Cumulative effects from this process should not be confused with long-term effects – when short-term effects have disappeared and long-term effects are subclinical, reirradiation can still be problematic. [ 46 ]  These doses are calculated by the radiation oncologist and many factors are taken into account before the subsequent radiation takes place.


During the first two weeks after  fertilization , radiation therapy is lethal but not  teratogenic . [ 47 ]  High doses of radiation during pregnancy induce  anomalies ,  impaired growth  and  intellectual disability , and there may be an increased risk of  childhood leukemia  and other tumors in the offspring. [ 47 ]


In males previously having undergone radiotherapy, there appears to be no increase in genetic defects or congenital malformations in their children conceived after therapy. [ 47 ]  However, the use of  assisted reproductive technologies  and  micromanipulation techniques  might increase this risk. [ 47 ]


Hypopituitarism  commonly develops after radiation therapy for sellar and parasellar neoplasms, extrasellar brain tumors, head and neck tumors, and following whole body irradiation for systemic malignancies. [ 48 ]  40–50% of children treated for childhood cancer develop some endocrine side effect. [ 49 ]  Radiation-induced hypopituitarism mainly affects  growth hormone  and  gonadal hormones . [ 48 ]  In contrast,  adrenocorticotrophic hormone  (ACTH) and  thyroid stimulating hormone  (TSH) deficiencies are the least common among people with radiation-induced hypopituitarism. [ 48 ]  Changes in  prolactin -secretion is usually mild, and vasopressin deficiency appears to be very rare as a consequence of radiation. [ 48 ]


Delayed tissue injury with impaired wound healing capability often develops after receiving doses in excess of 65 Gy. A diffuse injury pattern due to the  external beam radiotherapy 's  holographic isodosing  occurs. While the targeted tumor receives the majority of radiation, healthy tissue at incremental distances from the center of the tumor are also irradiated in a diffuse pattern due to beam divergence. These wounds demonstrate  progressive, proliferative endarteritis , inflamed arterial linings that disrupt the tissue's blood supply. Such tissue ends up chronically  hypoxic ,  fibrotic , and without an adequate nutrient and oxygen supply. Surgery of previously irradiated tissue has a very high failure rate, e.g. women who have received radiation for breast cancer develop late effect  chest wall  tissue fibrosis and hypovascularity, making successful reconstruction and healing difficult, if not impossible. [ 5 ]


There are rigorous procedures in place to minimise the risk of accidental overexposure of radiation therapy to patients. However, mistakes do occasionally occur; for example, the radiation therapy machine  Therac-25  was responsible for at least six accidents between 1985 and 1987, where patients were given up to one hundred times the intended dose; two people were killed directly by the radiation overdoses. From 2005 to 2010, a hospital in  Missouri  overexposed 76 patients (most with brain cancer) during a five-year period because new radiation equipment had been set up incorrectly. [ 50 ]


Although medical errors are exceptionally rare, radiation oncologists, medical physicists and other members of the radiation therapy treatment team are working to eliminate them. In 2010 the  American Society for Radiation Oncology  (ASTRO) launched a safety initiative called   Target Safely  that, among other things, aimed to record errors nationwide so that doctors can learn from each and every mistake and prevent them from recurring. ASTRO also publishes a list of questions for patients to ask their doctors about radiation safety to ensure every treatment is as safe as possible. [ 51 ]


Radiation therapy is used to treat early stage  Dupuytren's disease  and  Ledderhose disease . When Dupuytren's disease is at the nodules and cords stage or fingers are at a minimal deformation stage of less than 10 degrees, then radiation therapy is used to prevent further progress of the disease. Radiation therapy is also used post surgery in some cases to prevent the disease continuing to progress. Low doses of radiation are used typically three gray of radiation for five days, with a break of three months followed by another phase of three gray of radiation for five days. [ 52 ]


Radiation therapy works by damaging the  DNA  of  cancer cells  and can cause them to undergo  mitotic catastrophe . [ 53 ]  This DNA damage is caused by one of two types of energy,  photon  or  charged particle . This damage is either direct or indirect  ionization  of the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming  free radicals , notably  hydroxyl  radicals, which then damage the DNA.


In photon therapy, most of the radiation effect is through free radicals. Cells have mechanisms for repairing single-strand DNA damage and  double-stranded DNA  damage. However, double-stranded DNA breaks are much more difficult to repair, and can lead to dramatic chromosomal abnormalities and genetic deletions. Targeting double-stranded breaks increases the probability that cells will undergo  cell death . Cancer cells are generally less  differentiated  and more  stem cell -like; they reproduce more than most healthy differentiated cells, and have a diminished ability to repair sub-lethal damage. Single-strand DNA damage is then passed on through cell division; damage to the cancer cells' DNA accumulates, causing them to die or reproduce more slowly.


One of the major limitations of photon radiation therapy is that the cells of solid tumors become deficient in  oxygen . Solid tumors can outgrow their blood supply, causing a low-oxygen state known as  hypoxia . Oxygen is a potent  radiosensitizer , increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. [ 54 ]  Much research has been devoted to overcoming hypoxia including the use of high pressure oxygen tanks,  hyperthermia therapy  (heat therapy which dilates blood vessels to the tumor site), blood substitutes that carry increased oxygen, hypoxic cell radiosensitizer drugs such as  misonidazole  and  metronidazole , and hypoxic  cytotoxins  (tissue poisons), such as  tirapazamine .  Newer research approaches are currently being studied, including preclinical and clinical investigations into the use of an  oxygen diffusion-enhancing compound  such as  trans sodium crocetinate  as a radiosensitizer. [ 55 ]


Charged particles such as  protons  and  boron ,  carbon , and  neon  ions can cause direct damage to cancer cell DNA through high-LET ( linear energy transfer ) and have an antitumor effect independent of tumor oxygen supply because these particles act mostly via direct energy transfer usually causing double-stranded DNA breaks. Due to their relatively large mass, protons and other charged particles have little lateral side scatter in the tissue – the beam does not broaden much, stays focused on the tumor shape, and delivers small dose side-effects to surrounding tissue. They also more precisely target the tumor using the  Bragg peak  effect. See  proton therapy  for a good example of the different effects of intensity-modulated radiation therapy (IMRT) vs.  charged particle therapy . This procedure reduces damage to healthy tissue between the charged particle radiation source and the tumor and sets a finite range for tissue damage after the tumor has been reached. In contrast, IMRT's use of uncharged particles causes its energy to damage healthy cells when it exits the body. This exiting damage is not therapeutic, can increase treatment side effects, and increases the probability of secondary cancer induction. [ 56 ]  This difference is very important in cases where the close proximity of other organs makes any stray ionization very damaging (example:  head and neck cancers ). This X-ray exposure is especially bad for children, due to their growing bodies, and while depending on a multitude of factors, they are around 10 times more sensitive to developing secondary malignancies after radiotherapy as compared to adults. [ 57 ]


The amount of radiation used in photon radiation therapy is measured in  grays  (Gy), and varies depending on the type and stage of cancer being treated. For curative cases, the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy.


Preventive (adjuvant) doses are typically around 45–60 Gy in 1.8–2 Gy fractions (for breast, head, and neck cancers.) Many other factors are considered by  radiation oncologists  when selecting a dose, including whether the patient is receiving chemotherapy, patient comorbidities, whether radiation therapy is being administered before or after surgery, and the degree of success of surgery.


Delivery parameters of a prescribed dose are determined during  treatment planning  (part of  dosimetry ). Treatment planning is generally performed on dedicated computers using specialized treatment planning software. Depending on the radiation delivery method, several angles or sources may be used to sum to the total necessary dose. The planner will try to design a plan that delivers a uniform prescription dose to the tumor and minimizes dose to surrounding healthy tissues.


In radiation therapy, three-dimensional dose distributions may be evaluated using the  dosimetry  technique known as  gel dosimetry . [ 58 ]


The total dose is fractionated (spread out over time) for several important reasons. Fractionation allows normal cells time to recover, while tumor cells are generally less efficient in repair between fractions. Fractionation also allows tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given. Similarly, tumor cells that were chronically or acutely hypoxic (and therefore more radioresistant) may reoxygenate between fractions, improving the tumor cell kill. [ 59 ]


Fractionation regimens are individualised between different radiation therapy centers and even between individual doctors. In North America, Australia, and Europe, the typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week. In some cancer types, prolongation of the fraction schedule over too long can allow for the tumor to begin repopulating, and for these tumor types, including head-and-neck and cervical squamous cell cancers, radiation treatment is preferably completed within a certain amount of time. For children, a typical fraction size may be 1.5 to 1.8 Gy per day, as smaller fraction sizes are associated with reduced incidence and severity of late-onset side effects in normal tissues.


In some cases, two fractions per day are used near the end of a course of treatment. This schedule, known as a concomitant boost regimen or hyperfractionation, is used on tumors that regenerate more quickly when they are smaller. In particular, tumors in the head-and-neck demonstrate this behavior.


Patients receiving  palliative radiation  to treat uncomplicated painful bone metastasis should not receive more than a single fraction of radiation. [ 60 ]  A single treatment gives comparable pain relief and morbidity outcomes to multiple-fraction treatments, and for patients with limited life expectancy, a single treatment is best to improve patient comfort. [ 60 ]


One fractionation schedule that is increasingly being used and continues to be studied is hypofractionation. This is a radiation treatment in which the total dose of radiation is divided into large doses. Typical doses vary significantly by cancer type, from 2.2 Gy/fraction to 20 Gy/fraction, the latter being typical of stereotactic treatments (stereotactic ablative body radiotherapy, or SABR – also known as SBRT, or stereotactic body radiotherapy) for subcranial lesions, or SRS (stereotactic radiosurgery) for intracranial lesions. The rationale of hypofractionation is to reduce the probability of local recurrence by denying clonogenic cells the time they require to reproduce and also to exploit the radiosensitivity of some tumors. [ 61 ]  In particular, stereotactic treatments are intended to destroy clonogenic cells by a process of ablation, i.e., the delivery of a dose intended to destroy clonogenic cells directly, rather than to interrupt the process of clonogenic cell division repeatedly (apoptosis), as in routine radiotherapy.


