Historically, radiotherapy is the second method for treating cancer through ionising radiation.
In an appendix, we describe the main stages of the history of this therapy.
We can distinguish;
Physical foundations of radiotherapy :
Classification of ionising particles used in radiotherapy
Several types of ionising radiations are used
Diffusion (propagation outside the beam’s path) explains why the regions situated outside the irradiation beam can receive a parasitical dose of radiation.
It is measured in Grays (in honour of the great British physicist Hal Gray - 1905-1965 - who worked in Cavendish Laboratory - Cambridge, UK): 1 Gy represents the deposition of 1 Joule per kg of matter. In previous denominations, 1 Gy is equivalent to 100 Rad.
A dose of 5 Gy in one shot to the whole body of a man is a lethal dose for approximately 50% of subjects (DL 50).
70 Gy is the dose which is generally prescribed (in several fractions) for head and neck cancers exclusively treated by radiotherapy.
Biological action of radiotherapy :
The action of ionising radiation in living tissue takes place in three phases:
Generally, we distinguish between the direct effect in relation to direct impact of the beam on cellular macromolecules, in particular DNA, and the indirect effect in relation to macromolecule modifications provoked by free radicals originating from water radiolysis. These indirect effects are the major component (70-80%) of beam impact on living tissue.
A few explanations are given in specific pages on physicochemical effects and on water radiolysis.
In the presence of oxygen, specific radicals are created with a strong oxidising power interacting with water to induce the formation of hydrogen peroxide which is a strong oxidising molecule. The 'oxygen effect' is observed in radiobiology with an increased radiosensitivity of well oxygenated cells compared to hypoxic cells.
Direct effect: (the lower part of the diagram): interaction between a DNA molecule and an electron displaced after absorption of a photon (in green). The DNA modification is relatively easy to repair.
Indirect effect: (the higher part of the diagram): an electron detached by a photon (in green) will interact with a water molecule and produce radicals (for instance HO• which will then provoke a lesion of the DNA molecule). It is generally estimated that free radicals may provoke a DNA lesion if they are produced at a distance of less than 2nm. The indirect effect is the major effect obtained for low LET beams (Linear Energy Transfer).
The main lesions are:
Generally, during irradiation, one double strand break occurs for 20 single strand breaks.
Notions in radiobiology:
Survival curves
The radiosensitivity of healthy cells or tumour cells can be determined by the preparation of survival curves after irradiation, and for cancer cells, at best using in vitro clonogenic culture (study of stem cells).
The curve which is obtained can be transformed into a mathematical model giving the proportion of surviving cells after irradiation. The mathematical model which correlates at best with the experimental curves for mammalian cells is a linear quadratic model, or ballistic model:
where S is the survival at the dose D and α and β are two coefficients. In semilogarithmic coordinates, the curve is biphasic with an initial linear portion, then a shoulder, then a distal linear portion.
Thanks to modelling of survival curves, it is possible to formulate various hypotheses concerning the cell death induced by ionising radiation. According to this linear quadratic model, cell death can be in relation to:
For the same cell line, radiosensitivity varies according to:
Cell characteristics
Many hypotheses have been formulated concerning this discrepancy between in vitro radiosensitivity and in vivo radiocurability:
Cellular death after radiotherapy is delayed, some cells being capable of dividing up to 9 times before the clone dies.
.This cellular death seems to result from the progressive accumulation of chromosomal abnormalities with the various cell cycles, which results in a deficiency in the normal protein products of genes and a stopping of the metabolism, with a depletion of ATP storage and a perturbation of the mechanisms of ionic membrane transport: the cell dies by necrosis when it enters into mitosis.
Radiation can also provoke cellular death by apoptosis, between phases of the cell cycle, especially for lymphoma cells, but also for salivary and lachrymal gland cells and in the intestinal crypts.
The mechanisms involved in this apoptosis are relatively unknown: they could be the consequence of alterations of the cell membrane, with an elevation of intracellular calcium which would stimulate the nuclear calcium-dependant endonucleases.
The P-53 protein is a protective tumour suppressor gene: it induces apoptosis via protein P-21 or blocks the cell-cycle in G1 in order for the cell to repair the damage induced by radiation. After irradiation, an elevation of P-53 is observed, which can be either a symptom of cellular death by apoptosis or of cellular repair, according to the radiosensitivity mechanism of the cells (apoptosis or late necrosis).
The Bcl-2 gene protects against apoptosis by activating an antioxidising metabolic pathway and suppressing the lipid peroxidation produced within the cell by apoptotic signals.
PKC inhibits also the apoptotic cascade.
Numerous growth factors and cytokines are implied for inhibiting apoptosis via the activation of PKC, IGF-1 and α- FGF.
Treatment parameters:
A dose of 5 Gy in a single fraction corresponds to the lethal dose in 50% of subjects (DL50),
The absorbed dose is different from the emitted energy due to interactions between radiation and biological tissue. Each particle, either photons or electrons, will transfer its energy to the electrons of the crossed tissue, thud creating new secondary electrons or photons which in turn react with neighbouring molecules.
Thus, the absorbed energy will be higher, not at the surface but at a depth, which depends on the incident energy (the higher the energy, the deeper the depth): this is known as the increasing depth-dose or build-up.
Thus, clinically, very severe epidermitis will be observed with low energetic beams (photons 1.25 Mev of 60Cobalt) and absent with high energy from accelerators (photons of 25 MeV).
Absorption of electrons
Electrons are very rapidly absorbed which allows superficial irradiation.
Fractionation - Spreading:
For example:
They emit electrons or photons and have the same general characteristics as an X-Ray tube.
Classified according to increasing emitted energy, we can distinguish between contact-therapy devices, Cobalt accelerators and linear accelerators. The in-depth absorption is proportional to the energy of the emitted beam.
The general diagram of radiotherapy tables takes into account the various treatment needs.
the electron energy is proportional to the length of the accelerator tube . The interposition of a cathode target generates photons.
The external aspect of a linear accelerator is very similar, independently of its manufacturer. Modern accelerators can modify the size and shape of the beam via a multi-leaf system and can control the transmitted beam using portal imaging devices.
In clinical practice, we use photons from 4 to 25 MeV, which penetrate much deeper than 60Co photons and 8 to 30 MeV electrons.
Their absorption curves are interesting and demonstrate the possibility of obtaining deep irradiation.
The more energetic the accelerators are, the deeper they can treat tumours . However the normal tissue on the beam path always receives a small but noteworthy dose for which new optimising techniques have recently been developed.
Conversely, the path of electrons is finite, depending only on their initial energy: they are therefore of great interest in the irradiation of tumours situated close to critical deeper organs such as the spinal cord.
Goals of radiotherapy:
Neccessary conditions: absence of remote metastases.
In these conditions, treatment will often last several weeks since it is necessary to use high tolerated dose, whilst respecting healthy tissue and precisely targeting the tumour.
Radiotherapy is a major weapon for fighting against cancer. The following indications are those for which it is the most efficient and often replaces mutilating and inefficient surgical procedures.
In order to be curative, the necessary dose to control the tumour should be inferior to the tolerated dose of the critical neighbouring organs. These doses are defined to within an accuracy of 5 to 10% and vary from one individual to another, more or less according to a Gauss curve. The margin between success and failure is relatively narrow, and a rigourous technique is therefore mandatory: we alternate between the risk of local relapse and, for a few supplementary Grays, the risk of necrosis.
Generally speaking, vegetating tumours are more radiosensitive than infiltrating tumours due to the oxygen effect.
The following table, borrowed from Pr Jean-Pierre Gérard, shows the sensitivity of various tumours:
This second table, also borrowed from Pr Jean-Pierre Gérard, shows the importance of tumour volume among malpighian tumours in order to obtain tumour sterilisation.
The greater the volume, the higher the necessary dose. Generally speaking, cutaneous and conjunctive tissue does not regularly tolerate a dose above 65-70 Gy, except in the case of a very small volume.
In order to be efficient, radiotherapy should be able to irradiate the whole tumour (and in particular its microscopic extensions to neighbouring healthy tissue).
The treatment should be short and relativey non-aggressive, like, for instance, split-course irradiation allowing the patient to recover between two radiotherapy treatment sessions.
Radiotherapy can be used alone (in order to preserve organs) or in association with surgery (either pre-operatively or more often post-operatively treating both the primitive tumour and the satellite node territories). Among these tumours:
Irradiation should deliver the necessary and sufficient dose to a given target volume and, at the same time, offer the best protection possible to surrounding healthy tissue. Treatment execution involves several important steps.
Certain preventive measures should be discussed according patient status:
One should also verify that healing of scars from previous surgery has been obtained.
The precise delimitation of the volume to be irradiated, taking into account the organs at risk and the dose delivered within such volumes is the responsibility of the radiotherapist helped by the medical physicist. Below is an example of treatment planning for a case of prostate cancer (the cancer volume is too small to be irradiated, therefore the whole prostate is irradiated (in orange). The rectum is one of the main organs at risk (in green) for which irradiation should be reduced as far as possible.
Recent technological progress :
Radiotherapists (and the industry) have endeavoured over the last 20 years to improve radiotherapy techniques, in particular to increase the dose on the tumour volume whilst decreasing the toxicity to healthy tissue, which represents the treatment’s collateral damage.
Four major intentions of such progress:
better treatment supports adapted to every patient to avoid movement during irradiation (for instance avoiding different pelvic curvatures when lying on the couch),thermoformed personal fixations for cervical, lumbar or pelvic regions.where necessary, stereotaxic fixation (for brain tumours)
The rigorous application of such devices avoids many reproducibility errors due to changes in patient position between fractions.
Image fusion is now daily practice.
3D reconstruction increases the accuracy for target drawing but also for organs at risk.
One of most important patient movements is due to breathing: hence the idea to synchronise irradiation with respiratory movements using respiratory gating. Two techniques are available:
the position of the organs to be irradiated is located when the patient blocks his/her breathing for a short period of time (either in forced inspiration or forced expiration) and the irradiation occurs only during these periods,
the position of the organs is located through a reference point (on the skin, in the organ) that a machine linked to the accelerator is capable of recognising and the irradiation follows the patient's natural movements.
3D isodose curves are now regularly plotted allowing the medical physicist to propose more and more precise ballistic improvements.
The 'beam’s eye view' technique enables the precise calculation of the dose received by each body volume. It also allows permanent irradiation control via 'digitally reconstructed radiographs' (portal imaging).
The use of 3D techniques (and possibly 4D techniques if the duration of irradiation is taken into account) enables considerably improved accuracy in the prediction and calculation of the dose actually received by critical organs ('room view technique'). The pictures are fascinating but the genuine benefit they offer the physicist is debatable.
Progress in simulation (due to progress in computer calculation speed) allows physicians to modify certain beam characteristics and to study the effects of such modifications.
The computer then calculates a determined number of loops and optimises the physicist’s first proposition. This inverse calculation should, in theory, strongly reduce parasitic doses to organs at risk and allow an increase in the dose to the tumour.
By multiplying the number of fields (which can be directly set between the computer and the accelerator) and by modifying the irradiation volume, this inverse calculation can define very complex irradiation volumes (see an example for cervical nodes with dosimetry in sagittal and coronal views.
These techniques are used for complex irradiation with a curative intent or when second or further irradiation treatment becomes necessary.
checking of patient position through more elaborated techniques than the laser beam alone,
checking of accelerator arm position,
checking of the positions of each of the collimator leaves,
more accurate checking of irradiation duration for the various fields,
continuous recording of all treatment components.
The images obtained during treatment can therefore be compared with those obtained during treatment preparation ('digitally reconstructed radiographs'). Such controls have revealed minor variations in patient positioning that were previously unknown.
