Radiotherapy

7.1.	RADIOTHERAPY
Radiation therapy, radiation oncology or radiotherapy, sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation. Generally used as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative in a number of types of cancer localized to one area of the body. It may also be used as part of curative therapy, to prevent tumour recurrence after surgery or to remove a primary malignant tumour (early stages of breast cancer, for example). Radiation therapy is synergistic with chemotherapy and can be used before, during, and after chemotherapy to treat susceptible cancers. Radiation therapy is commonly used in treatment of cancerous tumours due to its ability to control cell growth. Ionizing radiation works by damaging the DNA of exposed tissue leading to cellular death. To spare normal tissues (such as skin or organs which radiation must pass through to treat the tumour), shaped radiation beams are aimed from several angles of exposure to intersect the tumour. This will provide a much larger absorbed dose at the location of the tumour than in the surrounding, healthy tissue. Beside the tumour itself, the radiation fields can also include the draining of lymph nodes if they are clinically or radiologically involved with the tumour. Also if there is a risk of subclinical malignant spreading. It is necessary to include a margin of normal tissue around the tumour to allow for uncertainties in daily set-up and internal tumour motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumour position. Radiation oncology is the medical speciality concerned with prescribing radiation, and it is distinct from radiology (the use of radiation in medical imaging and diagnosis). Radiation may be prescribed by a radiation oncologist with the intention to cure ("curative") or for adjuvant therapy. It may also be used as palliative treatment, where cure is not possible and the aim is for local disease control or symptomatic relief. It can also be used for therapeutic treatment where the therapy has benefits for survival and it can be curative. Radiation therapy is often combined with surgery, chemotherapy, hormone therapy, immunotherapy or some mixture of the four. Most common types of cancer can be treated with radiation therapy in some way. The precise treatment (curative, adjuvant, therapeutic, or palliative) will depend on the tumour type, location, stage, as well as the general health of the patient. Total body irradiation (TBI) is a radiation therapy technique used to prepare the body to receive a bone marrow transplant. Brachytherapy, in which a radiation source is placed inside or adjacent to the area requiring treatment, is another form of radiation therapy that minimizes exposure of healthy tissue during procedures to treat cancers of breast, prostate and other organs. Radiation therapy works by damaging the DNA of cancerous cells. This DNA damage is caused by one of two types of energy, photon or charged particle. This damage is either direct or indirect ionization of the atoms in the DNA chain. Indirect ionization occurs as a result of the ionization of water, forming free radicals (notably hydroxyl radicals) which then damage the DNA. In photon therapy, most of the radiation effect is due to free radicals. Cells have mechanisms to repair single-strand DNA damage, and therefore double-stranded DNA breaks prove to be the most efficient technique to cause cell death. Cancer cells are generally undifferentiated and stem cell-like; they reproduce more than most healthy differentiated cells and have a diminished ability to repair sub-lethal damage. Single-strand DNA damage is then passed on through cell division resulting in accumulation of DNA damage which cause them to die or reproduce at a slower rate.

Charged particles such as proton, boron, carbon, and neon ions can cause direct damage to cancer cell DNA through high-LET (linear energy transfer), and thus have anti-tumour effect. The effect is independent of tumour oxygen supply because these particles act mostly via direct energy transfer causing double-stranded DNA breaks. Due to their relatively large mass, protons and other charged particles have little lateral side scatter in the tissue. The beam does not broaden much. It stays focused on the tumour shape, and delivers small dose side-effects to surrounding tissue. They also target the tumour more precisely using the Bragg peak effect. See proton therapy for a good example of the different effects of IMRT vs. charged particle therapy. The charged particle procedure reduces the damage to healthy tissue between the charged particle radiation source and the tumour. It also sets a definite range for tissue damage after the tumour has been reached. In contrast, IMRT use uncharged particles causing its energy to damage healthy cells when it exits the body. This exiting damage is not therapeutic, and can increase treatment side effects and increase the probability of secondary cancer induction. This difference is very important in cases where there is close proximity to other organs which makes any stray ionization very damaging (example: head and neck cancers). This x-ray exposure is especially harmful for children, due to their growing bodies. They have a 30% risk of a second malignancy after 5 years post initial RT