Different cancer types have different radiation sensitivity. While predicting the sensitivity based on genomic or proteomic analyses of biopsy samples has proven challenging, [ 62 ] [ 63 ]  the predictions of radiation effect on individual patients from genomic signatures of intrinsic cellular radiosensitivity have been shown to associate with clinical outcome. [ 64 ]  An alternative approach to genomics and proteomics was offered by the discovery that  radiation protection  in microbes is offered by non-enzymatic complexes of  manganese  and small organic metabolites. [ 65 ]  The content and variation of manganese (measurable by electron paramagnetic resonance) were found to be good predictors of  radiosensitivity , and this finding extends also to human cells. [ 66 ]  An association was confirmed between total cellular manganese contents and their variation, and clinically inferred radioresponsiveness in different tumor cells, a finding that may be useful for more precise radiodosages and improved treatment of cancer patients. [ 67 ]


Historically, the three main divisions of radiation therapy are:


The differences relate to the position of the radiation source; external is outside the body, brachytherapy uses sealed radioactive sources placed precisely in the area under treatment, and systemic radioisotopes are given by infusion or oral ingestion. Brachytherapy can use temporary or permanent placement of radioactive sources. The temporary sources are usually placed by a technique called afterloading. In afterloading a hollow tube or applicator is placed surgically in the organ to be treated, and the sources are loaded into the applicator after the applicator is implanted. This minimizes radiation exposure to health care personnel.


Particle therapy  is a special case of external beam radiation therapy where the particles are  protons  or heavier  ions .


A review of radiation therapy randomised clinical trials from 2018 to 2021 found many practice-changing data and new concepts that emerge from RCTs, identifying techniques that improve the therapeutic ratio, techniques that lead to more tailored treatments, stressing the importance of patient satisfaction, and identifying areas that require further study. [ 68 ] [ 69 ]


The following three sections refer to treatment using X-rays.


Historically conventional external beam radiation therapy (2DXRT) was delivered via two-dimensional beams using kilovoltage therapy X-ray units, medical linear accelerators that generate high-energy X-rays, or with machines that were similar to a linear accelerator in appearance, but used a sealed radioactive source like the one shown above. [ 70 ] [ 71 ]  2DXRT mainly consists of a single beam of radiation delivered to the patient from several directions: often front or back, and both sides.


Conventional  refers to the way the treatment is  planned  or  simulated  on a specially calibrated diagnostic X-ray machine known as a simulator because it recreates the linear accelerator actions (or sometimes by eye), and to the usually well-established arrangements of the radiation beams to achieve a desired  plan . The aim of simulation is to accurately target or localize the volume which is to be treated. This technique is well established and is generally quick and reliable. The worry is that some high-dose treatments may be limited by the radiation toxicity capacity of healthy tissues which lie close to the target tumor volume.


An example of this problem is seen in radiation of the prostate gland, where the sensitivity of the adjacent rectum limited the dose which could be safely prescribed using 2DXRT planning to such an extent that tumor control may not be easily achievable. Prior to the invention of the CT, physicians and physicists had limited knowledge about the true radiation dosage delivered to both cancerous and healthy tissue. For this reason, 3-dimensional conformal radiation therapy has become the standard treatment for almost all tumor sites. More recently other forms of imaging are used including MRI, PET, SPECT and Ultrasound. [ 72 ]


Stereotactic radiation is a specialized type of external beam radiation therapy. It uses focused radiation beams targeting a well-defined tumor using extremely detailed imaging scans. Radiation oncologists perform stereotactic treatments, often with the help of a neurosurgeon for tumors in the brain or spine.


There are two types of stereotactic radiation.  Stereotactic radiosurgery  (SRS) is when doctors use a single or several stereotactic radiation treatments of the brain or spine.  Stereotactic body radiation therapy  (SBRT) refers to one or several stereotactic radiation treatments with the body, such as the lungs. [ 73 ]


Some doctors say an advantage to stereotactic treatments is that they deliver the right amount of radiation to the cancer in a shorter amount of time than traditional treatments, which can often take 6 to 11 weeks. Plus treatments are given with extreme accuracy, which should limit the effect of the radiation on healthy tissues. One problem with stereotactic treatments is that they are only suitable for certain small tumors.


Stereotactic treatments can be confusing because many hospitals call the treatments by the name of the manufacturer rather than calling it SRS or SBRT. Brand names for these treatments include Axesse,  Cyberknife ,  Gamma Knife , Novalis, Primatom, Synergy,  X-Knife ,  TomoTherapy , Trilogy and  Truebeam . [ 74 ]  This list changes as equipment manufacturers continue to develop new, specialized technologies to treat cancers.


The planning of radiation therapy treatment has been revolutionized by the ability to delineate tumors and adjacent normal structures in three dimensions using specialized CT and/or MRI scanners and planning software. [ 75 ]


Virtual simulation, the most basic form of planning, allows more accurate placement of radiation beams than is possible using conventional X-rays, where soft-tissue structures are often difficult to assess and normal tissues difficult to protect.


An enhancement of virtual simulation is  3-dimensional conformal radiation therapy (3DCRT) , in which the profile of each radiation beam is shaped to fit the profile of the target from a  beam's eye view  (BEV) using a  multileaf collimator  (MLC) and a variable number of beams. When the treatment volume conforms to the shape of the tumor, the relative toxicity of radiation to the surrounding normal tissues is reduced, allowing a higher dose of radiation to be delivered to the tumor than conventional techniques would allow. [ 10 ]


Intensity-modulated radiation therapy (IMRT) is an advanced type of high-precision radiation that is the next generation of 3DCRT. [ 76 ]  IMRT also improves the ability to conform the treatment volume to concave tumor shapes, [ 10 ]  for example when the tumor is wrapped around a vulnerable structure such as the spinal cord or a major organ or blood vessel. [ 77 ]  Computer-controlled X-ray accelerators distribute precise radiation doses to malignant tumors or specific areas within the tumor. The pattern of radiation delivery is determined using highly tailored computing applications to perform  optimization  and treatment simulation ( Treatment Planning ). The radiation dose is consistent with the 3-D shape of the tumor by controlling, or modulating, the radiation beam's intensity. The radiation dose intensity is elevated near the gross tumor volume while radiation among the neighboring normal tissues is decreased or avoided completely. This results in better tumor targeting, lessened side effects, and improved treatment outcomes than even 3DCRT.


3DCRT is still used extensively for many body sites but the use of IMRT is growing in more complicated body sites such as CNS, head and neck, prostate, breast, and lung. Unfortunately, IMRT is limited by its need for additional time from experienced medical personnel. This is because physicians must manually delineate the tumors one CT image at a time through the entire disease site which can take much longer than 3DCRT preparation. Then, medical physicists and dosimetrists must be engaged to create a viable treatment plan. Also, the IMRT technology has only been used commercially since the late 1990s even at the most advanced cancer centers, so radiation oncologists who did not learn it as part of their residency programs must find additional sources of education before implementing IMRT.


Proof of improved survival benefit from either of these two techniques over conventional radiation therapy (2DXRT) is growing for many tumor sites, but the ability to reduce toxicity is generally accepted. This is particularly the case for head and neck cancers in a series of pivotal trials performed by Professor  Christopher Nutting  of the Royal Marsden Hospital. Both techniques enable dose escalation, potentially increasing usefulness. There has been some concern, particularly with IMRT, [ 78 ]  about increased exposure of normal tissue to radiation and the consequent potential for secondary malignancy. Overconfidence in the accuracy of imaging may increase the chance of missing lesions that are invisible on the planning scans (and therefore not included in the treatment plan) or that move between or during a treatment (for example, due to respiration or inadequate patient immobilization). New techniques are being developed to better control this uncertainty – for example, real-time imaging combined with real-time adjustment of the therapeutic beams. This new technology is called image-guided radiation therapy or four-dimensional radiation therapy.


Another technique is the real-time tracking and localization of one or more small implantable electric devices implanted inside or close to the tumor. There are various types of medical implantable devices that are used for this purpose. It can be a magnetic transponder which senses the magnetic field generated by several transmitting coils, and then transmits the measurements back to the positioning system to determine the location. [ 79 ]  The implantable device can also be a small wireless transmitter sending out an RF signal which then will be received by a sensor array and used for localization and real-time tracking of the tumor position. [ 80 ] [ 81 ]


A well-studied issue with IMRT is the "tongue and groove effect" which results in unwanted underdosing, due to irradiating through extended tongues and grooves of overlapping MLC (multileaf collimator) leaves. [ 82 ]   While solutions to this issue have been developed, which either reduce the TG effect to negligible amounts or remove it completely, they depend upon the method of IMRT being used and some of them carry costs of their own. [ 82 ]   Some texts distinguish "tongue and groove error" from "tongue or groove error", according as both or one side of the aperture is occluded. [ 83 ]


Volumetric modulated arc therapy (VMAT) is a radiation technique introduced in 2007 [ 84 ]  which can achieve highly conformal dose distributions on target volume coverage and sparing of normal tissues. The specificity of this technique is to modify three parameters during the treatment. VMAT delivers radiation by rotating gantry (usually 360° rotating fields with one or more arcs), changing speed and shape of the beam with a  multileaf collimator  (MLC) ("sliding window" system of moving) and fluence output rate (dose rate) of the medical linear accelerator. VMAT has an advantage in patient treatment, compared with conventional static field intensity modulated radiotherapy (IMRT), of reduced radiation delivery times. [ 85 ] [ 86 ]  Comparisons between VMAT and conventional IMRT for their sparing of healthy tissues and Organs at Risk (OAR) depends upon the cancer type. In the treatment of  nasopharyngeal ,  oropharyngeal  and  hypopharyngeal  carcinomas VMAT provides equivalent or better protection of the organ at risk (OAR). [ 84 ] [ 85 ] [ 86 ]  In the treatment of  prostate cancer  the OAR protection result is mixed [ 84 ]  with some studies favoring VMAT, others favoring IMRT. [ 87 ]


Temporally feathered radiation therapy (TFRT) is a radiation technique introduced in 2018 [ 88 ]  which aims to use the inherent non-linearities in normal tissue repair to allow for sparing of these tissues without affecting the dose delivered to the tumor. The application of this technique, which has yet to be automated, has been described carefully to enhance the ability of departments to perform it, and in 2021 it was reported as feasible in a small clinical trial, [ 89 ]  though its efficacy has yet to be formally studied.


Automated treatment planning has become an integrated part of radiotherapy treatment planning. There are in general two approaches of automated planning. 1) Knowledge based planning where the treatment planning system has a library of high quality plans, from which it can predict the target and dose-volume histogram of the organ at risk. [ 90 ]  2) The other approach is commonly called protocol based planning, where the treatment planning system tried to mimic an experienced treatment planner and through an iterative process evaluates the plan quality from on the basis of the protocol. [ 91 ] [ 92 ] [ 93 ] [ 94 ]


In particle therapy ( proton therapy  being one example), energetic ionizing particles (protons or carbon ions) are directed at the target tumor. [ 95 ]  The dose increases while the particle penetrates the tissue, up to a maximum (the  Bragg peak ) that occurs near the end of the particle's  range , and it then drops to (almost) zero. The advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue.


