with its time dependence, can
then be fitted to a linear-quadratic model with a time factor
of reparation and repopulation , as derived above: -ln (N /
N o ) = a .D + { 2. [(1- e - l .T ). (1- 1/l .T)] / l .T } . b .D 2 - ln2.T / T 2r . In the
general case, a complex equation arises for the surviving
fraction of N / N o cells , which, however, is simplified to: -ln (N / N o ) = a .D. {1 + R o
/ [( l + k ). a / b ]}] assuming an irradiation time long compared to the
effective half-life of the radioactivity in the target volume ) . From a comparison with the
corresponding formula for external fractionated radiotherapy, it
can be seen that the R o / l ratio here has a similar role as the fractionation dose d
.
During the exposure, that is continuous
with decreasing dose rate, in addition to radiation destruction
of cells, proliferation (repopulation) of tumor cells in the
lesion may also occur, especially in the later stages of therapy.
As long as the dose rate is higher than the critical value of ln2
/ ( a .
T 2r ), the number of cells in the tumor deposit will
decrease, later as the radiation decreases, tumor cell
proliferation may predominate - compare
with the above-mentioned "wasted" dose . dose
) in permanent brachytherapy . It is
therefore desirable to apply such a high activity
radiopharmaceuticals to rapidly kill, if possible, all clonogenic
cells from the accumulated radioactivity accumulated in the tumor
tissue before cell repopulation predominates. In this respect,
however, radiotoxicity is a common obstacle for those
healthy tissues and organs in which the radiopharmaceutical is
also inadvertently taken up ...
Dose
escalation - applied activity - is possible only with
careful dosimetric control and radiation monitoring
of radiopharmaceutical uptake in target deposits healthy
tissues and critical organs - "Determination of radiation dose from internal
contamination. MIRD method.".
Although the MIRD method in all its complexity is not yet
applicable in routine therapy, at least whole body
dosimetry (measurement of dose
rate at a distance of about 1-2 m from the patient's body) and hematological analysis of regularly collected blood
samples to monitor adverse effects on bone should be
performed. pulp - haematologic toxicity (for severe hematologic toxiocity is also necessary to
carry následené autologous transplantation of
hematopoietic stem cells) .
"Waste"
radioactivity
During the entire course of radioisotope therapy, the radioactive
substance used leaves the organism, mainly through the urinary
tract. The highest content of radioactivity in urine is at the
beginning of therapy, when a significant amount of free unbound
radioactive substance is excreted. Later, during the destruction
of the tumor tissue, the originally bound radiopharmaceutical is
released, which has already "fulfilled its role". The
relatively high content of radioactivity in the urine (to a
lesser extent also in other excrements) in patients during
radionuclide therapy should be taken into account from the point
of view of radiation protection - handling of radioactive
waste (see §5.6 " Radiation protection in workplaces with ionizing
radiation ").
Note: Not to be
confused, please exuded "the radioactivity of the
waste," with the aforementioned radiobiology
"unnecessary" or "waste" dose ( wasted
dose )!
Planning, monitoring and dosimetry of radionuclide therapy
The methods of dosimetric planning
and verification described above for external beam radiotherapy (section " Planning for
radiotherapy ") are not applicable to radionuclide
therapy . The situation here is more like chemotherapy or biological
treatment (described above in the
section " Chemotherapy and
biological treatment ") . However, we do not have to do radionuclide therapy
completely "blindly" (empirically,
at a flat rate) , as is the case with
pharmacological treatment. Methods of the
detection and imaging of emitted ionizing radiation
offer certain possibilities for monitoring , dosimetric
measurements and individual dosing in
targeted therapy with open radionuclide emitters. Determination
of radiation doses can be performed by measuring
biokinetics - the rate of accumulation
and subsequent excretion of the used
radiopharmaceutical in defined areas of interest of
tumor lesions and healthy tissues and critical organs. It is
possible to use mainly quantitative scintigraphy
on gamma cameras (planar, SPECT or PET, in
combination with CT), in a simpler case,
whole - body measurement of radiopharmaceutical retention, as
well as measurement of the activity of blood samples. These data
then, using the MIRD method (or simplified
variants), in principle make it possible to
determine the absorbed dose in the target loci and the undesired
dose in healthy tissues.
Even with the same activity of
the same radiopharmaceutical, the actual radiation doses
may vary significantly from patient to patient ,
depending on the accumulation capacity of the tumor tissue as
well as the functional status of the kidneys, bone marrow, liver,
heart and other organs. To ensure the optimal course and
effect of radioisotope therapy, it is therefore
appropriate to monitor how the radiopharmaceutical is taken up.
in the target tissue (tumor) and how it gradually disappears from
it. To minimize the side effects of radiation on
healthy tissue, it is also useful to monitor the concentration of
the radiopharmaceutical in individual other organs and
tissues (kidney, liver, bone marrow, heart, bladder,
blood samples). Based on this monitoring of
radiopharmaceutical distribution, it is in principle
possible to calculate (or estimate) effective radiation
doses - both desirable in target tissues and undesirable
in other organs.
The actual radionuclide
therapy is preceded by the stage of radiotherapy planning
, the main output of which is the determination of the applied
activity of the given radiopharmaceutical, or and a
schedule of repeated applications. The applied activity is most
often determined essentially on a flat-rate basis
, based on recommendations based on experiments and multicenter
studies in the preclinical phase of radiopharmaceutical testing.
To determine the radiation doses in individual organs from the
internal distribution of radioactive substances, the so-called MIRD
( Medical Internal Radiation Dose ) method is sometimes
used in these studies , including a number of physical and
biological factors - see §5.5, section " Internal contamination ".