BIOPHYSICAL BASIS OF RADIOTHERAPY
The properties of ionising radiation are the following: rectilinear spread decreases to the square of distance from the source (in air) It will decrease upon passing through an absorbent medium due to interactions between the ionising radiation and the medium. The decrease in radiation is dependent on the type and energy of the ionising radiation and on the absorbent properties of the medium. The most significant losses are observed for heavy, charged particles and the least significant losses for photon radiation. When energy increases the radiation loss decreases but with increasing atom number and specific density of the absorbent medium the losses increase as well.

Ionising radiation can only cause measurable biological effects when the emitted radiation possesses high levels of energy. Ion pairs can be created by direct interaction of irradiating particles and electrons of the electron field (alpha particles, protons, deuterons and other charged particles) or by indirect interaction. This occurs by using a mediator in the form of charged particles, released by the interaction of gamma radiation, X-rays and neutrons.

The relationship between physical exposure and biological effects is basically directly proportional: the longer the exposition, the more intensive the expected biological effect. Other influencing factors are time, spatial distribution and quality of the radiation.

A single exposure describes a situation where the radiation is delivered during a short period of time (minutes). Fractionated exposure refers to when the total exposure is divided into fractions delivered over a period of several weeks.

The biological effects increase proportional to the volume of the irradiated tissue. Different qualities of radiation will have different ionising abilities per unit of track, and therefore different biological effects. The types of radiation with the highest values of linear energy transfer (i.e. heavy particles) have the most harmful biological effects.

7.1.2. FUNDAMENTAL PRINCIPLES OF RADIOTHERAPY
When using ionising radiation for therapeutic purposes, it is always necessary to remember the radiobiological facts. Every dose of ionising radiation delivered to the human organism possess a certain strain which is accumulated over the course of the radiation cycles.

The main physical factor influencing the extent of biological effects of radiation is the absorbed dose (in Gy) within the tumour mass. The radiation procedure needs to be chosen in such a way, that the whole tumour is targeted homogenously with maximal dose. Meanwhile the surrounding healthy tissues receive as low dose as possible. The effect of given dose can differ based on the source of radiation and its linear energy transfer. Which is why the term relative biological effectiveness (RBE) was introduced. RBE is the ratio of standard ionisation dose to radiation dose with different linear energy transfer, which causes the same biological effect.

There are not only destructive and reparative processes inside the cells following the exposure to ionising radiation, but also proliferative processes take place within the tissues. This process helps to replace the destroyed and disintegrated cells. Different tissues show different speed of these proliferative processes.

The biological effects of radiation depend not only on the dose, but also on time. Therefore, in radio therapeutic practise the tumours are irradiated not only by a single dose, but in a fractionated way. The same dose is divided into several partial doses and applied in precisely set time intervals. This makes the final dose of radiation significantly lower. This phenomenon is explained by the ability of the tissue to recover from the exposure of radiation (so called recovery factor). The method of fractionated exposure is based on dividing the total needed dose into a series of partial doses. They are applied daily or in other regular time intervals (so called classic fractionation is the application of 2 Gy daily in the target volume, 5 fractions a week result in a total amount of 20-30 fractions, total dose of 40-60 Gy). All other fractionation regimes are usually related to biological dose equivalents in classic fractionation. There are several different types of fractionation. For example hypo fractionation regime (irradiating with less than 5 fractions a week) and hyper fractionation regime, which uses the method of irradiating with several fractions a day (2 to 3). Tissues characterised by fast proliferation and regeneration are usually more tolerant to hypo fractionation, while tissues with slow proliferation, reparation and regeneration show higher tolerance to hyper fractionation. The method of fractionation is always carefully chosen so that the suitable daily dose, total dose and number of fractions, along with the total number of days over which the dose is administrated, all lead to complete destruction of the tumour mass. But it must not exceed the tolerance of healthy tissues. The ratio between lethal tumour dose and dose tolerated by healthy tissues is called therapeutic ratio (also known as therapeutic index). If this ratio is lower than 1, the situation is very convenient for radiotherapy because the radiation dose can be applied to the tumour without any significant damage to the surrounding healthy tissues. If the ratio equals 1, the sensitivity of the tumour is limited. With continuous treatment there is a risk of a small percentage of complications. However if the ratio is higher than 1, the situation is not well suitable for radiotherapy. There are several ways of improving the effect of radiation on the tumour cell and thus increasing the therapeutic ratio: Increased supply of oxygen to the tumour – combination of radiation and hyperbaric oxygen.

