Radiotherapy Is the Second Method for Treating Cancer (Through Ionizing Radiations)

Cancer Radiotherapy Radiotherapy is the second method for treating cancer (through ionizing radiations)

•External radiotherapy : irradiation source is situated outside the patient (RX devices, cobalt, accelerators),

•Brachytherapy : radioactive sources are situated inside the patient

* sealed sources : ‐intersticial brachytherapy : sources placed inside the tumour

‐ endocavitary brachytherapy : sources inside natural cavities where tumours develop

* non sealed sources: ‐radioactive compounds are injected for particular tumours : I 131, P32, St189, ..

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 Some historical data on radiotherapy

1895: Wilhelm Conrad Röntgen in Würzburg ((y)Germany) discovers X‐rays. 1895: First therapeutic attempt to treat a local relapse of breast carcinoma by Emil Grubbe (Chicago) 1896: Discovery of natural radioactivity by Henri Becquerel in Paris 1896: First use of X‐Rays for stomach cancer by Victor Despeignes (Lyon ‐ France) 1896: Irradiation of a skin tumour in a 4‐year‐old by Léopold Freund (Vienna ‐ Austria) 1897: Thomson identifies the electrons for creating X‐Rays 1898: Discovery of radium by Pierre Curie and Maria Sklodowska Curie in Paris 1899: First real proof of cure by X ‐Rays ( two pictures taken at an interval of 30 years) 1901:First thiherapeuticuseof radium for skin 'bhhbrachytherapy' byDrDanlos (ôi(Hôpita l Saint‐Louis ‐ Paris) 1903: First scientific description of the effect of radiotherapy on lymphoma nodes (Drs Senn et Pusey) 1904: First treaty on radiotherapy by Joseph Belot in Paris 1905: Discovery of the sensitivity of seminoma to X‐Ray by Antoine Béclère in Paris 1913: Institut du Radium by Maria Sklodowska Curie and Claudius Regaud 1915:The atomic model by Ernest Rutherford (Cambridge ‐ UK) : radioactive active desintegration ‐ Development of RX tubes 1920: Structuration of French Radiotherapy by Maria Sklodowska‐Curie: Institut du Radium Some historical data on radiotherapy

1921: FdtiFoundation of the ItittInstitut du Cancer in Ville ju if (Ins titu t 'Gust ave Roussy' ‐ whowas a pathologist) with the brachytherapy unit of Jean Pierquin, Georges Richard and Simone Laborde. 1930: Institut Curie works on fractionation (Claudius Regaud, Henri Coutard, Antoine Lacassagne). 1932: Discovery of neutrons by Sir James Chadwick (Cambridge UK) 1934: Death of Marie Curie from pernicious anaemia (myelodysplasia) 1934:Discoveryofartificial radio‐elements by Irène and Frédéric Joliot‐Curie (Paris) 1934: Publication of 23% cure rate in head and neck cancer by X‐Rays ( Dr Henri Coutard ‐ Institut Curie) 1936:FrançoisBaclesse (Institut Curie) begins his work on conservative treatment of breast cancer 1948: first ZOE nuclear reactor (Frédéric Joliot) : productions of artificial radioelements 1951: First cobalt installation (Victoria Hospital ‐ London ‐ Ontario) 1952: First linear accelerator (Henry S. Kaplan in Stanford ‐ California) 1960: The 'Paris system' for brachytherapy with afterloading (Bernard Pierquin) 1973: Scanner invention par G.N. Hounsfeld (UK) 1990: First use of scanner and computers for IMRT 2000: One/two cured cancer patients owes recovery, partly to radiotherapy 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 bases of radiotherapy Physical fundamentals of radiotherapy

Classification of ionizing particles used in radiotherapy

Several types of ionizing radiations :

Non charged ionizing radiations Electromagnetic radiations Particule radiation: neutrons

Charged ionizing radiations β – Radiation Accelerated electrons α‐Radiation Protons Light ions Physical fundamentals of radiotherapy Non charged ionising radiations iiiionizing partilicles or photons

1.Electromagnetic radiation:

‐X photons emitted during the rearrangement of electrons: X‐Rays tubes, accelerators;