The electronic measurement of radiation beam intensity observed after crossing the patient enables the calculation of a quasi 'in vivo' dosimetry using scanographic calculations. Such calculations are much easier to achieve than those obtained using a small dosimeter placed on the patient's skin (see page on total body irradiation).
Hence the relevance of combining these classical radiotherapy techniques with other techniques either using different beams (protons, neutrons, ions), perisurgical irradiation or brachytherapy which are all methods capable of concentrating supplementary irradiation within a small volume.
Treatment supervisio:
This supervision concerns the technical conditions of irradiation, its tolerance and its efficiency as judged by physicians.
Supervision of the technical conditions of irradiation
Patient supervision throughout radiotherapy treatment is part the radiotherapist’s job, together with the prescription of necessary adjuvant treatment:
After completion of radiotherapy, a precise report should detail the doses delivered, the technique used and the tolerance observed and should be sent to the various physicians involved in the patient ‘s treatment and follow-up.
Late reactions :
Sequelae and late reactions typically occur at least six months after completion of irradiation, i.e. when acute reactions have been healed.
Whereas sequelae are unavoidable because inherent to treatment, late complications can be prevented when certain favouring factors can be avoided.
However the risk is low, evaluated at less than 1%; the incidence dramatically increases with associated chemotherapy reaching 8 to 10% in patients with Hodgkin’s disease treated by an association of radiotherapy and chemotherapy (the MOPP regimen).
Osteoradionecrosis :
The sequelae described below are late complications of radiotherapy which occur with a low incidence and necessitate preventive measures during the execution of radiotherapy. Certain are not totally avoidable and constitute 'therapeutic hazards'.
Certain favouring factors, can be clearly identified thus enabling prevention:
Radiologically, an osseous sequester can be observed in the middle of a demineralised bone.
Treatment is very long and can sometimes take years, associating analgesics, anti-inflammatory drugs, antibiotics and, for many authors, hyperbaric oxygen therapy. Repeated oxygen inhalation stimulates local angiogenesis, thus favouring tissue re-oxygenation and healing. A surgical procedure may be necessary to remove a necrotic bone fragment.
This complication mainly concerns head and neck radiotherapy.
It appears either after superficial ulceration or on an apparently healthy mucous membrane.
Its favouring factors are:
Treatment involves an association of antibiotics, analgesics, and anti-inflammatory drugs over several weeks. In the case of persisting progression, biopsies are necessary in order to eliminate the possible non sterilisation of the initial tumour, however biopsy may extend necrosis. In the case of histologically proven radionecrosis with resistance to medical treatment, electrocoagulation or a large excision are possible when necessary.
Other mucous radionecroses may be observed:
Radiation myelopathy :
Although, fortunately, this complication rarely occurs, radiation myelopathy is one of the most serious radiotherapy complications and concerns the treatment of head and neck cancers or spinal metastases. This complication can be avoided if the radiotherapy technique is perfect.
Isolated Lhermitte's sign
This is one of the most frequently observed manifestations. The patient describes, more or less early on (a few weeks or a few months after irradiation) dysesthesia resembling electrical shocks starting from the neck and irradiating to the four limbs during flexion movements of the neck. In most cases, spontaneous resolution occurs within a few weeks. However, rare cases develop Brown-Sequard syndrome.
Brown-Séquard syndrome
After a period of 6 to 18 months, early signs appear such as paresthesia (prickling, burning) or hypoesthesia involving superficial sensitivity, generally asymmetrical in one of the superior limbs.
Hemiplegia then develops on the face with diminution of deep sensitivity on the same side and loss or diminution of superficial sensitivity on the opposite side
Evolution is the worsening of motor disorders leading to tetraplegia and associated sphincter disorders.
Other clinical presentations
The diagnosis of radiation myelopathy in a patient with recent irradiation of the neck region should be considered. However, diagnosis should be confirmed by the radiotherapist after a clear dosimetry revision and after eliminating other differential diagnoses via imaging techniques.
It is important to search for a different aetiology in order to ensure efficient therapy.
It will, in fact, reveal the various pathologies mentioned above. In radiation myelopathy, RMI shows either a normal, an enlarged or an atrophic cord with contrast enhancement at the lesion. However, the image is not very specific.
The cause of such myelopathy is generally a small technical error such as the overlapping of two joining fields giving a higher dose at the overlap. Occasionally, the repeated study of the radiotherapy information contained in the medical file does not offer any explication. However, the technician may have reported difficulties in maintaining the patient still in the correct treatment position for each session, hence suggesting that the spinal cord may not always have been correctly protected in spite of rigorous preparation.
Improved irradiation techniques should reduce the incidence of such dramatic complications to zero.
These complications occur after irradiation of the mediastium or the lung.
Chronic radiation lung
Abdominal and pelvic complications :
Among the favouring factors are the radiotherapy dose, any previous surgical procedures on the abdomen (which creates fixing of intestinal loops by adherence and increases the risk of one particular fixed loop) and association with chemotherapy.
Sometimes, a more or less complete ileus (intestinal obstruction) may lead physicians to consider the necessity of a rapid surgical procedure or tumour relapse. Frequently, symptomatic medical treatment including digestive aspiration, parenteral rehydration, analgesics and antispasmodics will enable the patient to recover a normal transit.
The radiography of the small intestine shows multiple level stenoses, with many atrophic villosity zones.
Laparotomy should be avoided when possible since the surgeon will discover a jumble of glued loops which are difficult to dissect and he will be obliged to proceed to mutilating intestinal excisions.
Occasionally, a complete ulceration may be found in one intestinal loop generating peritonitis and necessitating surgical procedure.
Fistulae which are rare and will be treated in the palliative care chapter.
The symptoms of actinic cystitis are bladder irritation (hypogastric pains, pollakiuria, urgencies) and by haematuria. The cytobacteriological study of urine is negative. The clinical examination is normal. The pyelogram shows an inflammatory bladder. Cystoscopy reveals a frosted yellowish mucosa, with scattering haemorrhagic telangiectasia and torpid ulcerations with swollen borders. The use of bladder biopsy should be limited to cases with suspicion of cancer relapse (otherwise biopsy is likely to provoke haemorrhaging and fistula). The treatment of such cystitis is difficult and long and includes only symptomatic drugs.
Haematuria is of variable abundance: either moderate of a vesical type (i.e. terminal) or abundant and total with clots. When it is abundant, it is advised to avoid any local treatment or biopsy. When haemorrhages are very abundant or when there are several clots, bladder irrigation is installed in order to remove clots and wash the bladder with cold solutions. Occasionally, certain bleeding lesions can be electrocoagulated. However, cystitis is generally spread over the surface and urinary derivation may be necessary; arterial embolisation has occasionally been proposed with success.
Vesical retraction occurs many years after external radiotherapy. It involves intolerable discomfort (hypogastric pain, urgency, painful micturitions every thirty minutes or sometimes more frequently, in particular during the night, incontinence).The high urinary apparatus is also disturbed with renal insufficiency. The bladder capacity is reduced to less than 50cc. Diagnosis is simple using pyelography. Generally, the pelvic examination reveals a frozen pelvis. Cystoscopy shows an atrophic, frosted, bleeding mucosa with oedema and pseudo-tumour aspects. The enlargement of the bladder capacity by an intestinal graft is extremely difficult to perform in an irradiated pelvis. A transintestinal derivation may offer a solution if the functional disturbance becomes intolerable or when renal insufficiency becomes a genuine problem.
Surgery is among the favouring factors of ureteral stenosis, since it removes ureteral vascularisation and nerves thus rendering it fragile. The simultaneous use of chemotherapy also increases the risk of fibrosis.
Stenosis concerns the two last centimetres of the ureter when it is caused by brachytherapy, and can be more important spreading as far as the superior limit of the field when it is caused by external raditotherapy.
The histological study of stenosis reveals an obliterating endarteritis (typical of irradiation), then sclerosis with calcium depositions and complete fibrosis.
Therapy should be active. When possible, the use of endoprosthesis should be preferred (known as double J prosthesis) either by cystoscopy or by interventional radiology through the pyelic cavity. The prosthesis will progressively calibrate the ureter and avoid renal insufficiency. Surgical reimplantation is often very difficult due to major local sclerosis.
Actinic rectitis
Chronic post-radiotherapy rectitis can occur even if the patient suffered no acute rectitis during radiotherapy. The usual delay for its appearance is 6 to 14 months, but some late forms have been described. The occurrence of this complication is directly related to the dose received by the rectum (> 50 Gy) and the importance of the rectal surface receiving this dose (particularly after irradiation for prostate carcinoma).
The main symptoms are defecation difficulties, urgent needs, small faecal incontinence due to unrecognised flatulence, very foul-smelling gas, rectal discomfort, unexpected diarrhoea and rectal haemorrhages accompanying stools. Sometimes this rectal discomfort may become very invalidating rendering social life quite impossible. More rarely, low occlusion syndromes may be observed.
The macroscopic aspect of the rectum on rectoscopy is of small, more or less bleeding telangiectasies. Biopsies should be avoided since they are difficult to heal and may favour the apparition of fistulae (rare).
Treatment is difficult: endorectal corticosteroid washing, salicylates, coagulation with Argon laser, hyperbaric oxygen therapy.
It is therefore clear that prevention is the best way to avoid such complications for our patients.
Therapeutic associations :
Radiotherapy is generally associated with surgery and/or chemotherapy and/or hormonotherepy.
Recently, trials in prostate carcinoma have shown that associating medical castration with radiotherapy had a synergistic effect on radiotherapy for locally advanced disease, with increased disease-free survival and, nowadays, increased survival (RTOG trial, Bolla trial). Other trials have since been set up for less advanced cancer disease.
Notions of brachytherapy:
Some clinical applications of brachytherapy :
Many accessible superficial tumours can be treated by brachytherapy.
The radiotherapist’s ingenuity and accurate dose calculation are probably the two most important aspects.
Irradiation by other particles:
Hadrontherapy groups together the utilisation of particles of the physical family of hadrons: protons, neutrons, pions and, by extension, ions.
The great mass of these particles (compared to photons or electrons), their charge or absence of charge together with their interaction with matter confer them with specific characteristics (biological and ballistic) which may be very useful in radiotherapy.
As they are slowed down by their energy loss due to such interactions, the energy deposit per depth unit (or TEL) increases until the particle comes to a halt. There is therefore a sudden peak of energy (Bragg peak), situated at a depth which is in relation to the original energy. The skin dose to tumour dose ratio is approximately one to four.
Besides this very precise energy loss, the relative biological effect is far more important than for photons, due to the high number of interactions which occur in the mean depth of the DNA molecule (about 20 Å). Photon irradiation with a Cobalt source produces approximately 0.01 collisions during the crossing of this depth while protons produce 0.57 events. Heavy particles (such as Carbon Ions) will produce approximately 3 events, thus explaining the greater number of irreparable DNA lesions.
Protons can be produced by cyclotrons: they are injected at the centre of a magnet and are accelerated by magnetic and electric fields. Synchrotrons allow the variation of the proton energy. Protons are then reunited by several magnets in a quality beam to the irradiation target either via a direct beam or an isocentric gantry.
Main indications of protons are:
The transfer of lineic energy is approximately 50 times higher than for a photon, however the deposit is similar to that of a photon (no Bragg peak).
The production of neutrons is based on cyclotrons which accelerate either deuterium (maximal energy 50 MeV) or protons (maximal energy 65 MeV) which collide with a target in beryllium producing a spectrum of neutrons.
There are very few indications for neutron therapy:
This kind of experimental treatment is studied for highly radioresistant tumours such as brain glioblastoma.
Ions may be light like carbon, oxygen or even neon or they may be heavy such as argon or silicium.