Auger therapy  (AT) makes use of a very high dose [ 96 ]  of ionizing radiation in situ that provides molecular modifications at an atomic scale. AT differs from conventional radiation therapy in several aspects; it neither relies upon radioactive nuclei to cause cellular radiation damage at a cellular dimension, nor engages multiple external pencil-beams from different directions to zero-in to deliver a dose to the targeted area with reduced dose outside the targeted tissue/organ locations. Instead, the in situ delivery of a very high dose at the molecular level using AT aims for in situ molecular modifications involving molecular breakages and molecular re-arrangements such as a change of stacking structures as well as cellular metabolic functions related to the said molecule structures.


In many types of external beam radiotherapy, motion can negatively impact the treatment delivery by moving target tissue out of, or other healthy tissue into, the intended beam path. Some form of patient immobilisation is common, to prevent the large movements of the body during treatment, however this cannot prevent all motion, for example as a result of  breathing . Several techniques have been developed to account for motion like this. [ 97 ] [ 98 ]   Deep inspiration breath-hold  (DIBH) is commonly used for breast treatments where it is important to avoid irradiating the heart. In DIBH the patient holds their breath after  breathing in  to provide a stable position for the treatment beam to be turned on. This can be done automatically using an external monitoring system such as a  spirometer  or a camera and markers. [ 99 ]  The same monitoring techniques, as well as  4DCT  imaging, can also be for respiratory gated treatment, where the patient breathes freely and the beam is only engaged at certain points in the breathing cycle. [ 100 ]  Other techniques include using 4DCT imaging to plan treatments with margins that account for motion, and active movement of the treatment couch, or beam, to follow motion. [ 101 ]


Contact X-ray brachytherapy (also called "CXB", "electronic brachytherapy" or the "Papillon Technique") is a type of radiation therapy using low energy (50 kVp) kilovoltage  X-rays  applied directly to the tumor to treat  rectal cancer . The process involves endoscopic examination first to identify the tumor in the rectum and then inserting treatment applicator on the tumor through the  anus  into the rectum and placing it against the cancerous tissue. Finally, treatment tube is inserted into the applicator to deliver high doses of X-rays (30Gy) emitted directly onto the  tumor  at two weekly intervals for three times over four weeks period.  It is typically used for treating early rectal cancer in patients who may not be candidates for surgery. [ 102 ] [ 103 ] [ 104 ]  A 2015 NICE review found the main side effect to be bleeding that occurred in about 38% of cases, and radiation-induced ulcer which occurred in 27% of cases. [ 102 ]


Brachytherapy is delivered by placing radiation source(s) inside or next to the area requiring treatment. Brachytherapy is commonly used as an effective treatment for cervical, [ 105 ]  prostate, [ 106 ]  breast, [ 107 ]  and skin cancer [ 108 ]  and can also be used to treat tumors in many other body sites. [ 109 ]


In brachytherapy, radiation sources are precisely placed directly at the site of the cancerous tumor. This means that the irradiation only affects a very localized area – exposure to radiation of healthy tissues further away from the sources is reduced. These characteristics of brachytherapy provide advantages over external beam radiation therapy – the tumor can be treated with very high doses of localized radiation, whilst reducing the probability of unnecessary damage to surrounding healthy tissues. [ 109 ] [ 110 ]  A course of brachytherapy can often be completed in less time than other radiation therapy techniques. This can help reduce the chance of surviving cancer cells dividing and growing in the intervals between each radiation therapy dose. [ 110 ]


As one example of the localized nature of breast brachytherapy, the SAVI device delivers the radiation dose through multiple catheters, each of which can be individually controlled. This approach decreases the exposure of healthy tissue and resulting side effects, compared both to external beam radiation therapy and older methods of breast brachytherapy. [ 111 ]


Radionuclide therapy (also known as systemic radioisotope therapy, radiopharmaceutical therapy, or molecular radiotherapy), is a form of targeted therapy. Targeting can be due to the chemical properties of the isotope such as radioiodine which is specifically absorbed by the thyroid gland a thousandfold better than other bodily organs. Targeting can also be achieved by attaching the radioisotope to another molecule or antibody to guide it to the target tissue. The radioisotopes are delivered through  infusion  (into the bloodstream) or ingestion. Examples are the infusion of  metaiodobenzylguanidine  (MIBG) to treat  neuroblastoma , of oral  iodine-131  to treat  thyroid cancer  or  thyrotoxicosis , and of hormone-bound  lutetium-177  and  yttrium-90  to treat  neuroendocrine tumors  ( peptide receptor radionuclide therapy ).


Another example is the injection of radioactive yttrium-90 or holmium-166 microspheres into the  hepatic artery  to radioembolize liver tumors or liver metastases. These microspheres are used for the treatment approach known as  selective internal radiation therapy . The microspheres are approximately 30  μm  in diameter (about one-third of a human hair) and are delivered directly into the artery supplying blood to the tumors. These treatments begin by guiding a  catheter  up through the femoral artery in the leg, navigating to the desired target site and administering treatment. The blood feeding the tumor will carry the microspheres directly to the tumor enabling a more selective approach than traditional systemic chemotherapy. There are currently three different kinds of microspheres:  SIR-Spheres ,  TheraSphere  and QuiremSpheres.


A major use of systemic radioisotope therapy is in the treatment of  bone metastasis  from cancer. The radioisotopes travel selectively to areas of damaged bone, and spare normal undamaged bone. Isotopes commonly used in the treatment of bone metastasis are  radium-223 , [ 112 ]   strontium-89  and  samarium ( 153 Sm) lexidronam . [ 113 ]


In 2002, the  United States Food and Drug Administration  (FDA) approved  ibritumomab tiuxetan  (Zevalin), which is an anti- CD20   monoclonal antibody  conjugated to yttrium-90. [ 114 ]
In 2003, the FDA approved the  tositumomab /iodine ( 131 I) tositumomab regimen (Bexxar), which is a combination of an iodine-131 labelled and an unlabelled anti-CD20 monoclonal antibody. [ 115 ]
These medications were the first agents of what is known as  radioimmunotherapy , and they were approved for the treatment of refractory  non-Hodgkin's lymphoma .


Intraoperative radiation therapy  (IORT) is applying therapeutic levels of radiation to a target area, such as a  cancer  tumor, while the area is exposed during  surgery . [ 116 ]


The rationale for IORT is to deliver a high dose of radiation precisely to the targeted area with minimal exposure of surrounding tissues which are displaced or shielded during the IORT. Conventional radiation techniques such as external beam radiotherapy (EBRT) following surgical removal of the tumor have several drawbacks: The tumor bed where the highest dose should be applied is frequently missed due to the complex localization of the wound cavity even when modern radiotherapy planning is used. Additionally, the usual delay between the surgical removal of the tumor and EBRT may allow a repopulation of the tumor cells. These potentially harmful effects can be avoided by delivering the radiation more precisely to the targeted tissues leading to immediate sterilization of residual tumor cells. Another aspect is that wound fluid has a stimulating effect on tumor cells. IORT was found to inhibit the stimulating effects of wound fluid. [ 117 ]


Medicine has used radiation therapy as a treatment for cancer for more than 100 years, with its earliest roots traced from the discovery of X-rays in 1895 by  Wilhelm Röntgen . [ 118 ]   Emil Grubbe  of Chicago was possibly the first American physician to use X-rays to treat cancer, beginning in 1896. [ 119 ]


The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of  Nobel Prize –winning scientist  Marie Curie  (1867–1934), who discovered the radioactive elements  polonium  and  radium  in 1898. This began a new era in medical treatment and research. [ 118 ]   Through the 1920s the hazards of radiation exposure were not understood, and little protection was used. Radium was believed to have wide curative powers and radiotherapy was applied to many diseases.


Prior to World War 2, the only practical sources of radiation for radiotherapy were radium, its "emanation",  radon  gas, and the  X-ray tube .  External beam radiotherapy  (teletherapy) began at the turn of the century with relatively low voltage (<150 kV) X-ray machines.  It was found that while superficial tumors could be treated with low voltage X-rays, more penetrating, higher energy beams were required to reach tumors inside the body, requiring higher voltages.  Orthovoltage X-rays , which used tube voltages of 200-500 kV, began to be used during the 1920s.  To reach the most deeply buried tumors without exposing intervening skin and tissue to dangerous radiation doses required rays with energies of 1 MV or above, called "megavolt" radiation.  Producing megavolt X-rays required  voltages  on the X-ray tube of 3 to 5 million  volts , which required huge expensive installations.  Megavoltage X-ray units were first built in the late 1930s but because of cost were limited to a few institutions. One of the first, installed at  St. Bartholomew's hospital , London in 1937 and used until 1960, used a 30 foot long X-ray tube and weighed 10 tons. Radium produced megavolt  gamma rays , but was extremely rare and expensive due to its low occurrence in ores.  In 1937 the entire world supply of radium for radiotherapy was 50 grams, valued at £800,000, or $50 million in 2005 dollars.


The invention of the  nuclear reactor  in the  Manhattan Project  during World War 2 made possible the production of artificial  radioisotopes  for radiotherapy.  Cobalt therapy ,  teletherapy  machines using megavolt gamma rays emitted by  cobalt-60 , a radioisotope produced by irradiating ordinary cobalt metal in a reactor, revolutionized the field between the 1950s and the early 1980s.  Cobalt machines were relatively cheap, robust and simple to use, although due to its 5.27 year  half-life  the cobalt had to be replaced about every 5 years.


Medical  linear particle accelerators , developed since the 1940s, began replacing X-ray and cobalt units in the 1980s and these older therapies are now declining. The first medical linear accelerator was used at the  Hammersmith Hospital  in London in 1953. [ 71 ]  Linear accelerators can produce higher energies, have more collimated beams, and do not produce radioactive waste with its attendant disposal problems like radioisotope therapies.