In order to more accurately
determine the applied activity in specific patients, it is in
principle possible to monitor the individual
pharmacokinetics of the patient (as
mentioned above). This monitoring can be
performed both in the preparatory phase of planning -
pre-therapeutic application of diagnostic activity
of the drug, labeled with the same or different *), more
suitable, radionuclide g - teranostics - and subsequent gamma
imaging , as well as during the actual therapy.
Appropriate diagnostic radiopharmaceuticals
labeled with g- radionuclides are used for scintigraphy (see §4.8 " Radionuclides and radiopharmaceuticals
for scintigraphy ") . A comprehensive teranostic approach is discussed in
§4.9, section " Combination of diagnostics and therapy -
teranostics ".
*) Even with the same marking carrier
substances other radionuclide chelating bond with another it is
necessary to consider the potential risk of altered
pharmacokinetic properties ...
For external
monitoring own radionuclide therapy is preferred that
the radionuclide is used, in addition to the main component b or a , whether or not a
significant component of the radiation g -
this is the case, for example, with radioiodine 131
I , samarium 153
Sm or lutetium 177
Lu . This radiation g freely (with some absorption)passes
through the tissue and its external detection can determine the
location and in principle the activity in tissues and organs. For
pure higher energy radionuclides b , such as 90 Y , bremsstrahlung
may be used for detection (gammagraphy) , but the accuracy of
localization and determination of organ activity is significantly
worse (for yttrium-90, however, there is a
possibility to use very weak annihilation radiation for PET
scintigraphy with better resolution than bremsstrahlung - is
analyzed in §1.4, passage " Ytrium 90 Y ") . Haematological
radiotoxicity can be monitored by analysis of blood samples taken
regularly.
........ ?? ..... add? .... + image MIRD
..... ?? .....
Using the outlined
measurements and calculations, it is possible in principle (but
rather only theoretically ...) to determine radiation doses and
the biological effect of radioisotope therapy. However, due to
the complexity of the distribution of radioactivity and its
dynamics, including the uncertainty of a number of important
parameters (the key unknown is radiosensitivity
) , this is only a very inaccurate
"qualified estimate" (error of
about 30-50%) . In practice, therefore, the
dosage of therapeutic radiopharmaceuticals is usually determined empirically
, based on accumulated experience.
Thyroid Therapy with Radioiodine 131 I
In the introduction to this chapter on radioisotope therapy, we
mentioned that for most tumor processes, we do not yet have
substances that would be sufficiently selectively taken up and
accumulated in tumor tissue. A notable exception - where " we
have a suitable selective uptake substance " - is thyroid
cancer , in which thyroid tumor cells usually retain the
ability to take up and accumulate iodine , as
well as healthy thyroid cells (this is
especially the case with differentiated thyroid cancer
cells ). .
Therefore, if we apply radioactive
iodine 131 I [T 1/2= 8 days, E b max = 606keV, g : 284keV (6%), 364keV (81%), 637keV (7%), 723keV (2%) -
physical properties §1.4., passage " 131 I
"; administration orally in the form of a solution of sodium
iodide ] , this
radionuclide is taken up in thyroid tumor cells (as well as inactive iodine, the chemical properties are
the same, the cells do not "recognize" it) , even in distant metastases . Sodium
iodide NaI penetrates thyroid cells by ion transport via the Na
/ I symporter (which is a
transmembrane glycoprotein with a molecular weight of 87 kDa) , in which it then enters the synthesis of thyroid
hormone. Beta radiation 131I, which has a relatively short range in the tissue (max. 3 mm, effective range R 90 is only about 0.8 mm) ,
eliminates tumor tissue "from the inside" with its
ionizing effects, and thus selectively , with
minimal radiation exposure to surrounding healthy tissues.
However, the radiation exposure of other tissues and organs
occurs due to the partial undesired uptake of
radioiodine in these tissues, as well as during the metabolic
processing and clearance of the radiopharmaceutical (blood,
kidneys, bladder). The condition for radioiodine to accumulate
effectively in thyroid cancer metastases is the removal
of all thyroid tissue itself. After surgical removal of
the thyroid gland, if necessary, carry out radiation
elimination possibleresidual
accumulating tissue by application of about 1-2 GBq of
radioiodine. For the actual therapy of thyroid cancer
, an A activity of about 3-7 GBq *) of radioiodine is then applied . In
tumor tissue accumulating differentiated thyroid metastases,
approximately (0.01-0.02)% A inj / g is taken up per gram [g] , which is approximately
0.3-0.8 MBq / g. The initial dose rate R o in the tumor tissue from this radioiodine concentration
is then approximately 40-80 mGy / hr, after which it decreases
exponentially with an effective half-life of approximately 2
days. The total cumulative absorbed dose in the tumor
lesion (after about 10 days) reaches about 30-60 Gy (follows from the above analysis in the passage " The
radiation dose and its distribution in radionuclide therapy "). The whole- body
dose from the therapeutic application of radioiodine is
about 0.04-0.13 Gy / MBq, depending on the specific physiological
situation of the patient(especially the
functional state of the kidneys). From this
whole-body dose it is possible to estimate the radiation dose in
the bone marrow causing hematological toxicity at
tyreologické radionuclide therapy.
*) As anachronism in the
literature still indicate the recommended value 3,7 or
therapeutic activity of 7.4 GBq resulting linear conversion from
long ago abandoned activity units millicuries [mCI] - values ??of
100 or 200 mCi, introduced as a rough empirical estimate in the
60s-70s of the 20th century.deviation from
flat-rate therapeutic activities.