Several studies are in progress. The French government has decided, within the framework of its cancer plan, to build an experimental facility in Lyon, although another project exists in Caen, within the vicinity of a Heavy Ion Facility (GANIL). Other countries already possessing or currently building hadrontherapy facilities are Japan, Germany, Italy and Austria.
The production of light ions requires the presence of a synchrotron to accelerate the ions using various energies. Many technical difficulties remain such as the construction of an isocentric gantry (as in standard radiotherapy).
The tumour margin may be accurately drawn by the beam using active raster scanning: every point of the tumour slice is treated (i.e. the Bragg peak targets this point), then another slice is treated by varying the beam energy.
Another interest characteristic of carbon ions would be the theoretical possibility of obtaining in vivo dosimetry: where ions deposit energy, positrons are produced and can be detected by PET-Scan.
The potential indications of this treatment would be:
In an appendix, we describe the main stages of the history of this therapy.
We can distinguish;
- External radiotherapy, where the irradiation source is situated outside the patient (RX devices, cobalt, accelerators),
- Brachytherapy where the radioactive sources are situated inside the patient:
- by sealed sources
- - intersticial brachytherapy : the sources are placed inside the tumour
In France, radiotherapy is used for the treatment of one out of two cancer patients. Half of the patients who are cured of their cancer, are treated by radiotherapy
- - endocavitary brachytherapy : the sources are inside natural cavities where tumours develop
- non sealed brachytherapy : radioactive compounds are injected into the patient for particular tumours : I 131, P32, St189, ..
Physical bases of radiotherapy
Radiobiology Notions
Treatment parameters
Main devices used in external radiotherapy
Goals and results of radiotherapy
Technical realisation of treatment
Treatment supervision and acute side effects
Late side effects
Therapeutic associations
Brachytherapy Notions
Other particles used in radiotherapy
Physical foundations of radiotherapy :
Classification of ionising particles used in radiotherapy
Several types of ionising radiations are used
Non charged ionising radiations
Electromagnetic radiation:
- X photons emitted during the rearrangement of electrons: X-Rays tubes, accelerators;
- γ photons emitted during nuclear disintegration: 60Cobalt source,192 Ir wires, 137Cs wires
Their main physical characteristics are:
Particule radiation: neutrons These particles are artificially produced by cyclotrons: their route is straight throughout matter. They interact by pulling protons out of crossed tissue. At a similar dose, their relative biological efficiency (RBE) is approximately 3 times higher than photons.
- no mass: they are propagated in a straight line;
- no charge: their interaction with matter is random with important leakage after crossing any depth of matter
Charged ionising radiations
β - Radiation
β - radiation particles are emitted by certain radioactive nuclei. They comprise electrons which interact with matter by moving the electrons within human tissue by electrostatic repulsion. Their route is more or less winding depending on their original energy. Their biological efficiency is very similar to that of X and γ photons.
Accelerated electrons
Produced by accelerators, they possess the same physical characteristics as ß Radiation. Their energy is chosen according to the depth at which the tumour to be treated is situated, but they do not penetrate and offer the major advantage of sparing tissue situated deeper than the tumour itself.
α Radiation
α particles are heavy, positively charged helium nuclei. These particles are spontaneously produced by instable nuclei and behave within matter by interacting with electrons and protons. Their route is very short; only a few millimetres in water. Their biological efficiency is 5 to 10 times higher than X or γ Photons, however their short penetration prevents their clinical use.
Protons
Produced by cyclotrons or synchrotrons, they loose their energy by colliding with electrons and nuclei. The in-depth dose distribution is very different from that of photons and is concentrated within a very narrow peak (Bragg peak). Thus, this type of irradiation is well adapted for deep small sized tumours situated close to radiosensitive healthy tissue. Nowadays, the main indications are choroidal melanoma, tumours at the base of the skull and tumours close to the spinal cord (chondroma, chondrosarcoma). The biological efficiency is less than that of neutrons.
Light ions
They can be produced by synchrotrons, have a similar penetration to protons but a biological efficiency comparable to that of neutrons. The main ion used in a few specialised centres is Carbon. They constitute an interesting research domain.
Interactions between radiations and tissues
When an ionising radiation beam penetrates human tissue, part of the radiation is absorbed (this is the useful part of the beam), another part is deviated from its path (depending on many factors) and the third part continues its path.Diffusion (propagation outside the beam’s path) explains why the regions situated outside the irradiation beam can receive a parasitical dose of radiation.
Photons transmit their energy to molecules by different fundamental interaction mechanisms; these phenomena lead to ionisations or electronic excitations, then to the emission of secondary photons of lesser energy when the molecules return to their stable stage. These secondary photons are, themselves, the origin of new interactions with excitations and ionisations in neighbouring molecules.Electromagnetic radiation interactions with tissues
Most of this interaction is not mechanical, as in photons, but is electrostatic with the electrons of crossed tissue. The electrons very rapidly loose their speed and then their energy. At the end of the path, their energy loss per unit of crossed depth is much higher than at the beginning of the path, thus giving electrons an advantage for the protection of deep and superficial tissues.Electron interactions with tissues
Expression of the absorbed dose
The absorbed dose represents the quantity of energy absorbed per unit of matter. It is totally different from the emitted energy.It is measured in Grays (in honour of the great British physicist Hal Gray - 1905-1965 - who worked in Cavendish Laboratory - Cambridge, UK): 1 Gy represents the deposition of 1 Joule per kg of matter. In previous denominations, 1 Gy is equivalent to 100 Rad.
A dose of 5 Gy in one shot to the whole body of a man is a lethal dose for approximately 50% of subjects (DL 50).
70 Gy is the dose which is generally prescribed (in several fractions) for head and neck cancers exclusively treated by radiotherapy.
Biological action of radiotherapy :
The action of ionising radiation in living tissue takes place in three phases:
It lasts a very short period of time, in the order of 10-13 second. It is characterised by the ionisations and molecular excitations following the energy deposit during the crossing of the beam.Physical phase
It lasts from a few seconds to a few minutes. The ionised and excited molecules react between each other and with neighbouring molecules.Physicochemical phase
Generally, we distinguish between the direct effect in relation to direct impact of the beam on cellular macromolecules, in particular DNA, and the indirect effect in relation to macromolecule modifications provoked by free radicals originating from water radiolysis. These indirect effects are the major component (70-80%) of beam impact on living tissue.
A few explanations are given in specific pages on physicochemical effects and on water radiolysis.
In the presence of oxygen, specific radicals are created with a strong oxidising power interacting with water to induce the formation of hydrogen peroxide which is a strong oxidising molecule. The 'oxygen effect' is observed in radiobiology with an increased radiosensitivity of well oxygenated cells compared to hypoxic cells.
Either by direct or indirect effect, ionising radiation alters the structure of macromolecules, thus disrupting the main functions of cellular life.Biological phase
DNA is the elective target of ionising radiation. When the cytoplasm and the nucleus of a cell are selectively irradiated, cellular death occurs with much lower doses and more often when irradiation attacks the nucleus: lethal cellular lesions are those which concern DNA .Action on nuclear acids
Direct effect: (the lower part of the diagram): interaction between a DNA molecule and an electron displaced after absorption of a photon (in green). The DNA modification is relatively easy to repair.Indirect effect: (the higher part of the diagram): an electron detached by a photon (in green) will interact with a water molecule and produce radicals (for instance HO• which will then provoke a lesion of the DNA molecule). It is generally estimated that free radicals may provoke a DNA lesion if they are produced at a distance of less than 2nm. The indirect effect is the major effect obtained for low LET beams (Linear Energy Transfer).
The main lesions are:
The capacity to repair double strand breaks depends on their nature: they are more difficult to repair if associated with a loss of chromosomal material, when links with proteins are created or if they are numerous and close to each other.
- most often single strand breaks without gap, by rupture of diester links. These breaks are generally not lethal since DNA repair can be made by a ligase in 2 to 10 minutes,
- more rarely, single strand breaks with gap, by the disappearance of a sugar or DBA base: the repair time is longer since it requires the action of both a polymerase and a ligase,
- occasionally, base alterations, which are non lethal lesions, but which can be the source of mutation if the lesion is not repaired or is repaired inaccurately. Eighty percent of theses lesions are repaired within 15 minutes by excision-synthesis mechanisms which require endonucleases, glycolases, polymerases and ligases,
- finally, double strand breaks which result from simultaneous events on the two strands or from two independent single break lesions. Every double strand break is lethal if not repaired and the number of induced double strand breaks induces the cellular radiosensitivity of a tissue.
Generally, during irradiation, one double strand break occurs for 20 single strand breaks.
Some radio-induced modifications of the protein structure may provoke physiological perturbations which can be lethal:Action on proteins
Lipid peroxidations diminish membrane fluidity inducing alterations in cell membrane functions.
- alteration of membrane permeability (for instance: on ionic pumps),
- diminution of intercellular communication by perturbation of proteins constituting a gap junction,
- modification of the transmembrane signal transduction.
Action on lipids
Notions in radiobiology:
Survival curves
The radiosensitivity of healthy cells or tumour cells can be determined by the preparation of survival curves after irradiation, and for cancer cells, at best using in vitro clonogenic culture (study of stem cells).
The curve which is obtained can be transformed into a mathematical model giving the proportion of surviving cells after irradiation. The mathematical model which correlates at best with the experimental curves for mammalian cells is a linear quadratic model, or ballistic model:
S = e(-αD - βD²)
where S is the survival at the dose D and α and β are two coefficients. In semilogarithmic coordinates, the curve is biphasic with an initial linear portion, then a shoulder, then a distal linear portion.
Thanks to modelling of survival curves, it is possible to formulate various hypotheses concerning the cell death induced by ionising radiation. According to this linear quadratic model, cell death can be in relation to:
- lethal lesions which cannot be repaired (αD component of the survival curve)
- the accumulation of sublethal lesions (β component of the survival curve); experimentally, the survival is increased when the irradiation dose is divided into two fractions separated by a time interval of around 6 hours, which is sufficient to enable the repair mechanisms to operate.
- the non-reparation of potentially lethal lesions; these are repairable lesions, which can actually occur if, after irradiation, the cells are maintained in culture conditions delaying the progression of the cell cycle; for example confluence, depletion of growth factors or incubation with inhibitors of DNA synthesis. On the contrary, the reparation of potentially lethal lesions is activated by βFGF in certain cell lines.
Variations in the radiosensitivity
Radiosensitivity varies from one cell line to another; haematopoietic stem cells and germinal stem cells are among the most radiosensitive. In general, the poorer a cell’s differentiation, the more radiosensitive it is.For the same cell line, radiosensitivity varies according to:
Cell characteristics
Parameters in relation with the irradiation technique
- position of the cells in the cell cycle cell cycle, the G2 and M phases are the most radiosensitive,
- the oxygenation tension ,
- pH,
- the DNA content, in
- the glutathione and thiol content,
- the repair system efficiency after radio-induced lesions.
The in vitro determination of SF2 or of D0 (the prolongation of the distal slope of the survival curve) does not systematically predict in vivo radiosensitivity, i.e. cure by radiation. In reality the D0 of tumour cell lines is not very different from the D0 of normal fibroblasts and the in vitro radiosensitivity of tumour cells from an in vivo non sensitive tumour is similar to the sensitivity of cells issued from radiocurable tumours.
- § role of Linear Energy Transfer. This value characterises the ionisation density in a unit of the path depth. The higher the LET, the greater the lethality due to the increased difficulty in repairing induced lesions,
.- fractionating and staggering of the dose (dose flow rate): when cells are irradiated with a low rate, they can repair their sublethal lesions during irradiation, eliminating the β component with a linear survival curve with a single α slope.