With  Godfrey Hounsfield 's invention of  computed tomography  (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery. CT-based planning allows physicians to more accurately determine the dose distribution using axial tomographic images of the patient's anatomy. The advent of new imaging technologies, including  magnetic resonance imaging  (MRI) in the 1970s and  positron emission tomography  (PET) in the 1980s, has moved radiation therapy from 3-D conformal to intensity-modulated radiation therapy (IMRT) and to image-guided radiation therapy  tomotherapy . These advances allowed radiation oncologists to better see and target tumors, which have resulted in better treatment outcomes, more organ preservation and fewer side effects. [ 120 ]


While access to radiotherapy is improving globally, more than half of patients in low and  middle income countries  still do not have available access to the therapy as of 2017. [ 121 ]


The  abscopal effect  is a hypothesis in the treatment of  metastatic cancer  whereby shrinkage of untreated tumors occurs concurrently with shrinkage of tumors within the scope of the localized treatment. R.H. Mole proposed the term "abscopal" ('ab' - away from, 'scopus' - target) in 1953 to refer to effects of  ionizing radiation  "at a distance from the irradiated volume but within the same organism". [ 1 ]


Initially associated with single-tumor, localized radiation therapy, the term "abscopal effect" has also come to encompass other types of localized treatments such as electroporation and intra-tumoral injection of therapeutics. [ 2 ]  However, the term should only be used when truly local treatments result in systemic effects. For instance, chemotherapeutics commonly circulate through the blood stream and therefore exclude the possibility of any abscopal response.


The mediators of the abscopal effect of  radiotherapy  were unknown for decades. In 2004, it was postulated for the first time that the immune system might be responsible for these "off-target" anti-tumor effects. [ 3 ]  Various studies in animal models of melanoma, [ 4 ] [ 5 ]  mammary, [ 5 ] [ 6 ]  and colorectal tumors [ 5 ] [ 7 ]  have substantiated this hypothesis. Abscopal effects of  Targeted intraoperative radiotherapy  have been seen in clinical studies, including in randomized trials where women treated with lumpectomy for breast cancer combined with whole breast radiotherapy showed reduced mortality from non-breast-cancer causes when compared with whole breast radiotherapy. [ 8 ] [ 9 ]  Furthermore, immune-mediated abscopal effects were also described in patients with metastatic cancer. [ 10 ]  Whereas these reports were extremely rare throughout the 20th century, the clinical use of immune checkpoint blocking antibodies such as  ipilimumab  or  pembrolizumab  has greatly increased the number of abscopally responding patients in selected groups of patients such as those with metastatic melanoma  [ 11 ] [ 12 ]  or lymphoma. [ 13 ]


Similar to immune reactions against  antigens  from bacteria or viruses, the abscopal effect requires  priming  of immune cells against tumor antigens. [ 10 ]  Local irradiation of a tumor nodule may lead to immunogenic forms of tumor cell death and liberation of tumor cell-derived antigens. These antigens can be recognized and processed by  antigen-presenting cells  within the tumor ( dendritic cells  and  macrophages ).  Cytotoxic T cells  which recognize these tumor antigens may in turn be primed by the tumor antigen-presenting cells. In contrast to the local effect of irradiation on the tumor cells, these cytotoxic T cells circulate through the blood stream and are thus able to destroy remaining tumor cells in distant parts of the body which were not irradiated. Accordingly, increases in tumor-specific cytotoxic T cells were shown to correlate with abscopal anti-tumor responses in patients. [ 11 ]  Vice versa, the abscopal effect is abolished after experimental depletion of T cells in various animal models. [ 5 ] [ 14 ]


Abscopal effects of ionizing radiation are often blocked by the immunosuppressive  microenvironment  inside the irradiated tumor which prevents effective T cell priming. This explains why the effect is so rarely seen in patients receiving radiotherapy alone. In contrast, the combination of immunomodulatory drugs such as ipilimumab and pembrolizumab can partially reconstitute systemic anti-tumor immune reactions induced after local tumor radiotherapy. [ 4 ]  The optimal combination of radiation dose and fractionation with immunomodulatory drugs is currently under intensive investigation. In this context, it was proposed that radiation doses above 10 to 12 Gray might be ineffective in inducing immunogenic forms of cell death. [ 15 ]  However, there is so far no consensus on the optimal radiation regimen needed to increase the chance of abscopal tumor regression.


Auger therapy   is a form of  radiation therapy  for the treatment of  cancer  which relies on low-energy  electrons  (emitted by the  Auger effect ) to damage cancer cells, rather than the high-energy  radiation  used in traditional radiation therapy. [ 1 ] [ 2 ]  Similar to other forms of radiation therapy, Auger therapy relies on radiation-induced damage to cancer  cells  (particularly  DNA  damage) to arrest  cell division , stop  tumor  growth and  metastasis  and kill cancerous cells. It differs from other types of radiation therapy in that electrons emitted via the  Auger effect  (Auger electrons) are released with low  kinetic energy . In contrast to traditional α- and β-particle emitters, Auger electron emitters exhibit low cellular toxicity during transit in blood or bone marrow. [ 3 ]


Due to their low kinetic energy, emitted Auger electrons travel over a very short range: much less than the size of a single cell, on the order of less than a few-hundred  nanometers . [ 4 ]  This very short-range delivery of energy permits highly targeted therapies, since the radiation-emitting  nuclide  will be in close proximity to the delivery site (e.g., a DNA strand) to cause cytotoxicity. [ 5 ]  However, this is a technical challenge; Auger therapeutics must enter their cell-nuclear targets to be most effective. [ 4 ] [ 6 ]  Auger therapeutics are radiolabelled biomolecules, capable of entering cells of interest and binding to specific sub-cellular components. These typically carry a radioactive atom capable of emitting Auger electrons. The Auger electron emission from the atom is stimulated by  radioactive decay, or by external pst (primary system therapy, such as X-ray) excitation. [ 6 ]


The electron energy in a vacuum may be accurately measured with an electron detector in a  Faraday cage , where the  bias  placed on the cage will accurately define the particle energy reaching the detector. The range of low-energy electrons in tissue or water, particularly electrons at the nanometer scale, cannot be easily measured; it must be inferred, since low-energy electrons scatter at large angles and travel in a zigzag path whose termination distance must be considered statistically and from differential measurements of higher-energy electrons at a much higher range. A 20  eV  electron in water, for example, could have a range of 20 nm for 103  Gy  or 5 nm for 104.7 Gy. For a group of 9–12 Auger electrons with energies at 12–18 eV in water (including the effect of water ionization at approximately 10 eV), an estimate of 106 Gy is probably sufficiently accurate. The illustration shows the simulated dose calculation in water for an electron using a  Monte Carlo   random walk [ 7 ]  which gives up to 0.1 MGy. For a moderately-heavy atom to yield a dozen or more Auger electrons from its inner-shell ionization, the Auger dose becomes 106 Gy per event.


With a large, localized dose  in situ  for molecular modification, the most obvious target molecule is the DNA duplex (where the complementary strands are separated by several nanometers). However, DNA duplex atoms are light elements (with only a few electrons each). Even if they could be induced by a photon beam to deliver Auger electrons, at under 1 keV they would be too soft to penetrate tissue sufficiently for therapy. Mid-range or heavy atoms (from bromine to platinum, for example) which could be induced by sufficiently hard X-ray photons to generate enough electrons to provide low-energy charges in an Auger cascade, will be considered for therapy.


When a normal cell transforms, replicating uncontrollably, many unusual genes (including viral material such as herpes genes which are not normally expressed) are expressed with viral-specific functions. The molecule proposed to disrupt the herpes gene is BrdC, where Br replaces a methyl (CH3) with nearly the same ionic radius and location (at the 5th position for BrdU, which has an oxygen molecule at the top). Therefore, BrdC could be oxidized and used as BrdU. Before oxidation, BrdC was unusable as dC or dU in mammalian cells (except for the herpes gene, which could incorporate the BrdC). The bromine atom is made from  arsenic , with the addition of an  alpha particle  in a  particle accelerator  to form  77 Br . It has a half-life of 57 hours and undergoes  electron capture : the  K-electron  is captured by a proton in an unstable nucleus, creating a K hole in Br, and leading to its Auger cascade and disrupting the herpes gene without killing the cell.


This experiment was performed during the 1970s at  Memorial Sloan Kettering Cancer Center  by Lawrance Helson and C. G. Wang, using 10 neuroblastoma  cell cultures , Two cultures were successful in terminating the cell replication with  77 Br   in vitro , and the experiments were followed by a group of  nude mice  with implanted tumors.


The  in vivo  mouse experiments were complicated when the mouse livers cleaved off the sugar component of BrdC rendering the mammalian and herpes genes to incorporate the  77 Br -containing base, making no distinction between them. However, the Auger dose with 77BrdC disrupted the herpes-specific gene in several transformed cell cultures. [ citation needed ]


The group of metal-based anticancer drugs originated with  cisplatin , one of the leading agents in clinical use. Cisplatin acts by binding to DNA, forming one or two intrastrand cross-links of the G-G  adduct  at 70% and the A-G adduct at ~20% of the major grooves of the  double helix . The planar  cis  compound (on the same side) is composed of a square molecule with two chloride atoms on one side and two ammonia groups on the other side, centered around the heavy  platinum  (Pt) which could initiate the Auger dose  in situ . Entering a cell with a low NaCl concentration, the aqua-chloride group would detach from the compound (allowing the missing chloride to link the G-G or A-G bases and bend the DNA helixes 45 degrees, damaging them). Although  platinum-based antineoplastics  are used in as much as 70 percent of all chemotherapy, they are not particularly effective against certain cancers (such as breast and prostate tumors).


The aqua-Cl rationale, detaching the chloride atom from the cisplatin when it enters a cell and binding them to G-G or A-G adducts in the major grooves of the DNA helixes, could be applied to other metals—such as  ruthenium  (Ru)-chemically similar to platinum. Ruthenium is used to coat the anode target of a mammography X-ray tube, enabling operation at any voltage (22–28  kVp ) depending on the compressed thickness of the breast and delivering a high-contrast image. Although ruthenium is lighter than platinum, it can be induced to provide an Auger dose  in situ  to the DNA adducts and deliver localized chemotherapy. [ 8 ] [ 9 ]


Monochromatic X-rays may be channeled from  synchrotron radiation , obtained from filtered Coolidge  X-ray tubes  or from the preferred transmission X-ray tubes. To induce  inner-shell ionization  with resonant scattering from a moderately-heavy atom with dozens of electrons, the X-ray  photon  energy must be 30 keV or higher to penetrate tissue in therapeutic applications. Although synchrotron radiation is extremely bright and monochromatic without thermal  scattering , its brightness falls off at the fourth power of photon energy. At 15–20 kV or higher an X-ray tube with a  molybdenum  target, for example, could deliver as much X-ray  fluence  as a typical synchrotron. A Coolidge X-ray tube brightens by 1.7 kVp and synchrotron brightness decreases by 4 kV, implying that it is not useful for Auger therapy. [ citation needed ]


In  radiation therapy ,  bolus  is a material which has properties equivalent to  tissue  when irradiated. It is widely used in practice to reduce or alter dosing for targeted radiation therapy.