Radio sensitizer are substances showing a significant oxygen effect and increase the amount of free radicals within the target volume which interfere with the reparative processes. The use of radiation with high linear energy transfer (LET) – for example when using a beam of fast neutrons, the effect is independent on the presence of oxygen. Neutrons represent highly ionising particles, which cause direct lethal damage to the tumour cells. Combination of radiotherapy and cytostatics has addative effect. The lethal effect of both the modalities is combined at the same sensitive point of the cell cycle.

7.1.3. METHODOLOGY OF RADIOTHERAPY
Methodology of radiotherapy is very difficult and it requires a complex approach. The process begins with determining the exact location of a tumour and calculating the target volume. The next step is the preparation of isodose plan i.e. determining the size of the spatial dose distribution, integral dose, dose delivered to the target organ and to other distinctive points. Also specification of the length of the therapy etc. All the important parameters characterising one specific radiotherapy plan, needs to be transformed into irradiation protocol in such a way that the setting determined for each field would be reproducible over the whole course of the fractionated exposure. There can be either systematic or random mistakes made during the course of radiotherapy. Systematic mistakes are made during the planning of radiotherapy and they are caused by incorrect determination of the target volume and incorrect calculation of the isodose plan. Random mistakes are related only to the individual fractions and are caused by incorrect setting of certain parameters. The extent of random mistakes does not have any significant effect on the overall result of the treatment.

Clinical problems of radiotherapy

Radiotherapy is one of the most effective tools used in the treatment of malignant tumours. However it needs to be used with consideration and all available medical and physical knowledge always have to be taken into account. It is important to realize that in some cases radiotherapy can be strictly contraindicated. These cases include very advanced malignancies, cachectic patients, disintegrated tumour, anaemia, febrile states etc.

Radiotherapists look very carefully for early reactions originating over the course of irradiation. These reactions are mainly skin related. In case of irradiating tumours located inside the body there is usually reactive changes found on the mucosa of exposed locations. Large doses of radiation cause systemic reaction (decrease in the blood formation). Patients with malignant tumours undergoing radiotherapy are being regularly observed at the radio therapeutic clinics, so that even late post-exposure changes can be monitored. For adults, the most common reactions are permanent damage to hair follicles, skin glands also skin atrophy and trophic changes of the irradiated mucosa. Significant breach of the tissue tolerance (which should not occur when the radiotherapy is correctly planned) can lead to chronic changes such as pulmonary fibrosis, damage to the spinal cord and changes in the hepatic and renal parenchyma. There is a significant reduction of the vascular network due to the limited tolerance of the vascular wall. Child patients require long-term observation following the completion of radiotherapy. This is due to the fact that their healthy, developing tissues are very radiosensitive. Examples of typical late effects of radiotherapy is stunted growth of long (and other) bones, changes in the teeth development, muscle hypoplasia, mammary gland hypoplasia or even aplasia etc. All of the above mentioned side effects of radiotherapy can be classified as somatic post radiation changes. Additional to these there can also be genetic and oncogenic effects of radiotherapy. Genetic effects can affect not only the irradiated individual, but also children and grandchildren. The results of oncogenic effects can be the development of secondary „primary“ tumours, the origin of which was initiated by the ionising radiation intended to cure the „first primary tumour“.