Many hypotheses have been formulated concerning this discrepancy between in vitro radiosensitivity and in vivo radiocurability:
Mechanisms of cell death:
- modification of the cell properties due to in vitro culture (lack of growth factors, need for specific tissue culture supports),
- in vivo selection by ionising radiation of radioresistant cells,
- in vivo induction of mutations by ionising radiation giving birth to a few radioresistant cells amidst a radiosensitive population,
- role of the stroma which is a support for the tumour, with its various cells (endothelial cells, lymphocytes, macrophages) able to secrete various cytokines modulating the radio-sensitivity like Tumor Necrosis Factor or Fibroblast Growth Factor.
- role of the stroma which is a support for the tumour, with its various cells (endothelial cells, lymphocytes, macrophages) able to secrete various cytokines modulating radiosensitivity, such as α Tumor Necrosis Factor or β Fibroblast Growth Factor.
Cellular death after radiotherapy is delayed, some cells being capable of dividing up to 9 times before the clone dies.
.This cellular death seems to result from the progressive accumulation of chromosomal abnormalities with the various cell cycles, which results in a deficiency in the normal protein products of genes and a stopping of the metabolism, with a depletion of ATP storage and a perturbation of the mechanisms of ionic membrane transport: the cell dies by necrosis when it enters into mitosis.
Radiation can also provoke cellular death by apoptosis, between phases of the cell cycle, especially for lymphoma cells, but also for salivary and lachrymal gland cells and in the intestinal crypts.
The mechanisms involved in this apoptosis are relatively unknown: they could be the consequence of alterations of the cell membrane, with an elevation of intracellular calcium which would stimulate the nuclear calcium-dependant endonucleases.
The P-53 protein is a protective tumour suppressor gene: it induces apoptosis via protein P-21 or blocks the cell-cycle in G1 in order for the cell to repair the damage induced by radiation. After irradiation, an elevation of P-53 is observed, which can be either a symptom of cellular death by apoptosis or of cellular repair, according to the radiosensitivity mechanism of the cells (apoptosis or late necrosis).
The Bcl-2 gene protects against apoptosis by activating an antioxidising metabolic pathway and suppressing the lipid peroxidation produced within the cell by apoptotic signals.
PKC inhibits also the apoptotic cascade.
Numerous growth factors and cytokines are implied for inhibiting apoptosis via the activation of PKC, IGF-1 and α- FGF.
Treatment parameters:
Dose absorption
The absorbed dose represents the quantity of energy absorbed per unit of matter. It is measured in Grays: 1 Gy represents 1 Joule deposited in 1 kg of matter.A dose of 5 Gy in a single fraction corresponds to the lethal dose in 50% of subjects (DL50),
The absorbed dose is different from the emitted energy due to interactions between radiation and biological tissue. Each particle, either photons or electrons, will transfer its energy to the electrons of the crossed tissue, thud creating new secondary electrons or photons which in turn react with neighbouring molecules.
Thus, the absorbed energy will be higher, not at the surface but at a depth, which depends on the incident energy (the higher the energy, the deeper the depth): this is known as the increasing depth-dose or build-up.
Thus, clinically, very severe epidermitis will be observed with low energetic beams (photons 1.25 Mev of 60Cobalt) and absent with high energy from accelerators (photons of 25 MeV).
 |
Dose variation at the entry and in depth in relation to the beam photon energy. |
Electrons are very rapidly absorbed which allows superficial irradiation.
 |
Dose distribution in water according to depth by an electron beam. |
Fractionation - Spreading:
Fractionation - Spreading
For a similar total dose, the biological efficiency EBR varies according to the dose per session, the total number of sessions (fractionation) and the total duration of treatment (spreading).For example:
22 Gy delivered for analgesic purposes during 6 sessions spread over 9 days will be more efficient than 22 Gy delivered in 11 sessions spread over two weeks.
However, the late toxicity of irradiation seems to be related to the dose per fraction, many protocols of hypofractionated radiotherapy are employed only for patients with a short life expectancy (radiotherapy for metastases for instance), who will not live long enough to develop such toxicities.
Interest of fractionation
Fractionation allows:- Repair of sublethal lesions i.e. lesions which become lethal by accumulating. The repair of sublethal lesions is far easier for normal cells than for tumour cells: thus fractionation increases the differential effect of ionising radiation.
- Repopulation, i.e. cell proliferation between fractions, which is beneficial when it concerns normal cells and is a way of reducing toxic effects, but which is detrimental when involving tumour cells. Hyperfractionated schedules generally include an increased total dose which compensates the tumour repopulation phenomenon.
- Reoxygenation of tumour tissue: well oxygenated cells are radiosensitive and are eliminated (apoptosis) after irradiation; hypoxic cells can then benefit from improved oxygenation and again become radiosensitive.
- Redistribution of cells in the cell cycle: radiation generally blocks cells in G2, which is the most sensitive cell cycle phase.
- Recently, many studies have involved accelerated hyper-fractionated schedules (noticeably in head and neck cancer) in order to increase the tolerance by normal tissue, to increase the total dose for improved tumour control and to diminish the tumour repopulation phenomenon.
- In daily practice, it is necessary to compare treatment modalities with atypical fractionation or spreading with standard treatment 'or equivalent dose' which is generally carried out with fractions of 1.8 Gy to 2.0 Gy five times per week.
They emit electrons or photons and have the same general characteristics as an X-Ray tube.
Classified according to increasing emitted energy, we can distinguish between contact-therapy devices, Cobalt accelerators and linear accelerators. The in-depth absorption is proportional to the energy of the emitted beam.
The general diagram of radiotherapy tables takes into account the various treatment needs.
Contact therapy devices.
General diagram of a radiotherapy device
A classical radiotherapy device comprises a very heavy and strong stand [1] (in the accelerator where the ions are produced) and a rotation axis of 360° [2] to allow the arm to rotate around the patient. Within the arm [3] there is either the Cobalt source or the Cathod which can also be moved vertically. In [4], a space is reserved for controlling the irradiation produced using an imaging system. The table is placed on a jack [5] which can move in almost every direction [6], and a specific device [7] is used to immobilise the patient during the treatment session.
They are X-ray tubes.
They deliver low energetic photon beams which are used for treating skin tumours in view of their short penetration into tissue. It is relatively easy to protect the adjacent healthy skin by placing light lead sheets in order to obtain a pleasant aesthetic result.
Such contact therapy is also used for superficial tumours of the rectum among elderly patients who are too weak to undergo rectal amputation.
The Cobalt device
Its technology is relatively simple and robust. The 60Cobalt source is a small disc which is accommodated in a movable drawer inside the lead head of the device. The source is concealed when the device is inactive. The head is situated on a 360° rotating arm
The beam geometry (which is only emitted when the source is in treatment position) can be modified for each patient. The use of masks, wedges and compensators gives great liberty in adapting the beam to the patient’s morphology.
The device is isolated in a lead walled room; during the session, the patient communicates with the technician via an interphone and a camera allows good visual contact with the patient whose immobility during treatment must be assessed.
The 60Cobalt emits a γ radiation beam of 1,25 MV; the maximum absorbed dose is situated around 0.5 cm under the skin. It is therefore mainly used for head and neck cancer (irradiation of relatively superficial tumours and nodes).In fact, its use is gradually becoming rarer due to the progress of linear accelerators and the new 'multi-leaf' collimation technology.
Linear accelerators
They comprise an electron source and an electromagnet which accelerates the electrons in a deep vacuum tube (accelerator).the electron energy is proportional to the length of the accelerator tube . The interposition of a cathode target generates photons.
The external aspect of a linear accelerator is very similar, independently of its manufacturer. Modern accelerators can modify the size and shape of the beam via a multi-leaf system and can control the transmitted beam using portal imaging devices.
In clinical practice, we use photons from 4 to 25 MeV, which penetrate much deeper than 60Co photons and 8 to 30 MeV electrons.
Their absorption curves are interesting and demonstrate the possibility of obtaining deep irradiation.
 |
With an 18 MeV accelerator, it is possible to irradiate up to 15cm deep tumours with little irradiation of healthy tissue situated on the beam path For a zone situated at a depth of 15cm, approximately 70% of the dose is delivered to the tumour. When using four field treatment, less than 50% of the dose is delivered to the neighbouring healthy tissue. |
Conversely, the path of electrons is finite, depending only on their initial energy: they are therefore of great interest in the irradiation of tumours situated close to critical deeper organs such as the spinal cord.
 |
This diagram clearly represents the very steep penetration loss by electrons in relation to adjacent healthy tissue. However, the tissue situated prior to this decrease receives a relatively strong irradiation dose. |
Curative radiotherapy
Goal: To definitively sterilise the cancer cells within the irradiated volume in order to obtain total cure of the cancer.Neccessary conditions: absence of remote metastases.
In these conditions, treatment will often last several weeks since it is necessary to use high tolerated dose, whilst respecting healthy tissue and precisely targeting the tumour.
Radiotherapy is a major weapon for fighting against cancer. The following indications are those for which it is the most efficient and often replaces mutilating and inefficient surgical procedures.
In order to be curative, the necessary dose to control the tumour should be inferior to the tolerated dose of the critical neighbouring organs. These doses are defined to within an accuracy of 5 to 10% and vary from one individual to another, more or less according to a Gauss curve. The margin between success and failure is relatively narrow, and a rigourous technique is therefore mandatory: we alternate between the risk of local relapse and, for a few supplementary Grays, the risk of necrosis.
Generally speaking, vegetating tumours are more radiosensitive than infiltrating tumours due to the oxygen effect.
The following table, borrowed from Pr Jean-Pierre Gérard, shows the sensitivity of various tumours:
| Histological tumours | Median dose for 90% of definitive sterilisation |
Leukaemia | 15 - 25 Gy |
Seminoma | 25 - 35 Gy |
Dysgerminoma | 25 - 35 Gy |
Wilms tumour | 25 - 40 Gy |
Hodgkin's disease | 30 - 45 Gy |
Non Hodgkin's Lymphoma | 35 - 55 Gy |
Malpighian carcinoma | 55 - 75 Gy |
Adenocarcinoma | 55 - 80 Gy |
Urothelial carcinoma | 60 - 75 Gy |
Sarcoma | 60 - 90 Gy |
Glioblastoma | 60 - 80 Gy |
Melanoma | 70 - 85 Gy |
| Tumour volume | Necessary dose |
| Infraclinical disease | 45 - 60 Gy |
| Tumour < 2 cm diameter | 60 - 64 Gy |
| Tumour > 2 cm - < 4 cm | 65 - 70 Gy |
| Tumour > 4 cm | 75 - 85 Gy |
In order to be efficient, radiotherapy should be able to irradiate the whole tumour (and in particular its microscopic extensions to neighbouring healthy tissue).
Palliative radiotherapy
Goal: to slow down the progression of already advanced local tumours or those with remote metastases which cannot be cured using local treatment.The treatment should be short and relativey non-aggressive, like, for instance, split-course irradiation allowing the patient to recover between two radiotherapy treatment sessions.
Symptomatic radiotherapy
Goal: to relieve the patient from a major symptom, for instance:Main radiotherapy indications:
- pain from bone metastases. The effect can generally be rapid, appearing after a few fractions (with an occasional transitory outbreak of the symptoms in relation to radiotherapy-induced inflammation or oedema). It is estimated that 75% of patients are partially or totally relieved from their pain at the end of treatment or in the following weeks;
- haemorrhage syndrome,
- compression such as spinal cord or radicular compression. Spinal cord compression is an emergency in radiotherapy: in order to be truly efficient (full patient recovery), this treatment should be administered as soon as the first symptoms appear (immediately following confirmation by RMI). It is relatively efficient if the patient still has leg sensitivity. The treatment consists of a few fractions in order to obtain a powerful effect. An emergency meeting should be organised between the physician, the surgeon and the radiotherapist at the patient's bedside in order to discuss and rapidly decide on the most appropriate treatment modality (surgery or radiotherapy).