X‐ray tube is a vacuum tube ttathat pr oduces X‐rays They are used in X‐ray machines. X‐rays are part of the electromagnetic spectrum an ionizing radiation with wavelengths shorter than ultraviolet light

A high voltage power source, for example 30 to 150 kilovolts (kV), is connected across cathode and anode to accelerate the electrons. The X‐ray spectrum depends on the anode material and the accelerating voltage . ‐. Coolidge tube, (hot cathode tube), is the most widely used. Very good quality vacuum (about 10‐4 Pa, or 10‐6 Torr). electrons produced by thermionic effect from a tungsten filament heated by an electric current. The filament is the cathode of the tube. The high voltage potential is between the cathode and the anode, the electrons are thus accelerated, and then hit the anode.

http://www.oncoprof.net/ ‐γ photons emitted during nuclear disintegration: ‐ 60Cobalt source,192 Ir wires, 137Cs wires are electromagnetic radiation of high freqqyuency : Gamma rays frequencies above 1019 Hz , energies above 100 keV , wavelength <10 picometers,

Their main physical characteristics are: •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

. http://www.oncoprof.net/ Legend: γ = Gamma rays HX = Hard X‐rays SX = Soft X‐Rays EUV = Extreme ultraviolet NUV = Near ultraviolet Visible light NIR = Near infrared MIR = Moderate infrared FIR = Far infrared

Radio waves: EHF = EtExtreme ly hig h frequency (Microwaves) SHF = Super high frequency (Microwaves) UHF = Ultrahigh frequency VHF = Very high frequency HF = High frequency MF = Medium frequency LF = Low frequency VLF = Very low frequency VF = Voice frequency ULF = Ultra low frequency SLF = Super low frequency http://www.oncoprof.net/ ELF = Extremely low frequency 2. Particule radiation: neutrons These partilicles are artific ia llyproddduced by cyclotrons: their route is straight throughout matter. They interact by pulling protons out of crossed tissue. At a siilimilar dose, the irreltilative bio log ica l effic iency (RBE) is approxitlimately 3 times hig her than photons.

Beam of electrons moving in a circle (cyclotron motion). Lighting is caused by ionisation of gas in a http://www.oncoprof.net/ bulb. Charged ionizing radiations

β – Radiation Accelerated electrons α‐Radiation Protons Light ions Physical fundamentals of radiotherapy

β – Radiation

β ‐ particles are emitted by certain radioactive nuclei. are electrons interact with matter by moving the electrons within 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.

http://www.oncoprof.net/ Physical fundamentals of radiotherapy

Accelerated electrons

Produced by accelerators, same ppyhysical characteristics as ß Radiation

Energy : chosen according to the depth of the tumour,

They do not penetrate:

Major advantage : sparing tissue situated deeper than the tumour. Physical fundamentals of radiotherapy

α – Radiation heavy particles = positively charged helium nuclei

Alpha particles consist of two protons and two neutrons bound together into a particle identical to a helium nucleus; written = He2+ or 42He2+. Net spin = zero, total energy of about 5MeV Highly ionizing low penetration Energy : chosen according to the depth at which the tumour,

Major advantage : sparing tissue situated deeper than the tumour.

Spontaneously produced by instable nuclei 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. Physical fundamentals of radiotherapy

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, proton irradiation is well adapted for deep small sized tumours situated close to radiosensitive healthy tissue.

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

http://www.oncoprof.net/ Sync hrot ro n

General diagram of Synchrotron Soleil The circular ring is the synchrotron, i.e. a particle accelerator that brings electrons to very high speeds. The synchrotron emits a "synchrotron radiation", especially X‐rays; these are sent into the various beamlines (the straight lines branching out of the synchrotron). Each beamline contains scientific instruments, experiments etc. and receives an intense beam of radiation. http://www.oncoprof.net/ Varian Clinac 2100C Linear Accelerator.