Irradiators used in radiotherapy

Sources of gamma radiation used in radiotherapy (in order to irradiate malignant tumours) usually employ radio nuclides emitting gamma radiation of suitable energy and convenient physical half-life. Particle accelerator is a device used for artificial acceleration of electrically charged elementary particles or ions in order to provide them with enough kinetic energy (α and ß particles emitted by the radioactive atoms’ nuclei possess rather low energy, and are therefore not suitable for radiotherapy) used in tumour irradiation. Accelerated particles can also be used in order to generate penetrative electromagnetic radiation.

Cobalt and caesium irradiators, gamma knife

Cobalt and caesium irradiators generate gamma radiation. They act as sources of so called telecurie therapy, i.e. irradiating by radioisotope sources located at a distance from the body. Cobalt irradiators belong among large irradiators, because they show high source activity (at least 3,7 . 1013 . s-1). They are usually used for deep radiotherapy. Radioactive cobalt 60Co (physical half-life of 5,29 years) emits two gamma radiation quanta characterised by energies reaching up to 1,33 and 1,17 MeV and high penetrability. 60Co is most commonly used in the form of flat rings or small rollers (1 x 1 mm) in an aluminium or steel container (24 x 24 mm). The protective cap is shaped like a sphere with diameter of up to 60 cm. The cap is made of lead and inside it contains a wolfram alloy/uranium core (both of them being more absorbent than lead). The cap has a channel-like opening through which it emits a primary beam of gamma radiation.

There are two mechanisms of irradiation: The source remains static and the primary gamma radiation beam is let out via a mobile curtain, placed immediately underneath the cover’s output channel; The source moves inside the cap, it rotates or slides out of the cap’s centre over the output channel.

Radioactive Caesium 137Cs emits gamma radiation quantum with energy level of 0,66 MeV. Its physical half-life is 30,4 years. It is used for irradiating pathological malignancies located within the depth of 5cm (maximum). Due to relatively long physical half-life of 60Co and 137Cs the intensity of gamma radiation produced by these irradiators decreases only very slowly over time. The scientist Lars Leksell was looking for options how to remove intracranial lesions atraumatically (without having to open the skull) with the help of ionising radiation. In 1951 he defined the principles of so called radio surgery. Radio surgery enables alteration of the pathological lesion after it has been precisely located by stereotactic methods. The basic principle itself is very simple. A sufficient amount of suitable ionising radiation sources are placed in such a way that the individual generated beams all intersect at a common focal point. In case of gamma knife, that means 201 sources of gamma radiation (cobalt isotope 60Co). While the dose delivered by individual sources (beams) is relatively small, the individual doses all add up at the common focal point, generating a very high radiation dose. This high dose causes appropriate biological response in the affected tissue – necrotic lesion. The dose delivered by one single beam would not cause any significant response. The radiobiological response of the tissue lasts from several days up to several years. The dose gradient outside the common focal point, where the beams intersect, sharply decreases within millimetre distances from the source. If the target we intend to hit during the functional stereotactic surgery is placed within the common focal point, a suitable radiation dose is able to generate small necrotic lesion in the pathologically changed tissue while the surrounding healthy tissues are untouched. The most common indication for radio surgery are arteriovenous malformations and both benign and malignant tumours (especially brain metastases).

Gamma knife – as a therapeutic method – shows zero mortality and very low morbidity. It eliminates certain risks of conventional radiotherapy, such as bleeding, infection and the need for postoperative convalescence. The patient can continue in his everyday routine the following day after the surgery. Betatron is a device used for accelerating electrons. Linear particle accelerator is used for accelerating charged particles with the use of electrical field (electrostatic, induction or resonant). Cyclotron is a cyclic particle accelerator used for accelerating heavy charged particles (protons, deuterons, alpha particles and ions) along a spiral track. The principle of the acceleration process is the same as the one applying to linear acceleration.