The following list is not exhaustive and its aim is simply to indicate how important radiotherapy is in the treatment of cancer.
Brain tumours
Radiotherapy slightly improves the very poor prognosis of these tumours:
- glioblastoma,
Head and neck tumours
- tumours of the tonsil and the tongue
- tumours of the larynx: in association with chemotherapy in order to preserve a normal voice for small tumours; otherwise post-operatively
- tumours of hypopharynx: most often after surgery except for inoperable tumours
Bronchial tumours
Apart from a few rare exceptions, bronchial tumours cannot be cured by radiotherapy alone. It is generally used:
The results of radiotherapy alone or in association with chemotherapy are identical to those obtained with surgery, without the risks and drawbacks of oesophagectomy. Survival remains modest.
Oesophageal tumours
The results of randomised trials clearly demonstrate the importance of radiotherapy in favour of the irradiation of the breast or the chest wall after surgery:Breast tumours
Unfortunately there have been no such clear trial results concerning the node territories. The irradiation of the armpit is a risk factor of lymphoedema. Radiotherapy of the internal mammary node is difficult without irradiating the heart.
- After lumpectomy: radiotherapy is mandatory to radically avoid local relapse (see results by Fisher)
- After mastectomy, radiotherapy is useful if margins are invaded.
Unfortunately, trials concerning node irradiation are relatively old: the technique used is sometimes doubtful and, at the time, there was no efficient chemotherapy such as anthracycline or docetaxel.
- Radiotherapy of the armpit is therefore subject to controversy: whereas most authors irradiate N+ tumours, many do not irradiate N- tumours.
- Concerning the internal mammary nodes, radiotherapy is necessary for certain authors when the tumour is located internally or if there are enlarged nodes. For others, chemotherapy is more useful.
Results are very poor even when associated with chemotherapy: it is very difficult to deliver a correct dose to this deeply situated organ which is surrounded by many organs at risk. On the other hand, liver metastases develop very quickly.Pancreas tumours
Many treatment modalities have been proposed without any proof of the superiority of one attitude compared to another. The usual treatment is therefore:Cervix uteri tumours
- Surgery alone,
- Surgery with pre-surgical or post-surgical brachytherapy
- External radiotherapy (often reserved for locally advanced disease)
- Radiotherapy with chemotherapy (many regimens exist, none having proved its superiority).
There have been no trials (and there probably never will be) establishing the superiority of any one method over others:Endometrial tumours
- Surgery is the most efficient treatment
- Brachytherapy is used post-operatively when infiltration of the endometrium is deep (sometimes radiotherapy)
- Rarely, for very obese patients, vaginal and endometrial brachytherapy is proposed to avoid surgery
Prostate tumours
Radiotherapy, associated with chemotherapy, remains an important treatment modality in lymphoma.
- Surgery is sometimes followed by radiotherapy if margins are positive
- Radiotherapy alone appears to give similar results to those obtained by surgery (generally in more advanced disease)
- Brachytherapy gives similar results to surgery. It can be administered alone or in association with external radiotherapy
- Hormonotherapy is associated to radiotherapy in locally advanced prostate cancer, with a clear increase in survival.
Bladder tumours
- The main treatment is surgery
- However, radiotherapy (associated with chemotherapy) is performed in order to preserve the bladder, and could be efficient in localised tumours
Rectum tumours
- It has been clearly demonstrated that pre-surgical irradiation of the pelvis improves the local control of rectal tumours.
- Post-surgical radiotherapy is used in the case of positive margins.
Testicular tumours
- Solely for pure seminoma: radiotherapy seems to be the perfect treatment for nodes
- However chemotherapy is so efficient, even in seminoma, that it is performed more and more often as an alternative to radiotherapy, even in localised tumours.
Soft tissue Sarcoma
- Radiotherapy should complete surgery in order ensure complete lesion sterilisation. A relatively high dose should be administered (approximately 65 Gy).
- Local control of soft tissue sarcoma is the only current method for curing patients.
Lymphoma
Technical treatment execution:
- Hodgkin's disease
- Non Hodgkin's Lymphoma
Skin tumours
- Surgery is most often carried out.
- However, radiotherapy using a low intensity beam (200 kV) allows complete sterilisation with very aesthetic results. It should be preferred in the case of surface or in-depth cancer spread.
Irradiation should deliver the necessary and sufficient dose to a given target volume and, at the same time, offer the best protection possible to surrounding healthy tissue. Treatment execution involves several important steps.
Decision to irradiate
This decision is taken during the multidisciplinary meeting with physicians of various specialities: radiotherapist, surgeon, medical oncologist, pathologist and radiologist after a clear description of the tumour and the general patient status.Certain preventive measures should be discussed according patient status:
The patient should not be agitated or ache to the extent that he/she cannot remain calm during treatment fractions: sufficient quality sedation should be obtained beforehand.
- Stomatology advice (treatment of dentition, and fluoride rinses for head and neck cancers),
- Nutritionist advice when needed,
- Corticosteroid therapy (before brain irradiation),
- Haematological values, especially for large volume irradiation after chemotherapy,
- All radiographical examinations (scanner, RMI) necessary for the precise identification the target volume.
One should also verify that healing of scars from previous surgery has been obtained.
Determining the target volume
It depends on:
- the size of the tumour (necessary radiological analysis),
- the natural history of cancer (systematic irradiation of supraclavicular nodes in oesophageal cancer of the upper third),
- the surgical operative report, the histological report (complete excision or not, capsular invasion in the node sample, and so on...)
IRCU Standards
According to IRCU standards (International Commission on Radiation Units and Measurements), various volumes are defined for irradiation:GTV: or gross target volume, related to the apparent volume of the tumour (in red)
CTV: or clinical target volume, related to the usual tumour extension to surrounding tissue (local tumour invasion) (oin orange)
Note that healthy sensitive tissue may be found in the PTV and constitutes a major treatment risk.PTV: or planning target volume : (in blue ) related to the patient and tumour movements and beam imperfections (the two latter factors are called IM for internal margin and SM for set-up margin). Note that organs at risk OR are represented in dark green.
 |
The diagram shows the various volumes to be considered. GTV is the volume as seen by physicians. CTV is the volume calculated according to the pathological knowledge of usual local invasion by cancer. PTV is a compromise taking into account various physiological phenomena (respiration, difficulties in positioning the patient, patient movement) IM and SM. Normal tissue (in dark green) is included in the PTV. The arrows show various attempts to reduce parasitical irradiation, the ideal being of course the smallest volume. |
The precise delimitation of the volume to be irradiated, taking into account the organs at risk and the dose delivered within such volumes is the responsibility of the radiotherapist helped by the medical physicist. Below is an example of treatment planning for a case of prostate cancer (the cancer volume is too small to be irradiated, therefore the whole prostate is irradiated (in orange). The rectum is one of the main organs at risk (in green) for which irradiation should be reduced as far as possible.
 |
This diagram shows that with 4 fields, approximately 85% of the dose (60 to 65 Gy) is received by the rectum and approximately 50% by the femoral heads. |
Recent technological progress :
Radiotherapists (and the industry) have endeavoured over the last 20 years to improve radiotherapy techniques, in particular to increase the dose on the tumour volume whilst decreasing the toxicity to healthy tissue, which represents the treatment’s collateral damage.
Four major intentions of such progress:
improved anatomical data acquisition,
improved beam definition,
improved calculation and optimisation of distributed dose,
improved control during treatment execution.
Improved anatomical data acquisition
Great progress has been made to improve the precision of radiotherapy.Patient positioning and fixing
This improvement has been made possible thanks to the development of personalised systems for each and every patient:better treatment supports adapted to every patient to avoid movement during irradiation (for instance avoiding different pelvic curvatures when lying on the couch),thermoformed personal fixations for cervical, lumbar or pelvic regions.where necessary, stereotaxic fixation (for brain tumours)
These fixation systems are used during the simulation phase (under scanner or RMI) allowing a precise positioning for dose calculation.
The rigorous application of such devices avoids many reproducibility errors due to changes in patient position between fractions.
Imaging system
Imaging techniques have undergone vast progress allowing the fusion of scanner or MRI slices. The use of Pet-Scan allows the differentiation between bronchial tumours and their pulmonary consequences (retractile condensation).Image fusion is now daily practice.
Definition of the volume to be irradiated
The definition of the volume to be irradiated is the responsibility of the radiotherapist who now has the necessary tools to display the target volume and the volume of organs at risk on the computer screen.3D reconstruction increases the accuracy for target drawing but also for organs at risk.
Detection and correction of target movements
However, as we previously explained, spontaneous patient movement and repositioning difficulties constitute a risk of parasitic irradiation. The latter has already been dealt with above. Spontaneous movements, however, are difficult to correct.One of most important patient movements is due to breathing: hence the idea to synchronise irradiation with respiratory movements using respiratory gating. Two techniques are available:
the position of the organs to be irradiated is located when the patient blocks his/her breathing for a short period of time (either in forced inspiration or forced expiration) and the irradiation occurs only during these periods,
the position of the organs is located through a reference point (on the skin, in the organ) that a machine linked to the accelerator is capable of recognising and the irradiation follows the patient's natural movements.
Other movements are difficult to identify (for instance, prostate position varies according to bladder vacuity, the presence of gas in the rectum, but also with breathing and the varying pelvic curvatures for each radiotherapy session).
Beam definition
To obtain regular good quality beams satisfying the radiotherapist’s needs is the fruit of close collaboration between the medical physicist and the radiotherapist and of a rigorous quality control program. Great progress has been made in this field:Improved simulation techniques
Medical physicists have very powerful computers at their disposal containing all the anatomical data, all the beam penetration data and the physical beam data concerning accelerators within the radiotherapy unit. They can therefore calculate the dose received on each part of the patient’s body.3D isodose curves are now regularly plotted allowing the medical physicist to propose more and more precise ballistic improvements.
Increasing the field number
A simple way to improve ballistics is to increase the field number during treatment. Hence, parasitic doses on organs at risk are reduced. Nowadays, this is simple to achieve since accelerators are automatically driven by computers in accordance with to dosimetry calculations.Multiple leaf collimators
Instead of having to lay heavy masks, necessitating complex manipulation and re-positioning for each field, modern accelerators are equipped with a lead multiple leaf device, situated in the accelerator head. Each leaf can be moved with millimetre precision and the multitude of leaves allows the construction of very complex volumes, with volume variation during irradiation time (intensity modulation).The 'beam’s eye view' technique enables the precise calculation of the dose received by each body volume. It also allows permanent irradiation control via 'digitally reconstructed radiographs' (portal imaging).
Intensity modulation (IMRT)
Further precision can be added by modifying the energy of the incident beam thus altering its penetration power. Intensity can also be modulated by modifying the duration of irradiation to each tumour zone.Dose calculation and optimisation
Improved calculation models
Up to very recently, all dosimetry calculations were made in 2D. The patient was considered as a cylinder and calculations were made for each slice.The use of 3D techniques (and possibly 4D techniques if the duration of irradiation is taken into account) enables considerably improved accuracy in the prediction and calculation of the dose actually received by critical organs ('room view technique'). The pictures are fascinating but the genuine benefit they offer the physicist is debatable.
Progress in simulation (due to progress in computer calculation speed) allows physicians to modify certain beam characteristics and to study the effects of such modifications.
Inverse calculation of the dose
Inverse calculation is an extrapolation of the medical physicist’s work. The computer receives the original data: such volume should receive such dose, however such other volume (organ at risk) should receive a smaller dose. The morphology of the irradiated zone and protected zones is drawn. The optimisation limit is set (in order for it to be maintained during treatment to avoid an excessive number of fields, excessive irradiation duration or varying patient positioning).The computer then calculates a determined number of loops and optimises the physicist’s first proposition. This inverse calculation should, in theory, strongly reduce parasitic doses to organs at risk and allow an increase in the dose to the tumour.