The linac within the Australian Synchrotron accelerate the linear particle accelerator (often shortened to linac) electron beam to energies of is a type of particle accelerator that greatly increases the 100 MeV. velocity of charged subatomic particles or ions by subjjgecting the charged particles to a series of oscillating electric potentials along a linear beamline; this method of particle acceleration was invented in 1928 by Rolf Widerøe.[1]

http://www.oncoprof.net/ cyclotron is a type of particle accelerator Cyclotrons accelerate charged particles using a high frequency alternating voltage (potential difference). http://www.oncoprof.net/ Light ions

They can be produced by sy,ynchrotrons, have a similar penetration to protons but a biological efficiency comparable to that of neutrons. The main ion used in a few specialized centres is Carbon. They constitute an interesting research domain. Interactions between radiations and tissues

When an ionizing 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)a nd the thir d 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. Interactions between radiations and tissues Electromagnetic radiation interactions with tissues

Photons transmit their energy to molecules by different fundamental interaction mechanisms; lead to ionisations or electronic excitations, 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.

Electron interactions with tissues

Interaction is electrostatic with the electrons of crossed tissue. Not mechanical, as in photons

The electrons very rappyidly 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. Expression of 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 BBiihritish phhiiysicist HlHal Gray ‐ 1905‐1965 ‐ who worked in Cavendish Laboratory ‐ Cambridge, UK):

1 Gy represents the ditideposition of 1 JJloule 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. Physicochemical effects of radiotherapy

Direct effect The ionized molecules are ions with free radicals, ions which are very reactive due to the presence of non-paired electrons. ions with free radicals will associate between themselves, perturbing the structure of macromolecules (such as DNA). The excited molecules can dissociate and give birth to free radicals, which are highly reactive and modify the structure of macromolecules by aberrant covalent links.

Indirect effect Water, which represents approximately 80% of human body weight undergoes radiolysis. •Ionisation of water molecules •Formation of radical ions •In the absence of oxygen: •In the presence of oxygen In the presence of oxygen, highly oxidising radicals are created which interact with various compounds to form hydrogen peroxide, a very strong oxidising molecule. The irradiation of well oxidised tissue will generate a greater quantity of hydrogen peroxide than in hypoxic conditions: thus explaining the 'oxygen effect', provoking higher cell radiosensitivity than in normoxic conditions Direct effect The ionised molecules are ions with free radicals, ions which are very reactive due to the presence of non-paired electrons. These ions with free radicals will associate between themselves, perturbing the structure of macromolecules (such as DNA). The excited molllecules can dissoc ia teand give bir th tfto free radica ls, whic h are hig hly reactive and modify the structure of macromolecules by aberrant covalent links.

R : R’ ——> R. + R’

R. + O2 ——> ROO.

ROO. + R’.——> ROOR Indirect effect

Water, which represents 80% of human body weight undergoes radiolysis.

•Ionisation of water molecules Irradiation effect on H2O H0• + H•

Water radiolysis

Dissoc ia tion in 2 radica lsnon‐chdharged, non paidired eltlectron, hig hlyreactive

•Formation of radical ions + ‐ H2O .——> H2O + e

+ + H2O ——> H + OH.

+ ‐ H2O + e ——> H2O

‐ H2O + e ——>H. + OH.

http://www.oncoprof.net/ H. + O2——> HO2. *In the absence of oxygen:

OH. + OH. ——> H2O2 HO2. + HO2. ——> H2O2 + O2 *In the presence of oxygen

In the presence of oxygen, highly oxidizing radicals are created which interact with various compounds to HO2. + H. ——> H2O2 form hydrogen peroxide, a very strong oxidizing molecule. ‐ ‐ e + O2——> O2 The irradiation of well oxidized tissue will generate a greater quantity of hydrogen peroxide than in hypoxic ‐ ‐ O2 + H2O ——> HO2.+ OH conditions: the 'oxygen effect’ provoking higher cell radiosensitivity than in normoxic conditions. Biological action of radiotherapy The action of ionizing radiation in living tissue has 3 phases:

1 Physical phase very short period of time, in the order of 10-13 second. Ionisations + molecular excitations following the energy deposit (crossing of the beam) 2 Physicochemical phase few seconds to a few minutes. The iidionized and excited molllecules react btbetween each other and with neihbighbour ing molecules. Distinguish : direct effect in relation to direct impact of the beam on cellular macromolecules, in particular DNA, indirect effect in relation to macromolecule modifications provoked by free radicals originating from water radiolysis. The major component (70-80%) of beam impact on living tissue.