It must be possible to mould the bolus to fill the tissue space. Lincolnshire and Spier's bolus, which is loosely packed in  polyethylene  bags, is suitable as the bolus bags take the shape of the skin surface these bags are easily smoothed to achieve a flat surface.


A specific thickness of bolus can be applied to the skin to alter the dose received at depth in the tissue and on the skin surface. A typical example of this is the application of a defined thickness of bolus to a chest wall for post-mastectomy chest wall treatment, to increase the skin dose. The thickness of bolus applied is dependent on the skin dose required and the angle of incidence of the treatment beams. For example, if oblique 6 MV beams are used for tangential pair, 1 cm of bolus effectively becomes 1.5 cm, i.e., "full bolus".


When a full bolus is applied, bolus thickness equal to the depth of the build-up region removes the  skin-sparing effect  of a  megavoltage x-ray  beam. On the other hand, there are boluses that do not require the selection of specific thicknesses to treat a certain depth. These types of boluses have densities higher than water but can be calculated from CT images by the Treatment Planning System (TPS). One of these boluses is commonly known as high-density and high-adaptation bolus (e.g.,  eXaSkin  and  eXaSkin Plus ).


Suitable material must be pliable and easily moulded to the skin surface, but retain a constant thickness. One example includes  paraffin  gauze.


For smaller areas which do not require the bolus to be moulded over the skin,  Perspex  can be used. The use of Perspex bolus is advantageous for electron set-ups because it is transparent. Since the f.s.d. for most electron fields is 95 cm, so that the movements of the couch are not isocentric, inaccuracies may arise for aligning angled fields when an opaque bolus is inserted.


To ensure that the patient receives the required dose, bolus of the right thickness must be placed correctly. Therefore, bolus requirements must be clearly documented in the setup sheets of the treatment card. When using bolus to compensate for missing tissue, the whole of the bolussed area must be level with the point on the patient where the f.s.d. is set, to ensure dose homogeneity.


When the bolus is used to reduce the skin-sparing effect, the bolus does not necessarily need to touch the skin all over the bolussed area as the scatter is of sufficiently high energy to be unaffected by an air gap. However, it is important that the bolus is uniform thickness. Some bolus materials are easily squashed and must be carefully measured at regular intervals.


A  bone-seeking radioisotope  is a  radioactive  substance that is given through a  vein , and collects in  bone cells  and in  tumor cells  that have spread to the  bone . It kills  cancer cells  by giving off low-level  radiation .


This article incorporates  public domain material  from  Dictionary of Cancer Terms .  U.S. National Cancer Institute .


The  Bragg peak  is a pronounced peak on the Bragg curve which plots the energy loss of  ionizing radiation  during its travel through matter. For  protons ,  α-rays , and other  ion rays , the peak occurs immediately before the particles come to rest. It is named after  William Henry Bragg , who discovered it in 1903 using alpha particles from radium, [ 1 ] [ 2 ]  and wrote the first empirical formula for ionization energy loss per distance with Richard Kleeman. [ 3 ]


When a fast  charged particle  moves through matter, it  ionizes  atoms of the material and deposits a  dose  along its path. A peak occurs because the interaction  cross section  increases as the charged particle's energy decreases. Energy lost by charged particles is inversely proportional to the square of their velocity, which explains the peak occurring just before the particle comes to a complete stop. [ 4 ]  In the upper figure, it is the peak for alpha particles of 5.49 MeV moving through air. In the lower figure, it is the narrow peak of the "native" proton beam curve which is produced by a  particle accelerator  of 250  MeV . The figure also shows the absorption of a beam of energetic  photons  ( X-rays ) which is entirely different in nature; the curve is mainly  exponential .


This characteristic of proton beams was first recommended for use in cancer therapy by Robert R. Wilson in his 1946 article, Radiological Use of Fast Protons. [ 5 ]  Wilson studied how the depth of proton beam penetration could be controlled by the energy of the protons. This phenomenon is exploited in  particle therapy  of cancer, specifically in proton therapy, to concentrate the effect of light  ion beams  on the  tumor  being treated while minimizing the effect on the surrounding healthy tissue. [ 6 ]


The blue curve in the figure ("modified  proton beam ") shows how the originally monoenergetic proton beam with the sharp peak is widened by increasing the range of energies, so that a larger tumor volume can be treated. The plateau created by modifying the proton beam is referred to as the spread out Bragg Peak, or SOBP, which allows the treatment to conform to not only larger tumors, but to more specific 3D shapes. [ 7 ]  This can be achieved by using variable thickness  attenuators  like spinning wedges. [ 8 ]  Momentum cooling in cyclotron-based proton therapy facilities enables a sharper distal fall-off of the Bragg peak and the attainment of high dose rates.  [ 9 ]


Chemoradiotherapy  ( CRT ,  CRTx ,  CT-RT ) is the combination of  chemotherapy  and  radiotherapy  to treat  cancer . [ 1 ]  Synonyms include  radiochemotherapy  ( RCT ,  RCTx ,  RT-CT ) and  chemoradiation . It is a type of  multimodal cancer therapy .


Chemoradiation can be  concurrent   [ 2 ]  (together) or  sequential  (one after the other). [ 3 ]


The chemotherapy component can be or include a  radiosensitizing agent . [ 2 ]


Chemoradiotherapy as  neoadjuvant therapy  before surgery has been shown to be effective in  esophageal cancer . [ 4 ]


Cobalt therapy   is the medical use of  gamma rays  from the  radioisotope   cobalt-60  to treat conditions such as  cancer .  Beginning in the 1950s, cobalt-60 was widely used in  external beam radiotherapy  (teletherapy) machines, which produced a beam of gamma rays which was directed into the patient's body to kill tumor tissue.  Because these "cobalt machines" were expensive and required specialist support, they were often housed in  cobalt units .  Cobalt therapy was a revolutionary advance in radiotherapy in the post-World War II period but is now being replaced by other technologies such as  linear accelerators . [ 1 ]


Before the development of medical  linear accelerators  in the 1970s, the only artificial radiation source used for  teletherapy  was the  x-ray tube .  Researchers found ordinary x-ray tubes, which used voltages of 50-150 keV, could treat superficial tumors, but did not have the energy to reach tumors deep in the body. To have the penetrating ability to reach deep-seated tumors without subjecting healthy tissue to dangerous radiation doses required rays with energy around a million electron volts (MeV), called "megavoltage" radiation. To produce a significant amount of MeV x-rays required potentials on the tube of 3-5 million volts (3-5 megavolts), necessitating huge, expensive x-ray machines. By the late 1930s these were being built, but they were available at only a few hospitals.


Radioisotopes  produced  gamma rays  in the megavolt range, but prior to  World War II  virtually the only radioisotope available for radiotherapy was naturally occurring  radium  (producing 1-2 MeV gamma rays), which was extremely expensive due to its low occurrence in ores. In 1937 the price of radium  US$25,000  (equivalent to $529,861 in 2023)   per   gram, [ 2 ]  and the total worldwide supply of radium available for beam radiotherapy (teletherapy) was 50   grams.


The invention of the  nuclear reactor  in the  Manhattan Project  during World War II made possible the creation of artificial radioisotopes for radiotherapy.  Cobalt-60 , produced by neutron irradiation of ordinary  cobalt  metal in a reactor, is a high activity gamma-ray emitter, emitting 1.17 and 1.33 MeV gamma rays with an activity of 44  TBq / g  (1,200  Ci /g).  The main reason for its wide use in radiotherapy is that it has a longer  half-life , 5.27 years, than many other gamma emitters. However, this half-life still requires cobalt sources to be replaced about every 5 years.


In 1949, Dr.  Harold E. Johns  of the  University of Saskatchewan  sent a request to the  National Research Council  (NRC) of Canada asking it to produce cobalt-60 isotopes for use in a cobalt therapy unit prototype. Two cobalt-60 apparatuses were then built, one in  Saskatoon  in the cancer wing of the University of Saskatchewan and the other in  London, Ontario . Johns collected depth-dose data at the University of Saskatchewan which would later become the world standard. [ 3 ]  The first patient to be treated with cobalt-60 radiation was treated on October 27, 1951, at the  War Memorial Children's Hospital  in London, Ontario. [ 4 ] [ 5 ]  In 1961 cobalt therapy was expected to replace X-ray radiotherapy. [ 6 ] : 14   In 1966,  Walt Disney 's lung cancer was treated with this procedure, but could not prevent his death. [ 7 ]


Dr.  Glenn T. Seaborg , chairman of the  United States Atomic Energy Commission ,  Nobel Prize  winner and former chancellor of the  University of California , dedicated the first cobalt facility of the new Radiation Therapy and Nuclear Medicine Wing of the  Cedars of Lebanon Hospital  on January 11, 1963 supervised by Dr. Henry L. Jaffe, Director of the new department. A pioneer in the use of the nicknamed "cobalt bomb" the Cedars unit was licensed in 1948 by the Atomic Energy Commission. [ 8 ]


The role of the cobalt unit has partly been replaced by the  linear accelerator , which can generate higher-energy radiation, and does not produce the  radioactive waste  that  radioisotopes  do with their attendant disposal problems. Cobalt treatment still has a useful role to play in certain applications and is still in widespread use worldwide, since the machinery is relatively reliable and simple to maintain compared to the modern linear accelerator. [ 9 ] [ 1 ]


As used in  radiotherapy , cobalt units produce stable, dichromatic beams of 1.17   and   1.33 MeV, resulting in an average beam energy of 1.25   MeV. Cobalt-60 has a  half-life  of 5.2713   years. [ 10 ] : 39


Henri Coutard [ a ]  (27 August 1876 – 16 March 1950) was a French  radiation therapist . He is known for his studies of  radiation therapy  for the treatment of  laryngeal cancer  and the development of the "protracted-fractional method" of radiation dosing.


Born in  Marolles-les-Braults  in the French department of  Sarthe , Coutard attended medical school at  University of Paris  and graduated in 1902. He served in the  French Army  and lived for several years in the  Jura Mountains  before returning to Paris to study the medical applications of  radium . During World War I, he worked in one of the radiological ambulance units overseen by the Polish-French physicist and chemist  Marie Curie . He became the chief of the  X-ray  department at the  Radium Institute  of the University of Paris in 1919, working closely with  Claudius Regaud  and other scientists. Coutard's early work demonstrating the efficacy of radiating patients with laryngeal cancer led to the adoption of radiation therapy as a primary course of cancer treatment. The protracted-fractional method consisted of long durations of radiation applied over several weeks.