By multiplying the number of fields (which can be directly set between the computer and the accelerator) and by modifying the irradiation volume, this inverse calculation can define very complex irradiation volumes (see an example for cervical nodes with dosimetry in sagittal and coronal views.
These techniques are used for complex irradiation with a curative intent or when second or further irradiation treatment becomes necessary.
Treatment execution and control
A further set of technical modifications during irradiation have also resulted in considerable progress.Transmission of irradiation data
The setting up of a computer network within the radiotherapy unit allows accelerator control via programs which take into account the various calculations explained above. This offers improved security levels for patient treatment:checking of patient position through more elaborated techniques than the laser beam alone,
checking of accelerator arm position,
checking of the positions of each of the collimator leaves,
more accurate checking of irradiation duration for the various fields,
continuous recording of all treatment components.
Control of fields using the portal imaging system
Accelerators produce beams which cross the patient and can be assessed either by radiographic images or by using numerical systems called portal imaging.The images obtained during treatment can therefore be compared with those obtained during treatment preparation ('digitally reconstructed radiographs'). Such controls have revealed minor variations in patient positioning that were previously unknown.
The electronic measurement of radiation beam intensity observed after crossing the patient enables the calculation of a quasi 'in vivo' dosimetry using scanographic calculations. Such calculations are much easier to achieve than those obtained using a small dosimeter placed on the patient's skin (see page on total body irradiation).
In summary:
All of these techniques reinforce the security of irradiation treatment and increase its technical possibilities. The only limitation is due to the beam itself which will always cross the patient before and after the tumour and will therefore deliver a parasitic dose, even if we endeavour to reduce it to a minimum.Hence the relevance of combining these classical radiotherapy techniques with other techniques either using different beams (protons, neutrons, ions), perisurgical irradiation or brachytherapy which are all methods capable of concentrating supplementary irradiation within a small volume.
Treatment supervisio:
This supervision concerns the technical conditions of irradiation, its tolerance and its efficiency as judged by physicians.
Supervision of the technical conditions of irradiation
Clinical supervision
- The correct functioning of irradiation generators is the work of medical physicists and electronic engineers who work within the radiotherapy unit.
- § The control of treatment duration and dose delivered for each fraction is ensured by the computer system linked to the accelerator.
- The good positioning of the patient and the beam is verified by the radiotherapist at the first treatment session using specific radiographic images (gammagraphies) or the portal imaging system.
- During the various treatment sessions, the technician plays a major role in repeating the radiotherapist’s explanations in order, to accurately install the patient according to the therapeutic planning, and to reassure him/her during installation and just before leaving the treatment room for the control visual display room in order to begin treatment.
Patient supervision throughout radiotherapy treatment is part the radiotherapist’s job, together with the prescription of necessary adjuvant treatment:
The interruption of irradiation can be necessary in the case of major intolerance.
- At the first consultation, at the beginning of treatment, the treatment modalities should be fully explained to the patient as well as the most frequently observed side-effects. Anxiety and depression should be considered and treated, hospitalisation should be envisaged in case of poor tolerance and advice on diet and hygiene should be given. The patient should be weighed regularly. The tumour should be described with great precision in order to obtain a reference for the appreciation of treatment efficiency.
- The following consultations should be planned every week. Their goal is to appreciate the patient’s general treatment tolerance (weight, general status, haematological toxicity), local tolerance (with prescription of appropriate treatment in the case of acute local reaction). The radiotherapist will also appreciate the tumour regression and discuss with the patient any potential psychological difficulties. If necessary (and in particular for head and neck cancers) dietary follow-up will be set up.
After completion of radiotherapy, a precise report should detail the doses delivered, the technique used and the tolerance observed and should be sent to the various physicians involved in the patient ‘s treatment and follow-up.
Late reactions :
Sequelae and late reactions typically occur at least six months after completion of irradiation, i.e. when acute reactions have been healed.
Whereas sequelae are unavoidable because inherent to treatment, late complications can be prevented when certain favouring factors can be avoided.
After head and neck irradiation
Hyposialia
It is both an acute reaction and a late sequela.
It is clinically manifested by xerostomia with difficulties in speaking and to swallowing. Its intensity is correlated to the irradiated volume of the salivary glands. Potential, although usually very partial recovery may be observed after a few years for doses lower than 40 Gy, but this recovery is purely quantitative. Qualitatively, the saliva never recovers its original properties after irradiation (alteration of buffer properties, diminution of anti-bacterial power by diminution of lysozymes and IgA). Hyposialia therefore predisposes to mouth infections and tooth decay.
The symptomatic treatment associates mouth washing with bicarbonate solutions and antiseptics and, if necessary, antifungic agents. The use of chewing-gum may facilitate salivation and the use of artificial saliva and water sprays can improve local comfort. The cessation of alcoholic and tobacco intoxication is essential.
Dental sequelae
They concern all teeth, be they situated within the irradiated volume or not.
They often begin in the form of decay at the tooth neck, principally for incisors and inferior canine teeth; occasionally, a dentine lesion can be seen with a fracture of the tooth neck or a blackish coloration of the irradiated tooth (ebony teeth)
The pathogenesis of such dental lesions can be the direct result of a radio-induced modification of the micro-circulation of the tooth pulp, or indirectly related to modifications in saliva (as seen above), with an acidification which promotes the development of decay bacteria, the reduction of the fluorine concentration and a diminution of enamel resistance.The treatment of these tooth alterations is above all preventive. Prior to irradiation, it is essential to;
- restore as healthy a buccal cavity as possible
- extraction of invaded or decayed teeth or teeth with major paradentitis,
- treatment of the teeth which can be conserved and will be secondarily used for prosthetic rehabilitation after treatment,
- tooth scaling,
- temporary ablation of bridges, which constitute supplementary irritation factors during irradiation.
- begin the withdrawal of tobacco and alcohol
- sensitise the patient to the importance of
A dental prosthesis will be fitted 8 to 12 month after radiotherapy.
- the maintenance of good mouth and tooth hygiene by regular brushing and antiseptic mouthwashes,
- daily fluorination to the end of life, by the use of a fluorine gel drip, applied 5 minutes per day. Since fluorine is not swallowed, no secondary fluorosis will occur.
Submental oedema
which induces a permanent crop.
Neck sclerosis
- characterised by the 'hardback' aspect of irradiated skin,
- it can be associated with telangiectasia
- its intensity is related to previous surgery (such as node dissection) or high radiation doses.
Trismus
Trismus is secondary to irradiation of the temporomandibular articulations and of the masticator muscles. It can be reduced by daily remedial mandible gymnastics.
After pelvic irradiation
- Castration among women after 12 Gy, in relation to the great sensitivity of the ovaries, which increases as the patient approaches menopause
- Temporary sterility for men after 5 Gy, definitive after 20 Gy, if the testes are in the irradiated field
- Vaginal dryness
- Impotence caused by the destruction of the pudental nerve
- Lymphoedema of the inferior limbs particularly when irradiation follows a lymphadenectomy
After irradiation of the limbs
- Stiffness caused by fibrosis of the joint capsule
- Muscle and skin fibrosis
- Skin atrophy and dryness
Radio-cancers
Radiocancers (such as osteosarcoma, spinal cell carcinoma) arise after an often very long latency period of ten years or more, preferentially in zones bordering the irradiation fields.However the risk is low, evaluated at less than 1%; the incidence dramatically increases with associated chemotherapy reaching 8 to 10% in patients with Hodgkin’s disease treated by an association of radiotherapy and chemotherapy (the MOPP regimen).
Osteoradionecrosis :
The sequelae described below are late complications of radiotherapy which occur with a low incidence and necessitate preventive measures during the execution of radiotherapy. Certain are not totally avoidable and constitute 'therapeutic hazards'.
Mandible bone radionecrosis (osteoradionecrosis)
In two thirds of cases, osteoradionecrosis of the mandible appears between 6 months and 5 years after irradiation, but its incidence remains low (5 to 10% of patients). It is related to the post-actinic sclerosis of the terminal branches of the inferior dental artery which is the only artery vascularising the mandible.Certain favouring factors, can be clearly identified thus enabling prevention:
Clinically the patient has localised pain. The radiography shows a heterogeneous and progressively extending bone demineralisation. At a later stage, the pain becomes very intense and is often increased by associated infection and inflammatory oedema. A gum breach appears through which small dead bone fragments are eliminated.
- dose higher than 60 Gy in a large mandible volume,
- extensive tooth decay,
- gum stripping caused by premature irradiation before sufficient healing after tooth extraction,
- advanced periodontal disease,
- tooth extractions complicated by alveolar infections or carried out in an irradiated mandibular region,
- interstitial brachytherapy without lead protection of the mandible.
Radiologically, an osseous sequester can be observed in the middle of a demineralised bone.
Treatment is very long and can sometimes take years, associating analgesics, anti-inflammatory drugs, antibiotics and, for many authors, hyperbaric oxygen therapy. Repeated oxygen inhalation stimulates local angiogenesis, thus favouring tissue re-oxygenation and healing. A surgical procedure may be necessary to remove a necrotic bone fragment.
Other osteoradionecroses
Other bones may be the site of osteoradionecrosis :- thoracic rib necrosis after mammary irradiation (using old techniques),
- hip osteoradionecrosis after pelvis irradiation (a form of rapid destructive coxarthrosis) requiring special hip prosthesis .
This complication mainly concerns head and neck radiotherapy.
It appears either after superficial ulceration or on an apparently healthy mucous membrane.
Its favouring factors are:
Clinically, it is a painful ulceration which is more or less necrotic with an indurate base which can spread in depth and cause bone denudation.
- poor nutritional status,
- continuation of tobacco and alcohol intoxication,
- local irritating factor or repeated local traumatisms (tooth with a cutting edge, poorly adapted bridge.
Treatment involves an association of antibiotics, analgesics, and anti-inflammatory drugs over several weeks. In the case of persisting progression, biopsies are necessary in order to eliminate the possible non sterilisation of the initial tumour, however biopsy may extend necrosis. In the case of histologically proven radionecrosis with resistance to medical treatment, electrocoagulation or a large excision are possible when necessary.
Other mucous radionecroses may be observed:
- on the oesophageal mucosa (with risk of fistula)
- on the stomach wall (ulceration - perforation)
- in the small intestine,
- in the vagina (for very large transfixing tumours with risk of cloaca)
Radiation myelopathy :
Although, fortunately, this complication rarely occurs, radiation myelopathy is one of the most serious radiotherapy complications and concerns the treatment of head and neck cancers or spinal metastases. This complication can be avoided if the radiotherapy technique is perfect.
Clinical manifestations
Clinically various presentations may occur:Isolated Lhermitte's sign
This is one of the most frequently observed manifestations. The patient describes, more or less early on (a few weeks or a few months after irradiation) dysesthesia resembling electrical shocks starting from the neck and irradiating to the four limbs during flexion movements of the neck. In most cases, spontaneous resolution occurs within a few weeks. However, rare cases develop Brown-Sequard syndrome.
Brown-Séquard syndrome
After a period of 6 to 18 months, early signs appear such as paresthesia (prickling, burning) or hypoesthesia involving superficial sensitivity, generally asymmetrical in one of the superior limbs.
Hemiplegia then develops on the face with diminution of deep sensitivity on the same side and loss or diminution of superficial sensitivity on the opposite side
Evolution is the worsening of motor disorders leading to tetraplegia and associated sphincter disorders.
Other clinical presentations
- Predominant symmetrical motor weakness, such as tetraparesia leading to tetraplegia,
- Amyotrophy, for example pseudo amyotrophic lateral sclerosis, with weakness in the extremities and pyramidal syndrome.
Pathogeny
Radiation myelopathy appears to be the result of both an indirect mechanism involving lesions of the arterioles and intramedullary capillaries, and a direct mechanism involving lesions of glial cells and neurones. Since spinal cord vascularisation adopts an alternate disposition in a given zone, the spinal cord may be less vascularised on one side, thus explaining the frequently assymetric clinical picture, at least in the early stages.The diagnosis of radiation myelopathy in a patient with recent irradiation of the neck region should be considered. However, diagnosis should be confirmed by the radiotherapist after a clear dosimetry revision and after eliminating other differential diagnoses via imaging techniques.
It is important to search for a different aetiology in order to ensure efficient therapy.
- In first instance, taking into account the previous cancer, a spinal or lepto-meningeal metastasis should be looked for, RMI being one of the most efficient examinations currently available.
- Non neoplastic myelopathies such as cervicarthrosic myelopathy, multiple sclerosis, syringomyelia... should then be eliminated.
It will, in fact, reveal the various pathologies mentioned above. In radiation myelopathy, RMI shows either a normal, an enlarged or an atrophic cord with contrast enhancement at the lesion. However, the image is not very specific.
The cause of such myelopathy is generally a small technical error such as the overlapping of two joining fields giving a higher dose at the overlap. Occasionally, the repeated study of the radiotherapy information contained in the medical file does not offer any explication. However, the technician may have reported difficulties in maintaining the patient still in the correct treatment position for each session, hence suggesting that the spinal cord may not always have been correctly protected in spite of rigorous preparation.
Treatment
The treatment of radiation myelopathy should be, above all, preventive:Once myelopathy has developed, the usual treatment involves corticosteroids to reduce the oedema which has a worsening effect on lesions, followed by nursing and physiotherapy.
- by respecting the tolerance dose of 45 Gy to the spinal cord with usual fractions of 2 Gy and by modifying the technique if the cord is at risk (multifield treatments),
- by avoiding, as much as possible, joining fields (for instance when treating two spine metastases),
- by treating patients with the best fixation techniques available, for instance with personalised thermoformed fixations, possibly with light sedation in order to ensure that the patient remains calm and still.
Improved irradiation techniques should reduce the incidence of such dramatic complications to zero.
| Mediastinal complications: |
These complications occur after irradiation of the mediastium or the lung.
It can be observed after an acute pericardial reaction which occurs at the end of irradiation. It involves typical clinical symptoms including precordial pain, dyspnoea, pericardial friction rub, elevation of the ST segment at electrocardiogram and normal chest X-ray. Ca125 may be increased in a non-specific manner. Vigorous anti-inflammatory treatment generally avoids progression to chronic pericarditis.Chronic actinic pericarditis
Chronic pericarditis is most often constrictive with important fibrosis (like in tuberculosis pericarditis) rather than with important pericardial effusion. Calcifications and thickening of the pericardium are often observed. The clinical manifestations are those of a difficult venous return to the right (similar to the symptoms of a pericardial tamponade).
Such complications occur when the heart is more or less in the irradiation field and has not been sufficiently protected during irradiation. In breast cancer, this complication is exceptional, even when irradiating internal mammary nodes, since specific masks are set up in order to protect most of the pericardium.
Chronic radiation lung
Pulmonary lung sclerosis only concerns the irradiated zone. It is extremely rare, even for high doses and very limited irradiation volumes (for instance for a small tumour in the lung, for the irradiation of a unique metastasis or for the tangential irradiation of breast carcinoma, even if the local dose may be as high as 50 Gy. The surrounding lungs are in fact well protected by masks.
However, in the case of total body irradiation (for instance in preparation for allogenic marrow graft for acute leukaemia, the dose to the lung is generally diffused to the whole lung and could lead to severe pulmonary sclerosis. However, generally speaking, the 20 Gy necessary to develop sclerosis are never delivered.
Symptomatology of such sclerosis is a restrictive syndrome by modification of type II pneumocytes.
Its treatment relies on corticosteroids which are very efficient if they are administered at the onset of the disease..
Abdominal and pelvic complications :
Chronic actinic ileitis
Actinic ileitis generally occurs at distance from irradiation of a pelvic (more rarely intestinal) tumour. Its manifestations are: transit disorders (König’s syndrome) with diffuse pain, then alternation of constipation and profuse diarrhoea. As the disease progresses, important atrophy of the villosities is observed with malabsorption disorders, a blind loop syndrome and various general deficiencies (hypoprotidaemia, massive oedema).Among the favouring factors are the radiotherapy dose, any previous surgical procedures on the abdomen (which creates fixing of intestinal loops by adherence and increases the risk of one particular fixed loop) and association with chemotherapy.
Sometimes, a more or less complete ileus (intestinal obstruction) may lead physicians to consider the necessity of a rapid surgical procedure or tumour relapse. Frequently, symptomatic medical treatment including digestive aspiration, parenteral rehydration, analgesics and antispasmodics will enable the patient to recover a normal transit.
The radiography of the small intestine shows multiple level stenoses, with many atrophic villosity zones.
Laparotomy should be avoided when possible since the surgeon will discover a jumble of glued loops which are difficult to dissect and he will be obliged to proceed to mutilating intestinal excisions.
Occasionally, a complete ulceration may be found in one intestinal loop generating peritonitis and necessitating surgical procedure.
Actinic cystitis
There are four forms of late complication of radiation on the urinary bladder:Fistulae which are rare and will be treated in the palliative care chapter.
The symptoms of actinic cystitis are bladder irritation (hypogastric pains, pollakiuria, urgencies) and by haematuria. The cytobacteriological study of urine is negative. The clinical examination is normal. The pyelogram shows an inflammatory bladder. Cystoscopy reveals a frosted yellowish mucosa, with scattering haemorrhagic telangiectasia and torpid ulcerations with swollen borders. The use of bladder biopsy should be limited to cases with suspicion of cancer relapse (otherwise biopsy is likely to provoke haemorrhaging and fistula). The treatment of such cystitis is difficult and long and includes only symptomatic drugs.
Haematuria is of variable abundance: either moderate of a vesical type (i.e. terminal) or abundant and total with clots. When it is abundant, it is advised to avoid any local treatment or biopsy. When haemorrhages are very abundant or when there are several clots, bladder irrigation is installed in order to remove clots and wash the bladder with cold solutions. Occasionally, certain bleeding lesions can be electrocoagulated. However, cystitis is generally spread over the surface and urinary derivation may be necessary; arterial embolisation has occasionally been proposed with success.
Vesical retraction occurs many years after external radiotherapy. It involves intolerable discomfort (hypogastric pain, urgency, painful micturitions every thirty minutes or sometimes more frequently, in particular during the night, incontinence).The high urinary apparatus is also disturbed with renal insufficiency. The bladder capacity is reduced to less than 50cc. Diagnosis is simple using pyelography. Generally, the pelvic examination reveals a frozen pelvis. Cystoscopy shows an atrophic, frosted, bleeding mucosa with oedema and pseudo-tumour aspects. The enlargement of the bladder capacity by an intestinal graft is extremely difficult to perform in an irradiated pelvis. A transintestinal derivation may offer a solution if the functional disturbance becomes intolerable or when renal insufficiency becomes a genuine problem.
Ureteral post-radiotherapy stenosis
This is a relatively frequent complication of the irradiation of cervix uteri carcinoma which necessitates rather high doses around the cervix: 60 - 80 Gy).The lower ureter crosses the arteries close to the cervix and can become sclerotic with an upstream dilatation of the pyelic ureter.Surgery is among the favouring factors of ureteral stenosis, since it removes ureteral vascularisation and nerves thus rendering it fragile. The simultaneous use of chemotherapy also increases the risk of fibrosis.
Stenosis concerns the two last centimetres of the ureter when it is caused by brachytherapy, and can be more important spreading as far as the superior limit of the field when it is caused by external raditotherapy.
The histological study of stenosis reveals an obliterating endarteritis (typical of irradiation), then sclerosis with calcium depositions and complete fibrosis.
Therapy should be active. When possible, the use of endoprosthesis should be preferred (known as double J prosthesis) either by cystoscopy or by interventional radiology through the pyelic cavity. The prosthesis will progressively calibrate the ureter and avoid renal insufficiency. Surgical reimplantation is often very difficult due to major local sclerosis.
Actinic rectitis
Chronic post-radiotherapy rectitis can occur even if the patient suffered no acute rectitis during radiotherapy. The usual delay for its appearance is 6 to 14 months, but some late forms have been described. The occurrence of this complication is directly related to the dose received by the rectum (> 50 Gy) and the importance of the rectal surface receiving this dose (particularly after irradiation for prostate carcinoma).
The main symptoms are defecation difficulties, urgent needs, small faecal incontinence due to unrecognised flatulence, very foul-smelling gas, rectal discomfort, unexpected diarrhoea and rectal haemorrhages accompanying stools. Sometimes this rectal discomfort may become very invalidating rendering social life quite impossible. More rarely, low occlusion syndromes may be observed.
The macroscopic aspect of the rectum on rectoscopy is of small, more or less bleeding telangiectasies. Biopsies should be avoided since they are difficult to heal and may favour the apparition of fistulae (rare).
Treatment is difficult: endorectal corticosteroid washing, salicylates, coagulation with Argon laser, hyperbaric oxygen therapy.
It is therefore clear that prevention is the best way to avoid such complications for our patients.
Therapeutic associations :
Radiotherapy is generally associated with surgery and/or chemotherapy and/or hormonotherepy.
Exclusive radiotherapy
Except in palliative situations, radiotherapy may be the exclusive treatment of a few very limited cancers: skin cancer, head and neck cancer, prostate, cervix uteri cancer, anal canal cancer or Hodgkin’s disease.
Associating surgery and radiotherapy
This is the most frequent association for localised cancers.As post-operative adjuvant treatment
In order to diminish the risk of local relapse, as soon as surgical healing is obtained, approximately one month after the surgical procedure.
A classical example: breast radiotherapy after lumpectomy (even if adjuvant chemotherapy is planned).
Other examples: cervical radiotherapy after head and neck surgery, brachytherapy after endometrial cancer.
Pre-operative treatment
This treatment is instituted to reduce the risk of per-operatory tumour graft or to reduce the size of tumours in order to render them surgically excisable. Up to the second month after radiotherapy, post-radiotherapy fibrosis is moderate and is not a real obstacle to safe surgery.
A classical example: pre-operative rectal irradiation.
Associating radiotherapy and chemotherapy
In general, chemotherapy is instituted when tumours have a great dissemination potential, but it can also be proposed in order to reduce the tumour volume before any surgical or radiotherapy procedure when the tumour is known to be chemosensitive.
Irradiation is therefore limited to the initial tumour location.
These associations may also increase the toxic effects of both treatments: haematological toxicity, cardiac toxicity, pulmonary toxicity (cf. the specific toxicities of chemotherapy drugs).
The association of radiotherapy and chemotherapy should not only provide additive effects but also synergistic activity.
New protocols have been set up (still more or less as experimental studies) in order to improve local control and to avoid important surgical mutilation:
A noteworthy association of radiotherapy and chemotherapy is prescribed for anal cancer with the FUMIR protocol (5-FU, mytomycin, radiotherapy) or FUPIR (5-FU, cisplatin, radiotherapy) which offer spectacular recovery of this cancer without anal amputation and with conservation of normal anal function. In many cases, these protocols also prove to be efficient for inguinal metastatic nodes of anal cancer.
- association of chemotherapy and radiotherapy in oesophageal cancer,
- association of radiotherapy, brachytherapy and chemotherapy for advanced cancers of the cervix uteri, in order to avoid mutilating pelvectomy,
- association of radiotherapy and chemotherapy in bladder cancer in order to avoid cystectomy,
- association of radiotherapy and chemotherapy in small laryngeal cancers to preserve the voice.
Associating radiotherapy and hormone therapy
It is standard to use anti-oestrogens as adjuvant chemotherapy for post-menopausal breast cancer or medical castration for pre-menopausal breast cancer with positive receptors. However, it has not been demonstrated that the use of hormonal treatment potentialises radiotherapy.Recently, trials in prostate carcinoma have shown that associating medical castration with radiotherapy had a synergistic effect on radiotherapy for locally advanced disease, with increased disease-free survival and, nowadays, increased survival (RTOG trial, Bolla trial). Other trials have since been set up for less advanced cancer disease.
Total body irradiation
After ablative chemotherapy of acute leukaemia and before allograft, the patient receives total body irradiation in order to avoid graft rejection. The patient receives a dose of 8 Gy (which represents a lethal dose if the patient is not rapidly grafted). This irradiation allows the destruction of the remaining autologous medullar cells which may reject the graft. The tolerance of such irradiation is very poor (as it is for many other aspects of leukaemia treatment).Notions of brachytherapy:
Basic principles
Brachytherapy consists in the use of radioactive sources to deliver radiotherapy inside the tumour.
The great difference compared to external radiotherapy is that the photon irradiation begins its path through the tumour where its activity very quickly decreases before irradiating adjacent healthy tissues.
The apparition of easy to handle radioelements (such as Iridium 192 or Caesium 137) and the post-loading technique enabled the rapid development of brachytherapy. First of all, hollow catheters or vectors (without any radioactivity) are placed within the tumour under local or general anaesthesia. When their correct position is checked and when dosimetry confirms a regular dose distribution, the catheters are then charged with radioactive elements.
The major advantage of brachytherapy is the possibility to deliver high doses in small volumes with, at least in theory, no parasitic dose to the surrounding organs. This requires extensive experience in order for the radiotherapist to correctly insert the catheters as well as accurate dosimetry. The initial 'surgical' nature of this irradiation requires detailed patient information and explanation.
The Paris system
Originally described by B. Pierquin and then improved by a number of radiotherapists, this system allows the irradiation of tumours of varying shapes and volumes. It consists in inserting parallel tubes. The radiotherapist chooses the number, the position and the space between the catheters so that the treated volume corresponds to the tumour volume.
In simple terms, if the volume to be treated is small, few catheters separated within small spaces will be inserted; if the volume is significant, many catheters will be inserted with a slightly larger space between them.
Homogeneous irradiation is difficult to obtain: the dose is higher in the immediate vicinity of the sources and lower at a distance.
The lines should therefore be parallel, on the same surface, equidistant and each source should have an identical irradiation rate (or kerma flow).
The irradiation duration is calculated according to the source activity, the desired dose and the risk of overdosing.
Various methods of brachytherapy
low rate brachytherapy
This is the standard brachytherapy with an irradiation duration of 1 to 5 days, with a low dose rate (30 to 100 cGy/hour). The dose at the contact of the source is high but quickly decreases (within a few mm) in inverse proportion to the square of the distance, thus allowing excellent protection of healthy surrounding tissue.
Patients should remain bedridden for a few days in lead-walled room; the use of source storage devices (curietrons) enables the improved protection of hospital personal when administering the necessary hygiene care during such prolonged treatment.high rate brachytherapy
This technique uses sources with elevated radioactivity thus reducing the irradiation time and, consequently, patient immobilisation. The session is performed within a blockhouse quite similar to those used in standard radiotherapy and using the same radioprotection measures.
Patients are 'charged' during a short period of time, and for certain tumours, they can return home (for instance in irradiation of the vaginal cuff after radical hysterectomy for corpus uteri cancer) or to a normal hospital room, between the irradiation sessions, with the non-radioactive implants still within the tumour.pulsed brachytherapy
This technique uses a very active point source which moves inside the catheters and stops for various periods of time at different places, according to the dose calculation. The longer the source stays in a position, the higher the irradiation will be around this position. The dose can therefore be completely adapted to the tumour (as in conformational radiotherapy). Pulse brachytherapy is a low rate brachytherapy.
This technique necessitates very sophisticated programs to calculate the movement of the source within each catheter and a special device to drive the source into its various positions.permanent implants
This technique has been developed for prostate cancer and uses 125Iodine . The application time is infinite since the small implants are inserted and then left inside the prostate. Dose calculation depends on the initial dose and on the half life of the radioactive element. With 125Iodine, 50% of the initial dose is delivered over the first 60 days, 75% over 120 days and 87% after 180 days.
Association with other treatments
Brachytherapy is often only part of the treatment.
Most often, it is associated with surgery (for of the majority of gynaecological tumours), with external radiotherapy (in gynaecology or for prostate cancer) and more recently with chemotherapy (potentialisation of radiotherapy).
Some clinical applications of brachytherapy :
Many accessible superficial tumours can be treated by brachytherapy.
Skin tumours
A skin cancer which is too large for surgery (i.e. the excision of which would be mutilating) or for contact radiotherapy (which would be too superficial) is a good indication for brachytherapy.
Here are a few examples:
lip cancer
eyelid cancer, which requires specific protection of the crystalline lens,
penis cancer, technique which avoids penis amputation with its severe psychological consequences.
Breast cancer
Some authors use this brachytherapy technique for breast carcinoma, for particularly large tumours, for simple lumpectomy and for patients who refuse mastectomy
The aesthetic results are often satisfactory.
Gynaecological cancers
They constitute the major indication of brachytherapy for cervix uteri and corpus uteri cancers. Treatment can be adminstered before surgery (with the cervix as the centre of the treatment), after surgery (vaginal cuff irradiation) or after external radiotherapy in order to obtain a higher localised dose.
preparation of gynaecological brachytherapy
application of gynaecological brachytherapy
Prostate cancer
Very recently, prostate tumours have been a subject of great interest for brachytherapy radiotherapists. The goal may be either to administer an overdose during external prostate radiotherapy whilst protecting surrounding organs, or to treat the entire prostate volume without any external radiotherapy.
One of the preferred techniques involves definitive implants of 125Iodine,
requiring the insertion, under general anaesthesia, of small implants, the radioactivy of which will progressively decrease in the treated patient,
who returns home the day after the implantation of definitive implants with simple advice for protecting his family circle.
Another technique uses temporary low rate implants with external therapy (We have taken the example of a technique set up by Dr Brune - Radiotherapist at the Centre François Baclesse)
Another technique uses temporary high rate implants with external radiotherapy (another technique set up by Dr Brune in our Institute)device for catheter implantation,
application of prostate brachytherapy,
dosimetry control.
Another technique would be to use these temporary implants as a unique treatment:high rate irradiation of prostate cancer
Bronchial carcinoma
High rate brachytherapy enables the administration of a supplementary 'boost' for tumours of the proximal bronchi, whilst protecting the surrounding normal lung tissue.
It can also endeavour to free the proximal bronchi from obstructing tumours, to reduce the risk of massive haemoptysis when surgery or external radiotherapy are no longer feasible.
The catheters are installed (generally two or three) using a bronchial fibroscope, and they guide the radioactive source which is then pushed (by the machine) to the required distance. Control radiographies verify the correct positioning of the catheters and the source.
Oesophageal cancer
This technique is rarely used in oesophageal cancer, but it may be interesting for clearing this tube. It requires the installation of an a intraoesophageal probing sound which maintains the radioactive source at a certain distance from the oesophageal mucosa.
Maxillary cancers
Mouth cancers, in particular maxillary cancers, are difficult to treat. When they relapse or when they are very close to the teeth, high rate brachytherapy protected by a cast adapted to the maxillary tumour can prove to be an efficient technique for preserving teeth.
Other tumours
Other tumours might also benefit from brachytherapy (for instance: a tumour of the tongue, of the cheek or large head and neck tumours.The radiotherapist’s ingenuity and accurate dose calculation are probably the two most important aspects.
Irradiation by other particles:
Hadrontherapy groups together the utilisation of particles of the physical family of hadrons: protons, neutrons, pions and, by extension, ions.
The great mass of these particles (compared to photons or electrons), their charge or absence of charge together with their interaction with matter confer them with specific characteristics (biological and ballistic) which may be very useful in radiotherapy.
Protons
Protons interact with nuclei (nuclear interactions) and to a greater extent with electrons (electronic interactions).As they are slowed down by their energy loss due to such interactions, the energy deposit per depth unit (or TEL) increases until the particle comes to a halt. There is therefore a sudden peak of energy (Bragg peak), situated at a depth which is in relation to the original energy. The skin dose to tumour dose ratio is approximately one to four.
 |
Diagram of the energy deposit of electrons, photons and protons. It is clear that almost the entire energy of protons is liberated in a very narrow peak known as the Bragg peak. |
Protons can be produced by cyclotrons: they are injected at the centre of a magnet and are accelerated by magnetic and electric fields. Synchrotrons allow the variation of the proton energy. Protons are then reunited by several magnets in a quality beam to the irradiation target either via a direct beam or an isocentric gantry.
Main indications of protons are:
- choroidal melanoma,
- chordoma, chondrosarcoma of the skull base or cervical spine,
- childhood cancers,
- meningioma inaccessible to surgery.
Neutrons
Neutrons are particles with indirect ionisation power. They interact with nuclei (elastic and inelastic diffusion, nuclear reactions, captures), which produce the emission of secondary charged particles (like protons, alpha particles of nuclear fragments heavier than carbon, oxygen, nitrogen or hydrogen) which are responsible for tissue ionisation and for the biological effect. |
| Interactions of neutrons with matter. Above: elastic diffusion with production of a proton and another neutron. Below: collision of a nucleus with the production of various charged particles: protons, nuclear fragments, electrons. |
The production of neutrons is based on cyclotrons which accelerate either deuterium (maximal energy 50 MeV) or protons (maximal energy 65 MeV) which collide with a target in beryllium producing a spectrum of neutrons.
There are very few indications for neutron therapy:
Another promising technique which is still in progress is therapy using boron neutron capture (BNCT): the tumour is saturated with 10B atoms because of the administration of boron to the patient. Neutrons are electively stopped by the boron, provoking a local nuclear fission in two atoms of 7Li and 4He.
- tumour of salivary glands (adenoid cystic carcinoma)
- radio resistant glioblastoma, in relation to important necrosis.
This kind of experimental treatment is studied for highly radioresistant tumours such as brain glioblastoma.
Ions
They combine the ballistic properties of protons (energy deposit with Bragg peak, low lateral dispersion) and the biological properties of neutrons (elevated TEL, no oxygen effect): generally speaking, hadrontherapy involves treatment by ions.Ions may be light like carbon, oxygen or even neon or they may be heavy such as argon or silicium.
Several studies are in progress. The French government has decided, within the framework of its cancer plan, to build an experimental facility in Lyon, although another project exists in Caen, within the vicinity of a Heavy Ion Facility (GANIL). Other countries already possessing or currently building hadrontherapy facilities are Japan, Germany, Italy and Austria.
The production of light ions requires the presence of a synchrotron to accelerate the ions using various energies. Many technical difficulties remain such as the construction of an isocentric gantry (as in standard radiotherapy).
The tumour margin may be accurately drawn by the beam using active raster scanning: every point of the tumour slice is treated (i.e. the Bragg peak targets this point), then another slice is treated by varying the beam energy.
 |
Principle of raster scanning: in [1] each tumour slice is scanned by the Bragg peak and receives high and precisely localised energy. The lateral and vertical movements are brought about by variations in electromagnetic fields. In [2], once the slice treated, the beam energy is modified and another slice is treated. |
The potential indications of this treatment would be:
- tumours of the base of the skull,
- facial sinus tumours,
- meningeal tumours inaccessible to surgery,
- paraspinal tumours,
- deep sarcoma,
- and perhaps many forms of radioresistant tumours.
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