In the presence of oxygen, specific radicals are created with a strong oxidizing power interacting with water to induce the formation of hydrogen peroxide which is a strong oxidizing molecule. The 'oxygen effect' is observed in radiobiology with an increased radiosensitivity of well oxygenated cells compared to hypoxic cells. Effect of radiotherapy on DNA

Indirect effect: an electron detached by a photon (in green) will interact with a water molecule and produce radicals (HO• which will then provoke a lliesion of the DNA molecule). Free radicals may provoke a DNA lesion if they are produc ed at a distanc e of less than 2nm. The indirect effect is the major effect obtained for low LET beams (Linear Energy Transfer).

Direct effect: interaction between a DNA molecule and an electron displaced after absorption of a photon (in green). The DNA modification is relatively easy to repair.

http://www.oncoprof.net/ 3 Biological phase Either by direct or indirect effect, ionizing radiation alters the structure of macromolecules, thus disrupting the main functions of cellular life.

Action on nuclileicacids

DNA is the elective target of ionizing radiation.

When the cytoplasm and the nucleus of a cell are selectively irradiated, cellular death occurs with much lower doses when irradiation attacks the nucleus: lethal cellular lesions are those which concern DNA functions. Action on nucleic acids

The main lesions are:

•most often single strand breaks without gap, by rupture of diester links. •not lethal since DNA repair by a ligase within 2 to 10 minutes,

•more rarely, single strand breaks with gap, by disappearance of a sugar or base: •the repair time is longer since it requires the action of both a polymerase and a ligase,

•occasionally, base alterations, non lethal lesions, but source of mutation if the lesion is not repaired or is repaired inaccurately (15 minutes) by excision-synthesis mechanisms which require endonucleases, glycolases, polymerases and ligases,

•finally, double strand breaks from simultaneous events on the two strands or from two independent single breaks. Every double strand break is lethal if not repaired

the number of induced double strand breaks induces the cellular radiosensitivity of a tissue. Action on proteins

Physiologically lethal perturbations :

•alteration of membrane permeability (for instance: on ionic pumps),

•diminution of intercellular communication by perturbation of proteins constituting a gap jtijunction,

•modification of the transmembrane signal transduction.

Action on lipids

Lipid peroxidations diminish membrane fluidity

radiobiology 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 ((ystudy of stem cells).

The curve which is obtained can be transformed into a mathematical model : proportion of surviving cells after irradiation. The mathematical model which correlates 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. http://www.oncoprof.net/ Biological effect : the survival curve. hypotheses concerning the cell death induced by ionizing radiation. According to this linear quadratic model, cell death can be in relation to: lethal lesions which cannot be repaired (α 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.

http://www.oncoprof.net/ Biological effect : interest of fractionation

The same dose of irradiation divided into two fractions is less toxic for cells which are capable of repair. In this experiment, with cells from the intestinal crypts of mice cell repair has taken place several times between the first and second dose thus explaining that the second curve also resembles a shoulder curve. With fractionation, normal tissue may repair and a higher dosage is feasible. 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 silingle ffiraction corresponds to the lhllethal dose in 50% of subjects (DL50),

The absorbed dose is different from the emitted energy due to itinteracti ons btbetween radia tion and biol ogi cal tissue. EhEach partic le, 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. 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 1251.25 Mev of 60Cobalt) and absent with high energy from accelerators (photons of 25 MeV). Treatment parameters

Photon energy absorption

Deep irradiation

Dose variation at the entry and in depth in relation to the beam photon energy.

http://www.oncoprof.net/ Absorption of electrons

Electrons are very rapidly absorbed which allows superficial irradiation.

Dose distribution in water according to depth by an electron beam.

http://www.oncoprof.net/ Treatment parameters

Fractionation ‐ Spreading

For a similar total dose, the biological efficiency EBR varies according to the dose per session, the total number of sessions fractionation thlhe total diduration 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.

the late toxicity of irradiation related to the dose per fraction, many protltocolsof hftitdhypofractionated radioth erapy are empldloyed only ftitfor patients with a shthort life expectancy (radiotherapy for metastases for instance), who will not live long enough to develop such toxicities. Fractionation ‐ Spreading

Interest of fractionation •Repair of sublethal lesions : 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.;

•accelerated hyper-fractionated schedules to increase the tolerance by normal tissue,.