In the late 1930s, Coutard moved to the United States, first working at the  California Institute of Technology  and then at the Chicago Tumor Institute. During this time, he accompanied the American entrepreneur  Spencer Penrose  to Colorado Springs to treat Penrose's  esophageal cancer . After Penrose's death in 1939, his radiotherapy equipment was donated to  Penrose Hospital  and Coutard became a radiotherapist at the newly-established Penrose Tumor Clinic. In the last decade of his life, Coutard's research became more erratic. He published a  monograph  in 1949 that was largely ignored by reputable journals and his peers. He experienced an  intracerebral hemorrhage  in December 1949 and died in  Le Mans  a few months later.


Henri Coutard was born on 27 August 1876 in  Marolles-les-Braults  in the French department of  Sarthe . His father, Louis Coutard, was a local government official, and his mother, Mélanie Marie Joséphine Coutard ( née  Ragot), sold  novelty items . [ 3 ] [ 4 ]  He had an older brother, Louis, and a younger sister, Helène. [ 3 ]


In 1887, Coutard enrolled at the  Lycée Montesquieu  [ fr ] , a state  boarding school  in  Le Mans . He received a  baccalauréat  in literature in 1893 and another in mathematics the following year. During this time, he also received an award for excellence in his school's military and gymnastics programs. After secondary school, he entered medical school at the  University of Paris , training in Parisian hospitals and completing an internship in  Nantes . [ 3 ]  His doctoral  thesis  was titled  Lesions extrapéritonéales de la vessie et du rectum dans les fractures du bassin  ("Extraperitoneal lesions of the bladder and rectum observed in cases of pelvic fracture"). [ 5 ]  It summarised eight cases from the literature and one from his previous patients. He defended his thesis on 17 July 1902. [ 3 ]


After medical school, Coutard enrolled as a medical officer and captain in the  Chasseurs Alpins , the elite  mountain infantry  force of the  French Army . [ 6 ]  After contracting  pulmonary tuberculosis  he moved to the  Jura Mountains  to recover, and during that time practiced general medicine. [ 4 ]  In 1912, he returned to Paris after becoming interested in the potential medical applications of  radioactivity . [ 3 ] [ 4 ]  Radioactivity had first been discovered in the element  uranium  by the physicist  Henri Becquerel  in 1896, and over the next several years, the French researchers  Marie  and  Pierre Curie  discovered the radioactivity of additional elements:  thorium ,  polonium , and  radium . [ 7 ]  Coutard began studying the properties of radium at an experimental laboratory co-founded by the physicist  Jacques Danne  [ fr ] . [ 3 ] [ 4 ]  His research centred on therapeutic applications of radium in animals, and he presented his work at the 1912 meeting of the  French Association for the Advancement of Science  [ fr ] . [ 3 ]


Coutard was  drafted  during World War I and worked as a  radiation therapist  in a military hospital near  Baccarat, Meurthe-et-Moselle , on the  Eastern Front . [ 3 ] [ 8 ]  There, he met  Claudius Regaud , a  radiobiologist  with whom he later collaborated. [ 3 ]  Coutard also worked in one of the radiological ambulance units overseen by Marie Curie. He attained the rank of  major  by the end of the war. [ 6 ] [ 9 ]


In 1919, Coutard became the chief of the  X-ray  department at the  Radium Institute  of the University of Paris, working with other scientists including Regaud and  Antoine Lacassagne . [ 4 ] [ 9 ]  Using a single X-ray unit in the basement of the institute, he conducted experiments on animals, administered  radiation therapy  to patients, and performed diagnostic imaging of the  pharynx  and  larynx . [ 9 ] [ 10 ]  In his early work during this period, he observed the recurrence of cancer when  tumours  were insufficiently irradiated and the need to avoid excessive irradiation of the eyes. He believed that the dose of radiation needed to be high enough to cause an observable reaction in the  mucous membrane , and coined the term  radioepithelitis  to describe this reaction. [ 11 ]  At the 1921 International Congress of Oto-Rhino-Laryngology in Paris, Coutard presented data from six patients with  laryngeal cancer  who he had treated with radiation. His work was well received, and physicians began adopting radiation therapy as a primary course of treatment for cancer. [ 4 ]


Scientists had differing opinions on the optimal timing of radiation doses. [ 12 ]  Coutard believed that long durations of radiation, applied over several weeks, produced the best results and theorised that this technique allowed  tissue  to recover between sessions. [ 13 ] [ 12 ]  He presented his method at the 1928  International Congress of Radiology , and it became known as "Coutard's method" or the "protracted-fractional method". [ 12 ] [ 14 ]  Using this technique, Coutard achieved the first reported cures of laryngeal cancer using radiation, and by about 1930 he had obtained data on the  five-year survival rate  of his technique. [ 15 ] [ 16 ]  Though he never published rigid standards for radiation doses, he meticulously recorded the treatments that he administered to each patient, using a  radiometer  that he constructed. [ 10 ] [ 17 ]  Over the next decade, he continued experimenting with different therapy regimens, including short, intensive doses and interrupted regimens. [ 10 ]  Radiotherapists from other countries visited the Radium Institute to meet Coutard and train with him, [ 9 ]  including Simeon T. Cantril, who later became the first president of the  American Society for Radiation Oncology . [ 18 ] [ 19 ]


Coutard grew interested in United States radiotherapy research, where supervoltage units ( X-ray generators  with a  peak kilovoltage  of several hundred kilovolts) were being produced. [ 20 ]  The physicist  Charles Christian Lauritsen , on behalf of his mentor  Robert Andrews Millikan , invited Coutard to work at the Kellogg Research Laboratory at the  California Institute of Technology . At the same time, Max Cutler of the Chicago Tumor Institute offered Coutard a leading position there. Coutard accepted both offers in late 1937. [ 21 ]  He resigned his position at the Radium Institute and was succeeded by  François Baclesse  [ lb ] . [ 22 ]  At Caltech, he studied  high-voltage  therapy and worked closely with Millikan and the physicist  Seeley G. Mudd . [ 13 ] [ 21 ]


After working at Caltech for six months, Coutard moved to  Chicago  and studied the use of short, concentrated doses of radiation for treating laryngeal cancer at the Chicago Tumor Institute, while teaching  graduate  courses there. [ 13 ]  Cutler's ambitions for the institute were curtailed as a result of the  Great Depression . [ 21 ]  He was unable to secure a supervoltage unit for Coutard, and the institute did not receive many patients. [ 23 ]  During this time, Coutard treated the American  entrepreneur  and  philanthropist   Spencer Penrose  for  esophageal cancer , having previously treated Penrose for laryngopharyngeal cancer in Paris in 1932. Penrose bought a radiotherapy unit for his home in  Colorado Springs, Colorado , and Coutard accompanied him there to continue his treatment. [ 24 ]


Penrose died in 1939, and stipulated that his radiotherapy equipment be donated to the local Glockner Hospital (now  Penrose Hospital ). His wife, Julie Penrose, used funds from their  El Pomar Foundation  to establish the Penrose Tumor Clinic at the hospital and invited Coutard to practice radiotherapy at the new clinic. [ 25 ]  He accepted, and moved to Colorado Springs in 1941. [ 13 ]


In the last decade of his life, Coutard's research became more erratic. He began to conduct unorthodox experiments, including the use of blocks of gold as  X-ray filters  and  homeopathic  theories of  beta particles , and stopped publishing papers in scientific journals. [ 13 ]  His ideas were criticised by his peers and he became increasingly isolated. [ 25 ]


Coutard published a  monograph  in 1949, reporting on his findings from Colorado Springs. [ 25 ]  According to the radiologist and historian E. R. N. Grigg, the monograph was a "rambling mixture of clinical observations, working hypotheses, and fantastic assumptions"; it was largely ignored by reputable journals as well as his peers. [ 13 ]


Coutard married Anne-Marie Adèle Rougier in Paris on 25 March 1919, at the end of World War I. [ 13 ] [ 26 ]  During his time at the Radium Institute, they lived on the outskirts of Paris. [ 12 ]  Anne-Marie remained in Paris when Henri worked in the United States, and she died of  leukemia  there in 1940. [ 13 ] [ 23 ]  After her death, Coutard married Suzanne Rosalie Jourgeon (née Mathot), the widow of one of his former patients in France. [ 13 ]  She moved to Colorado Springs and they lived within walking distance of the Penrose Tumor Clinic. When Suzanne's health deteriorated in 1949, she moved back to Paris to live with her children from her first marriage; she died there later that year. [ 25 ]


In late 1949 Coutard traveled to the Radium Station of Copenhagen, where the director, Jens Nielsen, was one of his few remaining followers. [ 25 ]  He experienced an  intracerebral hemorrhage  on a trip to France to visit his sister's family in December 1949. [ 27 ]  After several months of illness, Coutard died at his sister's home in Le Mans on 16 March 1950. [ 28 ]


While Coutard's experiments in final years were considered unorthodox by his peers, his earlier contributions helped radiation therapy become an established treatment for people with cancer. Grigg described Coutard's most important contribution as "teaching a generation of radiologists to observe their patients carefully and to record painstakingly the clinical course of treatment". [ 17 ]  Coutard's protracted-fractional method laid the groundwork for modern dose fractionation methods, [ 29 ]  and he is also remembered for being the first to present results on X-ray imaging of the larynx. During his lifetime, he published about 35 papers in addition to his 1949 monograph. [ 17 ]  His hometown, Marolles-les-Braults, later named a square near the center of the town after him. [ 28 ]


D50  in medicine is the half-maximal  dose : the dose that produces 50% of the maximum response. [ 1 ]   It may specifically refer to the radiation dose required to achieve a 50%  tumor control probability . [ 2 ]


Deep inspiration breath-hold  (DIBH) is a method of delivering  radiotherapy  while limiting  radiation exposure  to the heart and lungs. [ 1 ]  It is used primarily for treating left-sided  breast cancer .