By carefully monitoring
the dose distribution with the help of blood
sampling (and possibly quantitative scintigraphy and the
MIRD method, or at least whole-body dosimetry), the therapeutic
ratio can be optimized by individual
dosing , especially with regard to hematological
radiotoxicity . Without the risk of excessive
radiotoxicity, the applied activity can be significantly
increased in many cases (up to several tens of GBq),
which leads to a significant improvement in the
therapeutic effect and a reduction in the risk of tumor
cell repopulation, recurrence or need for repeated therapy.
Before
the actual radionuclide therapy of thyroid cancer, surgical
removal of the thyroid gland is performed - total
thyroidectomy (the patient must then
take thyroxine, a thyroid hormone, permanently) . This is followed by the application of the so-called elimination
dose of radioiodine (approx. 1-2GBq), which eliminates
any functional thyroid tissue remaining after surgery - to ensure
the bioavailability of radioiodine in
metastases. To detect metastases, scintigraphy is performed after
the application of diagnostic activity 131 I (and possibly hormonal
stimulation - discontinuation of TSH or application of thyrogen) - but it is not necessary for therapy ... Then the main therapeutic
activity is appliedradioiodine, the relevant part of
which can already be "undisturbed" in metastases and
cause the desired therapeutic effect there. Through 364keV
gamma-rays can be continuously radiometrically and scintigraphic monitoring
the course of therapy - whole body dosimetry, secretion and
activity of the organism deployment accumulating metastases.
Later, it is also advisable to perform laboratory monitoring of
thyroglobulin levels , which allows the detection of
recurrence. Therapeutic applications of radioiodine are performed
repeatedly if necessary (based on laboratory and
scintigraphic examinations) .
Many years of experience with
radionuclide therapy and thyroid gland show that in terms of curative
success, it is best to apply the first time.the
maximum possible activity of radioiodine, about 10-20
GBq (as far as possible in terms of
radiotoxicity) , so that all tumor cells of
metastases are eliminated in one go, without repopulation
and subsequent recurrence.
This method of radioisotope
therapy of thyroid cancer, performed in the workplaces of nuclear
medicine , is probably the most successful
radiotherapeutic method of cancer, leading to permanent cure -
the success rate is around 80%! Unfortunately, only in a very
special and relatively rare type of cancer - differentiated
thyroid cancer.
Therapy of
non-cancerous thyroid diseases
In addition to the treatment of thyroid cancer, there is
treatment with radioiodine 131Also used in the "less radical" therapy of
non-cancerous thyroid diseases. It is mainly hyperthyroidism
(thyrotoxicosis) - pathologically increased activity of the
thyroid gland, in which an excessive amount of thyroid hormone is
excreted into the body, which has a harmful (toxic) effect,
especially on the heart. Here, patients are administered about
200-600 MBq, occasionally more than 1000MBq, 131 I (again orally in the form of sodium iodide solution) , which is taken up in the thyroid gland and by the
radiative effects of radiation b eliminates part of
the thyroid cells , thereby increasing
its function reduces and returns to normal - euthyroidism. The
value of activity 131 I for application needs to be determined
relatively precisely individually here *) for
each patient based on thyroid accumulation, clearance and its
geometric size. With a lower applied activity, the therapeutic
effect would be insufficient, with a higher activity of 131 I, an excessive
number of cells would be eliminated and, on the contrary, the
thyroid gland would get into hypothyroidism - a
pathological decrease in function. Therapy for autonomic
adenoma of the thyroid gland is performed in a similar
way , while the applied activity (again individually dosed) is
usually higher (up to 3 GBq) and the duration of therapy is
longer (approximately 10 days).
*) Individually
applied activity - Marinelli equation
The activity of the radioiodine to be administered depends on the
type of disease, the size of the thyroid gland, the accumulation
of iodine in the thyroid gland and its clearance in the gland. To
determine the individual applied activity of A apl radioiodine, necessary to achieve the planned
therapeutic effect - the required radiation dose D [Gy] for the thyroid gland, a semiempirical so-called Marinelli
formula is used here (introduced
in 1948 by L.D.Marinelli, E.H.Quimby and G.J.Hine) :
A apl [MBq] =
D [Gy] . M th [g] . 22.5 / ( C [%] . Tef
[days] ) ,
where M th is the weight of the thyroid gland (or its target part - goiter, adenoma) estimated from the volume obtained by sonographic
examination, C is the percentage of radioiodine accumulation in the
thyroid gland 24 hours after application, Tef is the effective half-life decrease in radioiodine
activity in the thyroid gland. The coefficient of 22.5 includes
geometric effects and the mean energy of 191keV electrons of beta
radioiodine. The required target radiation doses D are
depending on the type of disease: mild hyperthyroidism 70-80 Gy,
Graves' disease to achieve euthyroidism approx. 150 Gy,
polynodose goiter 100-150 Gy, autonomic nodules 300-400 Gy.
Note: Radionuclide
therapy of the thyroid gland is seldom tested with other
radioisotopes, such as the 211 At astatus , which,
like iodine, accumulates in the thyroid gland.
Treatment of
hematological diseases with 32 P radiophosphorus
Radioactive phosphorus 32 P (T 1/2 = 14.3 days, E b max = 1.7MeV, iv application of approx. 200-500MBq in the
form of phosphate) was used for the
treatment of hematological malignancies , which
is partially bound in the bone marrow, where beta radiation, with
its radiative effects, acts in the prophase of red cell stem cell
division and thus reduces hematopoiesis. In addition, some 32 P is incorporated
into the nucleoproteins of mitotically active cells, including
tumor cells. Influence 32P when suppressing cell division, is not only affected
by ionizing radiation, but also by the biochemical effect.