•to compare treatment modalities with atypical fractionation or spreading with stddtandard tttreatment 'or equiltivalent d'dose' Common radiotherapy devices

They emit electrons or photons and have the same general characteristics as a

heating system, the cathode)

high tension (HT) circuit (up to 300 kV).

Diagram of a classical tube for producing X Rays: Electrons are produced by heating the cathode (C); the electrons are then accelerated by electricity towards the anode (A) which is usually a rotating cylinder. The collision produces photons (Rx). All of these devices are kept under deep vacuum. http://www.oncoprof.net/ Common radiotherapy devices

Classified : increasing emitted energy. The in‐depth absorption is proportional to the energy of the emitted beam.

General diagram of a radiotherapy device Cobalt source or the Cathod

very heavy and strong stand [1]

rotation axis of 360°[2]

controlli ng the iiditirradiation and iiimaging system

The table is placed on a jack [5] which can move in almost every direction [6],

http://www.oncoprof.net/ Common radiotherapy devices

contact therapy

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. Cobaltotherapy

Diagram of a cobalt device: Alcyon. The cobalt source [1] is situated in a tungsten cylinder [2] This cylinder turns in order to align the source and the collimator [6]. When locating the patient, a laser source [5] gives a precise beam simulating the γ rays [7]. When no treatment is performed, the source is protected by enriched uranium [3] and lead [4].

http://www.oncoprof.net/ Cobaltotherapy

The beam geometry (which is only emitted when the source is in treatment position) can be modified for each patient.

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 used for head and neck cancer (relatively superficial tumours and nodes).

The device is isolated in a lead walled room; Common radiotherapy devices

Cobaltotherapy

Patient in position under a cobalt device for irradiation. The irradiation head is situated just above the patient's thorax. This is an old picture which shows a cobalt device in operation. Cobalt is still in use in many countries because of its simple dose calculation and its ease of handling. The protection mask is a wooden support containing a polystyrene drawing of the mediastinum and the axillary nodes with protection by small lead shots which absorb radiation to the lung, abdomen and neck of the patient. Wedges and compensators may be added to improve adjustment to the patient’s morphology. This picture shows is standard 'mantelet field' irradiation for Hodgkin’s disease.

http://www.oncoprof.net/ Linear accelerators

They comprise an electron source and an electromagnet which accelerates the electrons in a deep vacuum tube (accelerator). Principle of photon production in an accelerator

Electrons are stronggyly accelerated and bombard a metal target with a high atomic number. Photons are produced in various directions from 0° (prolongation of the electron beam) to 90°. The less energetic beams are those produced with a high angle, whereas the most energetic beams are those produced in line with the electrons http://www.oncoprof.net/ General diagram of an accelerator Deviation of the electron beam at 270° in order to bring it into line with the patient

Production and acceleration of electrons

TtTarget and diffus ing primary filter First collimator.

. 5: Main diffusing filter. 6: Ionising room for electrons (when only electrons are used). 7: Multileaf collimator.

Electron applicator and calibrated beam

electron energy is proportional to the length of the accelerator tube .

The interposition of a cathode target generates photons http://www.oncoprof.net/ Linear accelerators

An electron injector is behind the machine, then a powerful electromagnet which considerably accelerates the electrons of various intensities. The electrons hit the target, situated perpendicularly to the accelerator arm. Photons are then produced which are collimated in a regular beam. This beam can be shaped with masks or multileaf collimator.. The table can be moved to a depth of one metre into a cavity in the floor in order to allow large field irradiation (such as total abdominal irradiation or total corporeal irradiation) .

http://www.oncoprof.net/ Linear accelerators In clinical practice, ppotoshotons from 4 to 25 MeV, 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.

http://www.oncoprof.net/ Linear accelerators

The more energetic the accellterators are, the deeper they can tttreat 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.

the very steep penetration loss by electrons in relation to adjacent healthy tissue. The tissue situated prior to this decrease receives a relatively strong irradiation dose.

http://www.oncoprof.net/ Comparison of the efficiency of various radiotherapy devices

up to 70% of the dose can be administered up to a depth of 10cm with an 18 MeV accelerator; a dose that cannot be administered using a Cobalt unit. Differently oriented beams allows the administration of a correct dose in a volume, although for deep tumours (more than 15cm deep), very few devices offer satisfactory dosimetry. http://www.oncoprof.net/ Goals of radiotherapy

Curative radiotherapy

Goal: To definitively sterilise the cancer cells within the irradiated volume to obtain total cure

Neccessary conditions: absence of remote metastases.

Radiotherapy is a major weapon for fighting against cancer.

To control the tumour : the necessary dose should be inferior to the tolerated dose of the critical neighbouring organs (accuracy of 5 to 10% according to a Gauss curve)

The margin between success and failure is relatively narrow, a rigourous technique is mandatory: risk of local relapse and, the risk of necrosis.

Vegetating tumours are more radiosensitive than infiltrating tumours due to the oxygen effect. sensitivity of various tumors

Median dose for 90% Histological tumours 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 Tumour volume Necessary dose Sarcoma 60 ‐ 90 Gy IfInfrac liilinica l 45 ‐ 60 Gy Glioblastoma 60 ‐ 80 Gy disease Melanoma 70 ‐ 85 Gy Tumour < 2 cm 60 ‐ 64 Gy diameter Tumour > 2 cm ‐ < 65 ‐ 70 Gy 4 cm Tumour > 4 cm 75 ‐ 85 Gy

http://www.oncoprof.net/ Goals of radiotherapy : others

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.

Symptomatic radiotherapy : against pain haemorrhage, spinal cord or radicular compression Main radiotherapy indications Brain tumours Head and neck tumours Bronchial tumours Oesophageal tumours Breast tumours Pancreas tumours Cervix uteri tumours Endometrial tumours Prostate tumours Bladder tumours Rectum tumours Testicular tumours Soft tissue Sarcoma Lyypmphoma Skin tumours Irradiation by other particles

The physical family of hadrons: protons, neutrons, pions and, by extension, ions.

The ir great mass, the ir charge or absence of charge ttthogether with the ir iitnterac tion with matter confer them with specific characteristics (biological and ballistic) which may be very useful in radiotherapy.

Protons

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. Irradiation by other particles Protons

Protons interact with nuclei (nuclear interactions) and to a greater extent with electrons (electronic interactions). 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 a sudden peak of energy (Bragg peak), situated at a depth which is in reltilation to theoriiigina lenergy.

very precise energy loss: the relative biological effect is far more important /photons

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.

http://www.oncoprof.net/ Irradiation by other particles 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 (protons, alpha particles of nuclear fragments heavier than carbon, oxygen, nitrogen or hydrogen) which are responsible for tissue ionisation and for the bbliologica l effect.

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 by 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: •tumour of salivary glands (adenoid cystic carcinoma) •radio resistant glioblastoma, in relation to important necrosis.

http://www.oncoprof.net/ Irradiation by other particles Ions They combine the 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 heavy such as argon or silicium. The production of light ions requires the presence of a synchrotron; 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. http://www.oncoprof.net/ Notions of brachytherapy

Basic principles

Brachytherapy consists in the use of radioactive sources to deliver radiotherapy inside the tumour the photon irradiation begins its path through the tumour where its activity very quickly decreases easy to handle radioelements (such as Iridium 192 or Caesium 137) hollow catheters or vectors (without any radioactivity) are placed within the tumour then charged with radioactive elements high doses in small volumes

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. 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.

http://www.oncoprof.net/ Radiation therapy, improves tumour oxygenation but also: increases HIF1 levels and transactivation of target genes through mechanisms associated with stress granule depolymerization and the production of free radicals.

The upregulation of HIF1 protects tumour and endothelial cells from damage by the cytotoxic therapy Features of hypoxia‐ inducible factor (HIF1) regulation. HIF1 transcriptional activity regulates numerous genes tha t anaerobic metblitabolism, angiogenesis stimulation and mechanisms for resistance to therapy. HIF1 transcriptional activity requires formation of a heterodimer consisting of HIF1α and HIF1β. The heterodimer binds to hypoxia response elements (HREs) in promoter regions of its target genes, where it activates transcription.