The technique involves a patient holding their breath during treatment. In DIBH techniques, treatment is only delivered at certain points in the breathing cycle, where the patient holds their breath. Since the relative positions of organs in the chest naturally changes during breathing, this allows treatment to be delivered to the target (tumour) while other organs are in the optimal position to receive least dose. [ 2 ]


In the DIBH technique, the patient is initially maintained at quiet tidal  breathing  (i.e. normal, relaxed breathing), [ 3 ]  followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100%  vital capacity , and simulation, verification, and treatment take place during this phase of breath-holding. [ 4 ]  DIBH is performed with several tangential fields for left-sided breast cancer. A patient is instructed to hold the breath while viewing the breathing pattern and the breath-hold position through a head-mounted mirror, thereby ensuring reproducibility of the breath-hold position in each delivery. [ 5 ]  A pair of video goggles may also be used for monitoring the breathing cycle. Patients who cannot maintain DIBH can still benefit from lung tracking techniques, for example  4DCT . [ 6 ]


There are two basic methods of performing DIBH: free-breathing breath-hold, and  spirometry -monitored deep inspiration breath hold. [ 7 ]


Free-breathing breath-hold, also known as real-time position management (RPM) DIBH utilises an infra-red camera and markers placed on the patient to track movement of their chest, and their breathing. [ 8 ]  Another device for DIBH is known as Abches that monitors the breathing pattern. [ 9 ]  With the Abches, a patient is instructed to hold the breath at a specified breathing position by viewing a breathing level indicator, thereby reproducing an identical breath-hold position. [ 10 ]


Spirometry based designs are known as active breathing coordinator (ABC) DIBH systems. ABC utilises a mouth piece for the patient which can be used to control the flow of air to provide more reproducible results. [ 11 ]


The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of  toxicity . [ 4 ]


Treatment of patients with the DIBH technique is feasible in a clinical setting. With this technique, consistent lung inflation levels are achieved in patients, as judged by both spirometry and verification films. Breathing-induced tumor motion is significantly reduced using DIBH compared to free breathing, enabling better target coverage. [ 12 ]


There is currently no clear selection criteria to predict which patients will benefit most from the DIBH technique, other than left  breast  laterality. There is evidence to suggest  parasagittal  cardiac contact distance is a promising metric for selection and should be assessed in all future DIBH planning studies. [ 7 ]


Diffusing Alpha-emitters Radiation Therapy  or  DaRT  is an  alpha-particle -based  radiation therapy  for the treatment of  solid tumors . [ 1 ] [ 2 ]


This therapy was developed at  Tel Aviv University  in Israel, by Professors Itzhak Kelson and Yona Keisari. The treatment is delivered by the intratumoral insertion of metal tubes called “seeds”, which have  Radium-224  atoms fixed to their surface. When the radium decays, its short-lived daughter Radon-220 is released from the seed through recoil energy. [ 3 ]  The daughters of Radon-220, in particular Pb-212, disperse in the tumor, and emit high-energy alpha particles, which destroy the tumor. Because the alpha-emitting atoms diffuse only a few millimeters in tissue, the DaRT eradicates the tumor cells and spares the surrounding healthy tissue. [ 3 ]


Alpha radiation is a nuclear phenomenon in which a heavy radionuclide emits an energetic alpha particle (consisting of two protons and two neutrons) and transmutes to a different radionuclide. The emitted alpha particle has a range in tissue of only 40-90 microns, which minimizes collateral damage when used for treatment purposes. However, this also limits its ability to destroy tumors that are many millimeters in diameter. Alpha radiation possesses a potent cell-killing capability because it has a high  linear energy transfer  (LET) which translates into a high  Relative Biological Effectiveness  (RBE). [ 4 ]


The invention of DaRT makes possible the use of alpha radiation for treating solid tumors, because it overcomes the range limitation of alpha particles in tissue. The daughter atoms of Radium-224 can each diffuse several millimeters in tumor tissue, while emitting alpha particles. The tumor-killing capability of DaRT comes mainly from the ability of alpha radiation to irreparably break the double stranded DNA in tumor cells. [ 5 ]  This capability does not seem to be dependent on the stage of the cell cycle or the level of oxygenation of the cancer cell. [ citation needed ]


Preclinical studies have demonstrated that DaRT can effectively damage all solid tumor types. Studies of 10 different tumor types in mice demonstrated that all responded to DaRT. [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ excessive citations ]


In preclinical studies, DaRT effectiveness was enhanced when combined with standard chemotherapies such as 5-FU. In addition, DaRT was able to turn the tumor into its own vaccine and stimulate a systemic anti-tumor immune response. [ 13 ]  This immune response was effectively augmented by addition of immunostimulants and/or inhibitors of immunosuppressive cells. This immune effect was observed not only as enhanced local tumor destruction at the primary tumor site, but also by elimination of tumor metastases in the lungs. [ 12 ] [ 14 ]   These results suggest that DaRT combined with immunotherapy induces a tumor-specific systemic immune response. [ citation needed ]


The first results of the DaRT in human patients, from a pilot study of 28 patients by Prof. Popovtzer (Israel) and Dr. Bellia (Italy), were published in 2020. [ 15 ]  From among this cohort of elderly patients (median age, 80.5 years), 61% had recurrent and previously treated tumors, including 42% who were radioresistant from prior therapy. Patients were diagnosed with histopathologically confirmed  squamous cell carcinoma  of the skin or  head and neck . One-hundred percent of tumors responded to DaRT, with complete responses occurring in greater than 78% of cases, and no major toxicity was noted.  Thirty days after treatment, there was no measurable radioactivity in the blood or urine of patients. Additional studies in larger populations are now ongoing to strengthen support regarding the safety and effectiveness of this technique of intratumoral alpha radiation-based tumor ablation. [ citation needed ]


In external beam  Radiotherapy , transverse and longitudinal  dose measurements  are taken by a radiation detector in order to characterise the radiation beams from medical  linear accelerators . [ 1 ]  Typically, an  ionisation chamber  and water phantom are used to create these radiation dose profiles.  Water  is used due to its tissue equivalence.


Transverse dose measurements are performed in the x (crossplane) or y (inplane) directions perpendicular to the radiation beam, and at a given depth (z) in the phantom. These are known as  dose profiles .
Dose measurements taken along the z direction create radiation dose distribution known as a depth-dose curve.


DVS (Dose Verification System) , developed by Sicel Technologies, was an implantable telemetric, radiation sensor. [ 1 ]  The device was used to measure the amount of  radiation  that was delivered to tumor and/or healthy tissue.  The DVS sensor contained a dosimeter and wireless transmitter inside a sealed, biocompatible glass capsule measuring 0.8 inches (20mm) long and 0.08 inches (2.1mm) across. The sensor was implantable transluminally or transdermally. The device had limited adoption by the radiation  oncology  community, sales were thus inadequate for profitability.


The company (Sicel) eventually ceased to exist circa 2011. [ 2 ]


A  dose-volume histogram  (DVH) is a  histogram  relating  radiation dose  to tissue  volume  in  radiation therapy  planning. [ 1 ]  DVHs are most commonly used as a plan evaluation tool and to compare doses from different plans or to structures. [ 2 ]  DVHs were introduced by Michael Goitein (who introduced radiation therapy concepts such as the "beam's-eye-view," "digitally reconstructed radiograph," and uncertainty/error in planning and positioning, among others) and Verhey in 1979. [ 3 ]  DVH summarizes 3D dose distributions in a graphical 2D format. In modern radiation therapy, 3D dose distributions are typically created in a computerized  treatment planning system  (TPS) based on a 3D reconstruction of a  CT  scan. The "volume" referred to in DVH analysis is a target of radiation treatment, a healthy organ nearby a target, or an arbitrary structure.


DVHs can be visualized in either of two ways: differential DVHs or cumulative DVHs. A DVH is created by first determining the size of the dose bins of the histogram. Bins can be of arbitrary size, 0.005 Gy, 0.2 Gy or 1 Gy for instance. [ 4 ]  The size is often a matter of tradeoff between accuracy and computational or memory cost (if we store the DVH in a database).


In a differential DVH, bar or column height indicates the volume of structure receiving a dose given by the bin. Bin doses are along the horizontal axis, and structure volumes (either percent or absolute volumes) are on the vertical. The differential DVH takes the appearance of a typical  histogram . The total volume of the  organ  that receives a certain dose is plotted in the appropriate dose bin. [ 5 ]  This volume is determined by the total number of  voxels  characterized by a specified range of dosage for the organ considered. The differential DVH provides information about changes in dose within the structure considered as well as visualization of minimum and maximum dose. [ 6 ]


The cumulative DVH is plotted with bin doses along the horizontal axis, as well. However, the column height of the first bin (e.g., [0, 1] Gy) represents the volume of structure receiving a dose greater than or equal to that dose. [ 5 ]  The column height of the second bin (e.g., (1, 2] Gy) represents the volume of structure receiving greater than or equal to that dose, etc. With very fine (small) bin sizes, the cumulative DVH takes on the appearance of a smooth line graph. The lines always slope and start from top-left to bottom-right. For a structure receiving a very homogeneous dose (100% of the volume receiving exactly 10 Gy, for example) the cumulative DVH will appear as a horizontal line at the top of the graph, at 100% volume as plotted vertically, with a vertical drop at 10 Gy on the horizontal axis.


A DVH used clinically usually includes all structures and targets of interest in the  radiotherapy  plan, each line plotted a different color, representing a different structure. The vertical axis is almost always plotted as percent volume (rather than absolute volume), as well. [ 7 ]


Clinical studies have shown that DVH metrics correlate with patient toxicity outcomes. [ 8 ]  A drawback of the DVH methodology is that it offers no spatial information; i.e., a DVH does not show where within a structure a dose is received. [ 9 ]  Also, DVHs from initial radiotherapy plans represent the doses to structures at the start of radiation treatment. As treatment progresses and time elapses, if there are changes (i.e. if patients lose weight, if tumors shrink, if organs change shape, etc.), the original DVH loses its accuracy. [ 10 ]


Radiation dosimetry  in the fields of  health physics  and  radiation protection  is the measurement, calculation and assessment of the  ionizing radiation  dose absorbed by an object, usually the human body. This applies both internally, due to ingested or inhaled radioactive substances, or externally due to irradiation by sources of radiation.


Internal dosimetry  assessment relies on a variety of monitoring, bio-assay or radiation imaging techniques, whilst external dosimetry is based on measurements with a  dosimeter , or inferred from measurements made by other  radiological protection instruments . [ 1 ]


Radiation dosimetry is extensively used for radiation protection; routinely applied to monitor occupational radiation workers, where irradiation is expected, or where radiation is unexpected, such as in the contained aftermath of the  Three Mile Island ,  Chernobyl  or  Fukushima  radiological release incidents. The public dose take-up is measured and calculated from a variety of indicators such as ambient measurements of gamma radiation, radioactive particulate monitoring, and the measurement of levels of  radioactive contamination .