Radioactive 32 P, which is assembled into a genetically important
molecules, DNA, RNA, nucleotides, at its radioactive decay
changes to a sulfur 32 S, which will change the chemical structure of DNA,
RNA. This leads to disorders or breakdown of these genetic
substances, with consequent chromosomal changes; the result is
cell death or slowing of tumor tissue proliferation.
Radiophosphorus 32 P was used mainly in
polycythemia ( polycythaemia vera - characterized by excessive production of red blood
cells with hyperplasia of hematopoietic tissue), where the purpose of treatment is to prevent stroke
and other adverse symptoms due to an increase in total red blood
cell volume. Radiophosphorus 32 P has also been tried to be used in chronic myeloid
leukemias, lymphogranuloma, lymphosarcoma, multiple myeloma -
some patients have a palliative effect. Overall, however,
radiophosphorus treatment is virtually abandoned
; in addition to the relatively small therapeutic effect (with an
overall high radiation exposure, especially hematological
radiotoxicity), one of the reasons is the risk of an increased
incidence of acute leukemia during this therapy.
Radionuclide therapy of tumors and
metastases
Open b -radionuclides
(or. alpha ) are often used for palliative radiotherapy
in advanced stages of cancer (especially
for metastatic bone disease , frequent e.g.
prostate cancer, breast and lung) , and for
the curative radiotherapy selected cancer. Other
possibilities of so-called radioimmunotherapy are
mentioned below.
The condition for the success
of palliative skeletal therapy is the presence of osteoblastic
activity in metastases - it is determined by a positive
finding on skeletal scintigraphy. After application of a suitable
osteotropic radiopharmaceutical labeledWith ß- radionuclide, this
radiopharmaceutical is relatively selectively taken up in the
osteoblastically reactive zone surrounding the metastatic bone
process. Local absorption of the radiation dose from b- radiation causes
local inhibition of nerve endings and thus the desired analgesic
effect . Unfortunately, there is usually no significant
reduction in the size of the tumor itself (metastasis) - the
effect is usually not curative, but only palliative.
In the past (50s-60s) the
above-mentioned radioactive phosphorus 32 P (approx. 500MBq, in the form of
phosphate ) was tested for this purpose ,
but due to the high radiation exposure of the bone marrow, it is
no longer used for palliative therapy of metastases. In addition
to the above radioiodine 131Several other radionuclides are now used in molecular
radiotherapy :
Strontium 89 Sr ( physical
properties §1.4., Passage 89
Sr )
(T 1/2 = 50.5 days, E b
max
= 1.5MeV; application approx. 150MBq, chloride)
Strontium has a similar metabolism to calcium and therefore 89 Sr is intensively
incorporated into the inorganic component of bone mass. In
metastatic bone lesions, the accumulation is up to 10 times
greater than in healthy bone tissue.
Yttrium 90 Y (physical
properties §1.4., Passage " 90
Y ")
(T 1/2 = 2.7 days, E bmax = 2.28MeV)
The main use of the 90 Y isotope , as a practically pure b- emitter, is in therapeutic
nuclear medicine, where high-energy beta-particles are used in radioimmunotherapy
, palliative therapy of metastases or radiation
synovectomy . The relatively longer reach of these beta
electrons in the tissue allows for even irradiation of larger
tumors, often showing heterogeneous blood flow and hypoxia. Due
to the high energy of beta radiation , the effect of
"crossfire" is significantly applied in 90
Y-radiopharmaceuticals (Fig . 3.6.8 on the right) . The most commonly used is 90 Y-ibritumomab tiuxetan for the treatment of lymphomas,
see below "Radioimmunotherapy
". The physical properties of the radionuclide yttrium-90
are discussed in detail in §1.4. Arcade"
Y-90 ".
Weak positron
annihilation radiation andd 90 Y
nEMA direct radiation importance is quite
intense bremsstrahlung flare. The test, however, the possibility
of using even so weak annihilation radiation 511keV for
imaging the biodistribution of therapeutic
radiopharmaceuticals labeled with 90 Y using positron emission tomography PET
(coincidence mode of detection, braking
radiation is strongly suppressed, so annihilation radiation can
be successfully detected)with higher
resolution than single photon scintigraphy (planar, SPECT) with
using braked
radiation.
Samarium 153 Sm (physical
properties §1.4., Passage "
153 Sm
")
(T1/2= 2days, E b max = 800keV,g70keV (5%) and 103 keV (28%); application approx. 2GBq,
chemical form EDTMP - ethylene diamine tetra methylene
phosphonate)
The chelate complex
153 Sm-EDTMP binds to hydroxyapatite
and selectively accumulates in bone tissue, especially in areas
of its increased turnover - in bone metastases there is about 5
times greater accumulation than in healthy bone tissue.
Rhenium 186 Re (physical
properties §1.4., Passage " 186 Re
")
(T1/2= 3,8dne, E bmax = 1.07MeV, weak g 137keV (9%); application approx. 1500MBq, chemical form
HEDP - hydroxy ethylidene diphosphonate)
This complex also binds to hydroxyapatite crystals. Note .: At the same chemical
form of HEDP is being piloted and rhenium 188
Re (T 1/2 =
0,7dne E b max = 2,12MeV, obtained
from the generator 188 W / 188 Re).
Some other radionuclides are
in the testing stage :
Lutetium 177 Lu (physical
properties §1.4., Passage " 177 Lu
")
(T 1/2 = 6.7 days, E bmax = 0.497MeV, g 113keV (3%) and 208 keV (6%)). Applications approx
1,5GBq Chem. Form 177
Glu- EDTMP for therapy of bone metastases, or 177 Lu-J591 - labeled monoclonal
antibody to prostate-specific membrane antigen . A
promising 177
Lu-rituximab, and 177
Lu-tetraxetan-tetulomab treatment of CD20- positive lymphomas. It
is discussed in more detail below in the section
" Radioimmunotherapy " .
Radium 223 Ra (physical
properties §1.4., Passage " 223
Ra ")
(T 1/2 = 11,4days,
decay series 223 Ra ( 11,4d
., a ) ®
219 Rn (4 s., a ) ® 215 Po (1.8 ms., a ) ® 211
Pb (36.1 min., b - ) ® 211 Bi (2.2 min., a ) ® 207
Tl (4.8 min., B - ) ® 207 Pb (stable), E a : 5.7MeV, 6.8MeV, 7.4MeV, 6.6MeV, E b max = 1.4MeV, E g : 0 , 15-1 MeV; application approx. 5MBq, chemical form
chloride 223 RaCl 2 ) .
Astatine 211 At
(T1/2= 7.2h,E a : 5.8MeV,
....., chem. Form 211 At-cMAb U36 - labeled chimeric
monoclonal antibody U36 with affinity for squamous cell tumors in
the head and neck, as well as 211 At-MABG -
metaastatobenzylguanidine for the treatment of neuroblastomas).
Bismuth 212 Bi
(T1/2= 60min., E a :
6,1MeV; 8,8MeV, E b max 2,25MeV, ...
Aktinum 225
Ac (physical properties
§1.4., Passage " 225
Ac ")
decays with a half-life of 10 alpha transformations with
a half-life of 10 days(in combination with
insignificant alpha-beta branch)for other short-term
radionuclides: 225 Ac (10d .; a ) ® 221 Fr (4.8m .; a ) ® 217 At (32ms .; a ) ® 213 Bi (46m .; b - ) ® 213 Po (4 m s .; a ) ® 209 Pb (3.3 h .; b - ) ® 209 Bi (stab.) , energy is released about 27 MeV.
Thorium 227 Th (physical
properties §1.4., Passage " 227
Th ")
(T1.2 = 18,7day,
decay series 227 Th (18.7 d., a ) ® 223
Ra (11.4 d., a ) ® 219 R (4 sec., a ) ® 215
Po (1.8 ms., a ) ® 211 Pb (36.1 min., b - ) ® 211 Bi (2.2 min., a ) ® 207
Tl (4.8 min., b - ) ® 207 Pb (stable), E a : 6MeV, 5.7MeV, 6.8MeV, 7.4MeV, 6.6MeV, E b max = 1.4MeV, Eg : 0.15-1 MeV; ............. add more ..........
Radiopharmaceuticals, labeled radionuclides that are
converted to other shorter radionuclides (or the entire decay
series), are sometimes referred to as " in vivo
generators "- see §1.4, section" In vivo generators in nuclear medicine ". Of the above, radium 223 Ra
is actinium 225
Ac and 227 Th .
The effectiveness of therapy
with the above radiopharmaceuticals can be improved by
concomitant administration of certain cytotoxic agents (eg
mytomycin or cisplatin) - cytostatics that act as radiosensitizers
. The magnitude of the applied activity, and thus the therapeutic
effect, is limited by
adverse toxic effects, especially haematological ones.
Although palliative care does
not usually cure cancer, its importance lies in the fact that in
a high percentage of patients it significantly improves
the quality of life for many months (with repeated
therapy even several years). There is some hope that in the
future, effective curative therapy will be
carried out on a similar principle , eg with specific anti-tumor
antibodies with bound radionuclide. In radioimmunotherapy
(see below), the monoclonal
antibody "brings" the emitter directly to the tumor
cells, so that the radiation is concentrated primarily on the
tumor tissue, with minimal radiation effects on normal tissues.
Similarly, it can be targeted to tumor cellschemotherapeutic
- cytostatic substance.
Radioimmunotherapy (RIT)
constitute a promising method to
"carry" therapeutic radionuclide to all sites of tumor,
even in minor tumor masses scattered throughout the body is an
appropriate antibody to a given tumor type
emitter b or and and its application to the body. The immune mechanism of
tumor cells ensures that such (monoclonal) antibodies are able to
"independently" find and selectively
bind appropriate antigens . A radioactive isotope is thus
introduced into the tumor site and the tumor tissue receives an
appropriate dose of radiation that can produce the desired
therapeutic effect. This effect can also be effective against refractory
ones
chemotherapy-resistant tumor tissue. Immunotherapeutics are able
to attack even very small tumors (such as
early metastases) that are not registered
by imaging techniques; possibly as well as circulating tumor
cells of that type.
It is a targeted
radiotherapy conducted only against specific types of
cells (unfortunately, this is only
theoretically, in reality, the selectivity is only relative, in
practice, optimal results are far from being achieved
) . Thus, radioimmunotherapy (RIT) consists
in the targeted uptake of radiolabeled tumor-associated
monoclonal antibodies (mAbs), which thus become cytotoxic to
tumor cells.
Targeted biological therapy
with (non-radioactive) monoclonal antibodies has been briefly
discussed above in the " Chemotherapy " section, " Monoclonal Antibodies " section. Radioimmunotherapy combines
biological and radiolytic mechanisms of tumor cell
destruction. Radionuclide-labeled monoclonal antibodies can
inactivate and destroy tumor cells in two ways :
1. By directly binding the antibody
to the appropriate antigen, activating a cascade of intracellular
signaling pathways that ultimately lead to tumor cell death.
2. Dominant, however, is the radiobiological
action of ionizing radiation from bound radionuclide. If a high -
energy radionuclide b (such as 90 Y with a maximum energy of 2.3 MeV and a range in the
tissue of about 5 mm, which represents about 100-200 cell
diameters, 131 I, or 177 Lu ) , this radiation can destroy
even those tumor cells that are not in direct contact with the
bound radiopharmaceutical - which do not have the appropriate
receptors, or where the antibody has not penetrated inside the
tumor due to reduced blood flow. These cells come under
"crossfire" of hard radiation from a radionuclide bound
to surrounding cells (as shown in Fig.
3.6.8 at the top right) .
Radioimmunotherapy of
lymphomas
The most commonly used radioimmunotherapeutic of this species is ibritumomab
tiuxetan labeled with 90 Y ( Zevalin), which is an
IgG1 monoclonal anti-CD20 antibody against non-Hodgkin's
follicular lymphomas from B cells to which a 90 Y radionuclide is
bound by a tituxetan chelator ; about 1GBq is applied. For the
same purpose it is used tositumomab labeled with 131 I ( Bexxar
); due to the significant g- component of radiation 131 I, scintigraphic monitoring can be performed. 1 77
Lu-rituximab and anti-CD37 radioimmunoconjugate 177
Lu-tetraxetane-tetulomab (Tetulomab is
more recently called Lilotomab) *) are also
promising
For the
treatment of CD20-positive lymphomas is promissing 177
Lu- is a relatively low-energy beta emitter (max.
Energy 497keV - physical properties §1.4., Passage " 177 Lu
") , max. reach in the tissue approx. 2mm - see the
table above. This may be advantageous because lymphoma tumor
cells often infiltrate normal tissues in a diffuse form. Shorter penetration of 177
Lu radiation (taken up in tumor cells) into
the surrounding tissues may lead to a more
favorable tumor / healthy tissue effect ratio. In addition, 177 Lu emits gamma
radiation ( 113keV (3%) and 208 keV (6%) ), which can be used for scintigraphic
imaging- monitoring of the biodistribution of the
radiopharmaceutical and dosimetric assessment of the course of
therapy. The energy and gamma radiation content is significantly
lower here than in 131 l, which is favorable in terms of whole-body radiation
exposure.
*) Anti-CD20 and anti CD37 are tried to be combined
. Lymphoma therapy usually begins with several cycles of the
anti-CD20 rituximab, or radiolabeled monoclonal antibodies
ibritumomab, tositumomab or rituximab. However, this may lead to
the selection of tumor cells with reduced CD20 expression and
thus to less effect of further subsequent anti-CD20 therapy.
However, in the situation of relapsing lymphoma after
unsuccessful anti-CD20 therapy, CD37 may become
a suitable alternative therapeutic target here., expressed by
transformed B-cells - anti-CD37 tetulomab can be introduced,
which, in addition, internalizes significantly faster within
tumor cells. Immunotherapy for lymphomas
with alpha- labeled monoclonal antibodies
thorium 227 Th -rituximab or anti-CD22 is in the laboratory stage .
Prostate cancer
For therapy of metastatic prostate cancer
was developed monoclonal antibody J591 on the
specific membrane prostate antigen (PSMA) labeled LUTETIA 177 Lu (or
yttrium 90
Y). On this basis, ligand 177 Lu-PSMA-617 was formed conjugated to a
DOTA chelator. This promising radiopharmaceutical shows a high
specificity of tumor targeting for prostate tumors and at the
same time a relatively low haematotoxicity (but
a certain problem may be a not neglibile uptake in the kidneys) . In advanced prostate ca with bone metastases are
further improved results with very low hematotoxicity using
alpha-radionuclide actinium-225 - 225Ac-PSMA-617; short-range alpha
radiation from bone metastases does not penetrate in the bone
marrow.
Neuroendocrine tumors
Somatostatin receptors (an
oligopeptide containing 14 or 28 amino acids) are usually
overexpressed on the cell surface of neuroendocrine tumors.
Therefore, in neuroendocrine tumors therapy with radiolabeled somatostatin
analogs is performed using the Peptide Receptor
RadioNuclide Therapy (PRRNT)
pathway. Radiolabeled somatostatin analogs 90Y-DOTATOC
([DOTA0, Thyr3] - octreotide) and 177Lu-DOTATATE ([DOTA0,
Tyr3, Trh8] - octreotate) are used; Tyr3 is a modified
octreotide, DOTA (1,4,7,10-tetraacetic acid)
is a bifunctional chelating molecule for the binding of a metal
atom of a radionuclide to a biomolecule of octreotide.
Recommended applied activity: 90Y-DOTATOC
/ DOTATATE 2.5-4.5 GBq in 2 fractions; 177Lu-DOTATOC
/ DOTATATE 5.5-7.5 GBq in 3-5 fractions. Intervals between
fractions 6-12 weeks. Of the adverse effects on critical tissues,
nephrotoxicity and haematotoxicity
in particular should be monitored.
To
optimize the therapy of both large and small tumors, combination
therapy with 90Y and 177Lu -labeled peptides is sometimes
recommended: application of 2.5-5 GBq 90Y
followed by 5.5-7 GBq 177Lu, in
2-6 cycles at 6-16 week intervals (or co-administration of a
"cocktail" of 177Lu
and 90Y).
For scintigraphic diagnostics,
these DOTA preparations labeled with 68Ga (PET gammagraphy), or indium-labeled octreotide
- 111In-pentetreotide
( OctreoScan for classical scintigraphy). In addition, 131I-MIBG (meta-iodobenzylguanidine) or 211At-MABG (meta-astatobenzylguanidine) are
used to treat neuroendocrine tumors, especially neuroblastoma and
pheochromocytone .
Testing of other labeled antibodies
A number of other agents are under investigation, eg 131 I-anti-CD45 (BC8)
for acute leukemia, 131 I-81C6 anti-tenascin for malignant brain tumors, 90 Y-anti-CD66 for
acute leukemia,153 Sm-DTPA-cetuximab, 180 Tm-DOPA-cetuximab, 153 Sm-bleomycin .... etc ... (...
comes to be added) .
An interesting and perhaps
promising means of targeted biological therapy could be the
so-called aptamers
(mentioned above in the section " Chemotherapy
and biological treatment ") , which can be specially created for selective binding
to various types of biomolecules. At the stage of experimental
testing, the radioactive designation is " escort"
aptamers that can selectively inject a
therapeutic radionuclide into those cancer cells.
A common problem
radioisotope immunotherapy is still relatively poor
specificity and prohibitively high cost
.
Radioimmunotherapy
is often performed in combination with the chemotherapeutic
immunotherapy (non-radioactive) monoclonal antibodies with a
suitable time interval.
For example, In lymphoma, rituximab is mentioned before
the administration of 90 Y-ibritumomab tiuxetan
(mentioned above in the section Chemotherapy
and biologic therapy).") In
an interval of several days, and repeated several hours prior to
application. In addition to the contribution of the direct
immunotherapy effect rituximab removed from blood available
target cell lymphoma, which increases the availability of binding
of radioactive 90 Y-ibritumomab tiuxetan in tumor
lesions.
Radioactive
microspheres - SIRT
At the intersection between the permanent interstitial
brachytherapy and biologically targeted radionuclide therapy is a
special method of SIRT ( Selective Internal
Radiation Therapy ), which is targeted irradiation of liver
tumors (primary or metastases) by introducing microspheres
of resin with bound ß-
radionuclide
(yttrium 90 Y, or 177Lu or 188
Re) into the branches of the hepatic artery, from where these
microspheres enter the liver metastases, where they are trapped
in their capillary vascular bed and irradiated these tumors internally
; there is also a reduction in the blood supply to the tumor - intrahepatic
radioembolization . Several million microspheres, each about
35 m in diameter,
with a total activity of about 1-2 GBq 90 Y , are
injected into the hepatica artery branch supplying the tumor. A
radiation dose of about 100-200 Gy is then reached inside the
tumor, during about 10 days. This method has a predominantly
palliative effect.
Radionuclide synovectomy
By its nature, this method of radioisotope therapy
does not directly fall into biologically targeted radiotherapy
(the radionuclide does not reach the target tissue
metabolically), but is a special case of intracavitary
permanent brachytherapy using open radionuclides.
Radionuclide synovectomy (sometimes called radiosynoviorthesis
- RSO ) is used to treat some chronic cancer
in which there is an excessive production of intra-articular
fluid ( hydropos ) in the hyperplastically enlarged
synovial lining of the joint. It is mainly rheumatoid arthritis,
recurrent joint effusions, recurrent decompensated
osteoarthritis, psoriatic arthritis and others. A suitable one is
injected into the joint cavityb
-radionuclide in the inert form of colloid
(aqueous suspension of citrate or sulfide) *), which is
practically all absorbed on the surface of the synovial membrane (colloidal particles are phagocytosed by
surface-deposited macrophages in the synovial membrane) and causes fibrotization and necrosis
of the synovial membrane surface layer . Due to the short range
of radiation b , the irradiation is limited to the synovial lining
without damaging the cartilage. The result of this therapy is the
reduction of excessive intra-articular fluid production, the
elimination of swelling and the disappearance of joint pain - a
local cessation of the inflammatory process, usually temporarily,
sometimes permanently.
*) In terms of the overall division of
radiotherapeutic methods, radionuclide synovectomy can be
described as a specific method of permanent
intracavitary brachytherapy using an open
radionuclide, which is taken up on the surface of the structure
to be radiation inhibited (synovial lining).
To achieve the optimal
radiation dose at different synovial membrane thicknesses in
different joints, it is appropriate to apply radionuclides with different
radiation energy b and thus different penetration
- radiation range (the larger the joint, the higher the energy b ), with activity
according to joint size . For treatment of knee
joint is used yttrium 90 Y (T1/2 = 2.7 days, E b max = 2.28 MeV; application of about 200MBq in the form of
citrate; physical properties §1.4., passage " 90 Y
") . For elbow, shoulder, wrist, ankle
rheium 186 Re is used (T 1/2 = 3.7 days, E b max = 1.08MeV, weak g 137keV (9%); application approx. 50-200MBq in the form
of sulphide; physical properties §1.4., Passage " 186 Re
") . For small joints of hands and
feet then erbium 169 Er (T 1/2 = 9.4 days, E b max = 352keV; application approx. 20-80MBq in the form of
citrate). For teraii knee and shoulder
joints are sometimes used and holmium 166
Ho (T 1/2 = 27 hours, E b
max
= 1,8MeV, weak g 48-58keV (9%) and 81keV (6%) by about 400MBq as
Fe-hydroxy-macroaggregates or boron-macroaggregates) . Previously used colloidal gold 198
Au (T 1/2 = 2.7 days, E b
max
= 961keV, g 412keV (96%) and 676keV (1%); application about 100MBq) had unfavorable physical properties (very strong component g , causing unwanted
radiation exposure even outside the target area) and is now abandoned.
3.7.
Technological use of radiation
Radiation technologies are processes of production and
modification of materials, based on physical and chemical changes
caused by irradiation with ionizing radiation. When properly
applied, ionizing radiation can be used to induce desired
changes in the irradiated material.
Radiation chemistry
An important area of application of radiation technologies is radiation
chemistry , which uses chemical reactions induced or
initiated by ionizing radiation. Radiation-formed ions
and radicals are chemically very reactive,
so irradiation can "trigger" a number of chemical
reactions in substances *). Some of these reactions have a chain
character - a relatively not too large dose of radiation
initiates the reaction, which then takes place spontaneously and
brings a significant effect. An example of such chain reactions
is radiation polymerization . The advantage of
polymers prepared in this way is, among other things, that the
resulting material is not contaminated with chemical catalysts or
initiators (which would have to be used in conventional
technologies).
*) Radiation-stimulated chemical reactions
with the co-operation of cosmic radiation
probably played a very important role in the synthesis of
molecules of more complex chemical substances, which later
enabled the origin and development of life - see
" Cosmic radiation"Part of" biological
significance of cosmic rays .
"These reactions occurred both on earth and especially in
space particles of interstellar dust, where the resulting
materials could more than 3 billion years to get to Earth in
meteorite impacts from broken comets.
Radiation
sterilization
High doses of radiation can preserve and sterilize
materials and objects - kill microorganisms (bacteria, spores,
viruses) on the surface and inside. For radiation sterilization, g radiation from
strong radionuclide irradiators with 60Co, or 137 Cs, is irradiated
with a dose of at least 25 kGy and higher. The whole process is non-destructive
, it can take place inside the product packaging, it can also be
used on heat-labile substances or unique objects (conservation of
exhibits in the museum).
Ion implantation
Another radiation-technological method is ion
implantation : Ions of suitable atoms, accelerated to
energies in the range of several keV to MeV (depending on the
depth of implantation), are injected into irradiated materials to
modify surface properties or doping
surfaces with suitable impurities, especially metals and
semiconductors. The main areas of application are components for
low-current electronics.
Radioisotopes in discharge lamps
Electric discharge lamps are hermetically sealed (sealed) glass
tubes or flasks (of heat-resistant glass,
mostly silicon) , fitted with metal
electrodes, with a suitable gas filling *).
Applying a sufficiently high voltage (hundreds of volts) to the
electrodes creates an electric discharge in the
gas charge , which emits light (or UV radiation)
of wavelength - color - depending on the
chemical (elemental) composition of the gas charge.
*) They can also be mercury or sodium vapors, or metal halides
(metal compounds with iodine or bromine) released by heating on
discharge.
If no free charges -
electrons and ions - are present in the gas charge, a relatively
high ignition voltage is required to start the
discharge in order for ionization by impact. Mercury and sodium
lamps use an auxiliary ignition electrode , located next
to one of the main electrodes, to which the supply voltage is
connected via a resistor (a small distance
between the electrodes causes a small auxiliary discharge, which
then spreads to the entire lamp volume) .
In some discharge lamps, such as fluorescent lamps , thermoemission
of electrons from tungsten wires is used to ignite the
discharge , into which a glow current is introduced for a short
time by means of a starter after switching on the
discharge lamp. (which is a small glow plug
with bimetallic electrodes, which short-circuit when heated by a
glow discharge) . Another possibility is
the electronic ignition of the discharge by applying a
short pulse of high voltage (approx. 3 kV) to the electrodes.
Different ways of igniting an electric discharge in discharge
lamps.
Left: Classic ignition of the discharge by an auxiliary
ignition electrode, high-voltage electronic pulse, or
thermoemission of hot wire electrons. Right:
Facilitation of ignition of the discharge by ionization from
radioactivity - admixture of gaseous radionuclide into the
charge, or admixture of radionuclide into the electrode material.
For easier ignition of the electric discharge,
at a lower ignition voltage, it is also possible to use pre- ionization
of the gas charge by means of ionizing radiation from radioactivity
. This can be achieved in two ways :
1 .
Mix a suitable gaseous radionuclide
into the gas charge , which emits electrons during beta
radioactivity causing weak ionization of the gas charge. It uses
the krypton 85 Kr (§1.4
passage " Krypton 85
Kr " ) in an amount of about 1 kBq.
Note:
Tritium 3 H
(about 1 kBq) is added to the glow plugs of some fluorescent
starters .
2 . Implant a radionuclide into
the surface layer of tungsten electrodes , which, due to its
radioactivity, emits beta or alpha radiation into the space of
the lamp, causing ionization of the gaseous charge.
"Thorium" electrodes with implanted thorium-232
(§1.4, passage " Thorium 232 Th ") in the form of oxide are used.
Note .: The main
reason however, there is improvement in metallurgical properties
of the electrode material ......
Radiation plant breeding
Specific radiation technology, based on the stochastic
effects of radiation on living tissue is radiation plant
breeding . It is about accelerating the
process of natural mutations (with the help of which new varieties have been created
for millennia) with the help of biological
effects of ionizing radiation. Seeds or plants are irradiated
with different doses of ionizing radiation and radiation-induced
genetic changes are monitored . This mimics the natural
processes of spontaneous mutations. Radiation generates random
genetic changes, which are often negative but also beneficial.
From the various mutants, those are selected whose properties are
desirable for further cultivation, breeding and development of new
positive properties in subsequent generations. If the
new trait is verified and stable, a new variety
is created - a variety . In mutation breeding, it is
necessary to choose from thousands of new plants the one that has
the desired final mutation.
Irradiation is performed
either once with higher doses (Gy units) , or the plants are
irradiated gradually over several months with
lower doses (dose rates of the order of mGy
/ min.) . In the latter method, the changes
are smaller, the plants are able to repair some significant DNA
defects by repair mechanisms; a wider range of mutations can be
obtained with less radiation damage to the cells.
After mutational irradiation,
the classic " breeding art " begins -
to select from a large number of new plants those with the
desired positive resulting mutation and to further cultivate and
propagate them. Most biologists believe that, unlike " genetic
engineering ", the technique of radiation breeding
carries lower risks for human health and the
natural environment.. .......... come to
add ......................- add
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