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Features of hypoxia‐inducible factor (HIF1) regulation. Whereas HIF1β is constitutively expressed, HIF1α protein levels are subject to a numbe of points of regulation. HIF1α consists of the following regulatory domains: bHLH(basic‐helix‐loop‐helix), PAS (Per‐ARNT‐Sim), NTAD (N‐terminal transactivation domain), CTAD (C‐terminal transactivation domain) ODD (oxygen‐ddtdependent degradation domain). The rate of synthesis of HIF1α is controlled by activation of the phosphatidylinositol 3‐kinase (PI3K)‐Akt and Ras pathways by a variety of stimuli.

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Features of hypoxia‐inducible factor (HIF1) regulation.

HIF1α protein is rapidly targeted by the von Hippel‐Lindau protein (VHL) complex for proteasomal degradation under normoxic conditions, following an oxygen‐ dependent prolyl hydroxylation of proline residues in the ODD. Activity of the prolyl hydroxylases (PHDs) is influenced by protein kinase C (PKC), PTEN and reactive oxygen species (ROS). Nitric oxide (NO) has variable effects on the stability of HIF1α, depending on the oxygenation state of the cell. Features of hypoxia‐inducible factor (HIF1) regulation.

Once HIF1α forms a heterodimer with its partner, HIF1β, The transcriptional activity is further regulated by cofactors, such as CREB binding protein (CBP) or factor‐inhibiting HIF (FIH). ARD, acetyl transferase

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Regulation of tumor oxydation/hypoxia Seven points of regulation of tumour oxygenation. Seven features are often present in tumours, contributing in a multifactorial and interrelated fashion to hypoxia.

Intravascular partial pressure of O2 (pO2) drops as oxygen is unloaded from haemoglobin in red blood cells (RBCs) as they traverse distally from feeding arterioles; this is termed a longitudinal oxygen gradient. The distance that oxygen can diffuse radially from a vessel is dependent on how much oxygen is present in the vessel. The extent and severity of hypoxia surrounding blood vessels will become more severe as intravascular pO2 drops. Seven points of regulation of tumour oxygenation. Seven features are often present in tumours, contributing in a multifactorial and interrelated fashion to hypoxia.

At the extreme, red blood cells lose virtually all oxygen and there is no oxygen available to diffuse out into the tumour. Seven points of regulation of tumour oxygenation. Seven features are often present in tumours, contributing in a multifactorial and interrelated fashion to hypoxia.

Shunt flow diverts blood around the tumour, stealing nutrients from the tumour bed Seven points of regulation of tumour oxygenation. Seven features are often present in tumours, contributing in a multifactorial and interrelated fashion to hypoxia.

| Low vascular density creates hypoxia in extravascular tumour tissue because of limitations on the diffusion distance of oxygen once it leaves the blood vessel.

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Seven points of regulation of tumour oxygenation. Seven features are often present in tumours, contributing in a multifactorial and interrelated fashion to hypoxia.

| Blood vessel s ttathat aeare haph az ar dl y oeoriented will be less eceefficient in supplying adequate oxygen to all regions of tissue

Oxygen consumption rate is the most dynamic feature of oxygen transport in tumours. Small changes in demand for oxygen create large changes in the extent and severity of hypoxia, because higher demand not only limits the diffusion distance of oxygen, it also more severely depletes vessels of oxygen, thereby exacerbating longitudinal oxygen gradient

Intravascular hypoxia reduces red blood cell deformability, increasing blood viscosity, which in turn reduces flow rate.

These diagrams provide a general pictorial depiction of these basic features. In reality, within any tumour there are microregional variations in oxygenation, with oxygen concentration decreasing radially from microvessels

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 How to measure tumor hypoxia ? Hypoxia marker drugs These drugs are 2‐nitroimidazoles; after entering cells they undergo 1–2 electron reduction in cells and the reduced drug is a highly reactive free radical that binds to macromolecules, including proteins. However, when oxygen is present, the drug is oxidized and reverts back to its original state, allowing it to diffuse out of the cell and eventually into the circulation. The rate of protein binding of the reduced drug increases exponentially with a decrease in partial pressure of O2, particularly below 10 mmHg. The presence of drug–protein adducts can be detected immunohistochemically using antibodies specific for the drug protein adduct. 18F‐labelled versions of these drugs are also being developed for positron‐emission tomography imaging. Hypoxia marker proteins

As HIF1 upregulates the synthesis of many proteins, it has been proposed that identification of such proteins in tissues could be markers of hypoxia.

Literally dozens of such proteins have been studddied at the preclllinical lllevel and in clinicaltrials.

Some of the more promiiising endogenous markers ildinclude carbibonic anhydrase IX (CA9), plasminogen activator inhibitor 1 (PAI1, also known as SERPINE), osteopontin and lysyl oxidase.

Combinations of markers might prove to be better predictors of clinical outcome than any single marker. Oxygen electrodes and optical probes Oxygen can be measured in any aqueous media using polarography. In principle, two electrodes are placed into the medium and a polarizing voltage of – 0.7 volts is applied across them. This voltage corresponds to the binding energy of outer shell electrons of oxygen. The electrons are captured by the cathode and the current generated is linearly proportional to oxygen concentration. In practice, the cathode is embedded into a needle that can be introduced into tissues and the anode is placed on the body surface. This technique has been used extensively in preclinical and clinical studies; the presence of hypoxia is an independent predictive factor for poor prognosis in many different tumour types.

Optical probes have also been developed: these are implanted into tissues and contain a fluorochrome that emits fluorescent light with a certain decay rate when illuminated. The rate of fluorescent light decay is proportional to the oxygen concentration in the region of measurement. These probes yield data similar to that of the oxygen electrode Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Effects of radiation therapy on HIF1 activity hihypoxic tumours will reoxygenateafter tttreatment with radia tion

First, mechanism increased free radicals after radiation

The second mechanism of HIF1α stabilization after reoxygenation was related to stress granules

These are protein–mRNAc omplexes that *form in cells ddiuring peridiods of stress *prevent the cell from using energy for protein translation.

Stress granule formation coincide with hypoxia in vivo and in vitro and disaggregate during reoxygenation, releasing HIF1‐regulated transcripts. Mechanisms for hypoxia‐inducible factor 1 (HIF1) upregulation and consequences after radiation therapy.

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Mechanisms for hypoxia‐inducible factor 1 (HIF1) upregulation and consequences after radiation therapy.

a | Untreated tumours often have hypoxic subregions. In hypoxic regions, stress granules form containing HIF1‐mediated transcripts, sequestering the transcripts from being translated into protein. b | After radiation treatment, better oxygenated cells die and there is an increase in perfusion,leading to reoxygenation of the previously hypoxic cells. S tress granules disaggregate,releasing HIF1‐regulated mRNAs, which can then go on to be translated into protein. Reoxygenation also causes hypoxia–reoxygenation injury, causing byproduction of reactive oxygen species (ROS), which stabilize HIF1α, even in the presence of improved oxygenation.

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Mechanisms for hypoxia‐inducible factor 1 (HIF1) upregulation and consequences after radiation therapy.

c | Macrophages are attracted to the dying tumour cells, become activated and release nitric oxide (NO), which also stabilizes HIF1α. d | The increase in HIF1 activity increases vascular endothelial growth factor (VEGF) levels, promoting endothelial cell survival, angiogenesis and tumour cell survival and proliferation. This is highly simplified. Reoxygenation does not completely eliminate hypoxia and there are oxygen gradients within tumours as opposed to categorical differences between aerobic and hypoxic cells.

Dewhirst,M et al., Nature Rev Cancer, 2008, 8 , 425 Radiation techniques are considered a non‐threshold carcinogen. However, quantifying the risk of the more commonly encountered low and/or protracted radiation exposures remains problematic and subject to uncertainty.

Therefore, a major challenge lies in providing a sound mechanistic understanding of low‐dose radiation and carcinogenesis. In the hypoxia – reoxygenation context.

This Perspective takes into account the differences that exist between the effects mediated by high‐ and low‐dose radiation exposure and how this affects the assessment of low‐dose cancer risk Bon week end !!!!!

Immunotherapy and immunotherapeutic strategies