Other significant radiation dosimetry areas are medical, where the required treatment  absorbed dose  and any collateral absorbed dose is monitored, and environmental, such as  radon  monitoring in buildings.


There are several ways of measuring absorbed doses from ionizing radiation. People in occupational contact with radioactive substances, or who may be exposed to radiation, routinely carry personal  dosimeters . These are specifically designed to record and indicate the dose received. Traditionally, these were lockets fastened to the external clothing of the monitored person, which contained photographic film known as  film badge dosimeters . These have been largely replaced with other devices such as  Thermoluminescent dosimetry (TLD),  optically stimulated luminescence (OSL), or  Fluorescent Nuclear Tract Detector (FNTD) badges. [ 2 ] [ 3 ]


The  International Committee on Radiation Protection  (ICRP) guidance states that if a personal dosimeter is worn on a position on the body representative of its exposure, assuming whole-body exposure, the value of Personal Dose Equivalent Hp(10), is sufficient to estimate an effective dose value suitable for radiological protection. Personal Dose Equivalent is a radiation quantity specifically designed to be used for radiation measurements by personal dosimeters. [ 4 ]  Dosimeters are known as "legal dosimeters" if they have been approved for use in recording personnel dose for regulatory purposes. In cases of non-uniform irradiation such personal dosimeters may not be representative of certain specific areas of the body, where additional dosimeters are used in the area of concern.


A number of electronic devices known as Electronic Personal Dosimeters (EPDs) have come into general use using semiconductor detection and programmable processor technology. These are worn as badges but can give an indication of instantaneous dose rate and an audible and visual alarm if a dose rate or a total integrated dose is exceeded. A good deal of information can be made immediately available to the wearer of the recorded dose and current dose rate via a local display. They can be used as the main stand-alone dosimeter, or as a supplement to other devices. EPD's are particularly useful for real-time monitoring of dose where a high dose rate is expected which will time-limit the wearer's exposure.


In certain circumstances, a dose can be inferred from readings taken by fixed instrumentation in an area in which the person concerned has been working. This would generally only be used if personal dosimetry had not been issued, or a personal dosimeter has been damaged or lost. Such calculations would take a pessimistic view of the likely received dose.


Internal dosimetry  is used to evaluate the  committed dose  due to the intake of radionuclides into the human body.


Medical dosimetry is the calculation of absorbed dose and optimization of dose delivery in  radiation therapy . It is often performed by a professional health physicist with specialized training in that field. In order to plan the delivery of radiation therapy, the radiation produced by the sources is usually characterized with  percentage depth dose curves  and  dose profiles  measured by a  medical physicist . [ 5 ]


In radiation therapy, three-dimensional dose distributions are often evaluated using a technique known as  gel dosimetry . [ 6 ]


Environmental dosimetry is used where it is likely that the environment will generate a significant radiation dose. An example of this is  radon  monitoring. The largest single source of radiation exposure to the general public is naturally occurring radon gas, which comprises approximately 55% of the annual background dose. It is estimated that radon is responsible for 10% of lung cancers in the United States. Radon is a radioactive gas generated by the decay of uranium, which is present in varying amounts in the Earth's crust. Certain geographic areas, due to the underlying geology, continually generate radon which permeates its way to the Earth's surface. In some cases the dose can be significant in buildings where the gas can accumulate. A number of specialised dosimetry techniques are used to evaluate the dose that a building's occupants may receive.


Records of legal dosimetry results are usually kept for a set period of time, depending upon the legal requirements of the nation in which they are used.


Medical radiation exposure monitoring  is the practice of collecting dose information from radiology equipment and using the data to help identify opportunities to reduce unnecessary dose in medical situations. [ 5 ]


To enable consideration of stochastic health risk, calculations are performed to convert the physical quantity absorbed dose into equivalent and effective doses, the details of which depend on the radiation type and biological context. [ 7 ]  For applications in  radiation protection  and dosimetry assessment the (ICRP) and the  International Commission on Radiation Units and Measurements  (ICRU) have published recommendations and data which are used to calculate these.


There are a number of different measures of radiation dose, including  absorbed dose  ( D ) measured in:


Each measure is often simply described as ‘dose’, which can lead to confusion. Non- SI  units are still used, particularly in the USA, where dose is often reported in rads and dose equivalent in  rems . By definition, 1 Gy = 100 rad and 1 Sv = 100 rem.


The fundamental quantity is the absorbed dose ( D ), which is defined as the mean energy imparted [by ionising radiation] (dE) per unit mass (dm) of material (D = dE/dm) [ 8 ]  The SI unit of absorbed dose is the gray (Gy) defined as one joule per kilogram. Absorbed dose, as a point measurement, is suitable for describing localised (i.e. partial organ) exposures such as tumour dose in radiotherapy. It may be used to estimate stochastic risk provided the amount and type of tissue involved is stated. Localised diagnostic dose levels are typically in the 0–50 mGy range. At a dose of 1 milligray (mGy) of photon radiation, each cell nucleus is crossed by an average of 1 liberated electron track. [ 9 ]


The absorbed dose required to produce a certain biological effect varies between different types of radiation, such as  photons ,  neutrons  or  alpha particles . This is taken into account by the equivalent dose (H), which is defined as the mean dose to organ T by radiation type R ( D T,R ), multiplied by a weighting factor  W R  . This designed to take into account the  biological effectiveness  (RBE) of the radiation type, [ 8 ]  For instance, for the same absorbed dose in Gy, alpha particles are 20 times as biologically potent as X or gamma rays. The measure of ‘dose equivalent’ is not organ averaged and now only used for "operational quantities". Equivalent dose is designed for estimation of stochastic risks from radiation exposures. Stochastic effect is defined for radiation dose assessment as the  probability  of cancer induction and genetic damage. [ 10 ]


As dose is averaged over the whole organ; equivalent dose is rarely suitable for evaluation of acute radiation effects or tumour dose in radiotherapy. In the case of estimation of stochastic effects, assuming a  linear dose response , this averaging out should make no difference as the total energy imparted remains the same.


Effective dose is the central dose quantity for radiological protection used to specify exposure limits to ensure that the occurrence of stochastic health effects is kept below unacceptable levels and that tissue reactions are avoided. [ 12 ]


It is difficult to compare the stochastic risk from localised exposures of different parts of the body (e.g. a chest x-ray compared to a CT scan of the head), or to compare exposures of the same body part but with different exposure patterns (e.g. a cardiac CT scan with a cardiac nuclear medicine scan). One way to avoid this problem is to simply average out a localised dose over the whole body. The problem of this approach is that the stochastic risk of cancer induction varies from one tissue to another.


The effective dose  E  is designed to account for this variation by the application of specific weighting factors for each tissue ( W T ). Effective dose provides the equivalent whole body dose that gives the same risk as the localised exposure. It is defined as the sum of equivalent doses to each organ ( H T ), each multiplied by its respective tissue weighting factor ( W T ).


Weighting factors are calculated by the International Commission for Radiological Protection (ICRP), based on the risk of cancer induction for each organ and adjusted for associated lethality, quality of life and years of life lost. Organs that are remote from the site of irradiation will only receive a small equivalent dose (mainly due to scattering) and therefore contribute little to the effective dose, even if the weighting factor for that organ is high.


Effective dose is used to estimate stochastic risks for a ‘reference’ person, which is an average of the population. It is not suitable for estimating stochastic risk for individual medical exposures, and is not used to assess acute radiation effects.


Radiation dose refers to the amount of energy deposited in matter and/or biological effects of radiation, and should not be confused with the unit of radioactive activity ( becquerel , Bq) of the source of radiation, or the strength of the radiation field (fluence). The article on the  sievert  gives an overview of dose types and how they are calculated. Exposure to a source of radiation will give a dose which is dependent on many factors, such as the activity, duration of exposure, energy of the radiation emitted, distance from the source and amount of shielding.


The worldwide average background dose for a human being is about 3.5 mSv per year  [1] , mostly from  cosmic radiation  and natural  isotopes  in the earth. The largest single source of radiation exposure to the general public is naturally occurring radon gas, which comprises approximately 55% of the annual background dose. It is estimated that radon is responsible for 10% of lung cancers in the United States.


Because the human body is approximately 70% water and has an overall density close to 1 g/cm 3 , dose measurement is usually calculated and calibrated as dose to water.


National standards laboratories such as the  National Physical Laboratory, UK  (NPL) provide calibration factors for ionization chambers and other measurement devices to convert from the instrument's readout to absorbed dose. The standards laboratories operates as a  primary standard , which is normally calibrated by absolute  calorimetry  (the warming of substances when they absorb energy). A user sends their secondary standard to the laboratory, where it is exposed to a known amount of radiation (derived from the primary standard) and a factor is issued to convert the instrument's reading to that dose. The user may then use their secondary standard to derive calibration factors for other instruments they use, which then become tertiary standards, or field instruments.


The NPL operates a graphite-calorimeter for absolute photon dosimetry. Graphite is used instead of water as its  specific heat capacity  is one-sixth that of water and therefore the temperature increase in graphite is 6 times higher than the equivalent in water and measurements are more accurate. Significant problems exist in insulating the graphite from the surrounding environment in order to measure the tiny temperature changes. A lethal dose of radiation to a human is approximately 10–20 Gy. This is 10–20 joules per kilogram. A 1 cm 3  piece of graphite weighing 2 grams would therefore absorb around 20–40 mJ. With a specific heat capacity of around 700 J·kg −1 ·K −1 , this equates to a temperature rise of just 20 mK.


Dosimeters in radiotherapy ( linear particle accelerator  in external beam therapy) are routinely calibrated using  ionization chambers [ 14 ]  or diode technology or gel dosimeters. [ 6 ]


Although the United States Nuclear Regulatory Commission permits the use of the units  curie , rad, and  rem  alongside SI units, [ 15 ]  the  European Union   European units of measurement directives  required that their use for "public health ... purposes" be phased out by 31 December 1985. [ 16 ]


The  EGS  ( Electron Gamma Shower ) computer code system is a general purpose package for the  Monte Carlo  simulation of the coupled transport of  electrons  and  photons  in an arbitrary geometry for particles with energies from a few keV up to several hundreds of GeV. [ 1 ]  It originated at  SLAC  but  National Research Council of Canada  and  KEK  have been involved in its development since the early 80s.


Development of the original EGS code ended with version EGS4. Since then two groups have re-written the code with new physics: