The SUV has emerged as a clinically useful, albeit controversial, semi-quantitative tool in PET analysis. [ 39 ]  Standardizing imaging protocols and measuring the SUV at the same time post-injection of the radiotracer, is necessary to obtain a correct SUV [ 40 ]  because imaging before the uptake plateau introduces unpredictable errors of up to 50% with SUVs. [ 41 ]  Noise, image resolution, and reconstruction do affect the accuracy of SUVs, but correction with phantom can minimize these differences when comparing SUVs for multi-centre clinical trials. [ 42 ] [ 43 ]  SUV may lack sensitivity in measuring response to treatment as it is a simple measure of tracer uptake in bone, which is affected by the tracer uptake in other competing tissues and organs in addition to the target ROI. [ 44 ] [ 45 ]


The quantification of dynamic PET studies to measure Ki requires the measurement of the skeletal  time-activity curves  (TAC) from the region of interest (ROI) and the  arterial input function  (AIF), which can be measured in various different ways. However, the most common is to correct the image-based blood time-activity curves using several venous blood samples taken at discrete time points while the patient is scanned. The calculation of rate constants or K i  requires three steps: [ 3 ]


The method was first described by Cunningham & Jones [ 46 ]  in 1993 for the analysis of dynamic PET data obtained in the brain. It assumes that the tissue impulse response function (IRF) can be described as a combination of many exponentials. Since A tissue TAC can be expressed as a convolution of measured arterial input function with IRF, C bone (t) can be expressed as:


C

 b
 o
 n
 e

 (
 t
 )
 =

 ∑

 k
 =
 1

 n

 α

 i

 .

 (

 C

 p
 l
 a
 s
 m
 a

 (
 t
 )
 ⊗
 e
 x
 p
 (
 −

 β

 i

 .
 t
 )

 )

 {\displaystyle C_{bone}(t)=\sum _{k=1}^{n}\alpha _{i}.{\bigl (}C_{plasma}(t)\otimes exp(-\beta _{i}.t){\bigr )}}


where,

 ⊗

 {\displaystyle \otimes }

  is a convolution operator, C bone (t) is the bone tissue activity concentration of tracer (in units: MBq/ml) over a period of time t, C plasma (t) is the plasma concentration of tracer (in units: MBq/ml) over a period of time t, IRF(t) is equal to the sum of exponentials, β values are fixed between 0.0001 sec −1  and 0.1 sec −1  in intervals of 0.0001, n is the number of α components that resulted from the analysis and β 1 , β 2 ,..., β n  corresponds to the respective α 1 , α 2 ,..., α n  components from the resulted spectrum. The values of α are then estimated from the analysis by fitting multi-exponential to the IRF. The intercept of the linear fit to the slow component of this exponential curve is considered the plasma clearance (K i ) to the bone mineral.


The method was first described by Williams et al. in the clinical context. [ 47 ]  The method was used by numerous other studies. [ 48 ] [ 49 ] [ 50 ]  This is perhaps the simplest of all the mathematical methods for the calculation of  K i  but the one most sensitive to noise present in the data. A tissue TAC is modelled as a convolution of measured arterial input function with IRF, the estimates for IRF are obtained iteratively to minimise the differences between the left- and right-hand side of the following Equation:


C

 b
 o
 n
 e

 (
 t
 )
 =

 C

 p
 l
 a
 s
 m
 a

 (
 t
 )
 ⊗
 I
 R
 F
 (
 t
 )

 {\displaystyle C_{bone}(t)=C_{plasma}(t)\otimes IRF(t)}


where,

 ⊗

 {\displaystyle \otimes }

  is a convolution operator, C bone (t) is the bone tissue activity concentration of tracer (in units: MBq/ml) over a period of time t, C plasma (t) is the plasma concentration of tracer (in units: MBq/ml) over a period of time t, and IRF(t) is the impulse response of the system (i.e., a tissue in this case). The  K i  is obtained from the IRF in a similar fashion to that obtained for the spectral analysis, as shown in the figure.


The measurement of Ki from dynamic PET scans require tracer kinetic modelling to obtain the model parameters describing the  biological processes  in  bone , as described by Hawkins et al. [ 22 ]  Since this model has two tissue compartments, it is sometimes called a two-tissue compartmental model. Various different versions of this model exist; however, the most fundamental approach is considered here with two tissue compartments and four tracer-exchange parameters. The whole kinetic modelling process using Hawkins model can be summed up in a single image as seen on the right-hand-side. The following differential equations are solved to obtain the rate constants:


d

 C

 e

 (
 t
 )

 d

 t

 =

 K

 1

 ∗

 C

 p

 (
 t
 )
 −
 (

 k

 2

 +

 k

 3

 )
 ∗

 C

 e

 (
 t
 )
 +

 k

 4

 ∗

 C

 b

 (
 t
 )

 {\displaystyle {\operatorname {d} \!C_{e}(t) \over \operatorname {d} \!t}=K_{1}*C_{p}(t)-(k_{2}+k_{3})*C_{e}(t)+k_{4}*C_{b}(t)}


d

 C

 b

 (
 t
 )

 d

 t

 =

 k

 3

 ∗

 C

 e

 (
 t
 )
 −

 k

 4

 ∗

 C

 b

 (
 t
 )

 {\displaystyle {\operatorname {d} \!C_{b}(t) \over \operatorname {d} \!t}=k_{3}*C_{e}(t)-k_{4}*C_{b}(t)}


The rate constant  K 1  (in units: ml/min/ml) describes the unidirectional clearance of fluoride from plasma to the whole of the bone tissue,  k 2  (in units: min −1 ) describes the reverse transport of fluoride from the ECF compartment to plasma,  k 3  and  k 4  (in units min −1 ) describe the forward and backward transportation of fluoride from the bone mineral compartment.


K i  represents the net plasma clearance to bone mineral only.  K i  is a function of both  K 1 , reflecting bone blood flow, and the fraction of the tracer that undergoes specific binding to the bone mineral  k 3  / ( k 2  +  k 3 ). Therefore,

 K

 i

 =

 (

 K

 1

 ∗

 k

 3

 k

 2

 +

 k

 3

 )

 {\displaystyle K_{i}=\left({\frac {K_{1}*k_{3}}{k_{2}+k_{3}}}\right)}


Hawkins et al. found that the inclusion of an additional parameter called fractional  blood volume  (BV), representing the vascular tissue spaces within the ROI, improved the data fitting problem, although this improvement was not statistically significant. [ 51 ]


Patlak method [ 52 ]  is based on the assumption that the backflow of tracer from bone mineral to bone ECF is zero (i.e., k 4 =0). The calculation of K i  using Patlak method is simpler than using  non-linear regression  (NLR) fitting the  arterial input function  and the tissue  time-activity curve  data to the Hawkins model. The Patlak method can only measure bone plasma clearance ( K i ), and cannot measure the individual kinetic parameters, K 1 , k 2 , k 3 , or k 4 .


The concentration of tracer in tissue region-of-interest can be represented as a sum of concentration in bone ECF and the bone mineral. It can be mathematically represented as


C

 b
 o
 n
 e

 (
 T
 )

 C

 p
 l
 a
 s
 m
 a

 (
 T
 )

 =

 K

 i

 ∗

 ∫

 0

 T

 C

 p
 l
 a
 s
 m
 a

 (
 t
 )
 d
 t

 C

 p
 l
 a
 s
 m
 a

 (
 T
 )

 +

 V

 o

 {\displaystyle {\frac {C_{bone}(T)}{C_{plasma}(T)}}=K_{i}*{\frac {\int \limits _{0}^{T}C_{plasma}(t)dt}{C_{plasma}(T)}}+V_{o}}


where, within the tissue region-of-interest from the PET image, C bone (T) is the bone tissue activity concentration of tracer (in units: MBq/ml) at any time T, C plasma (T) is the plasma concentration of tracer (in units: MBq/ml) at time T, V o  is the fraction of the ROI occupied by the ECF compartment, and

 ∫

 0

 T

 C

 p
 l
 a
 s
 m
 a

 (
 t
 )
 d
 t

 {\displaystyle \int \limits _{0}^{T}C_{plasma}(t)dt}

  is the area under the plasma curve is the net tracer delivery to the tissue region of interest (in units: MBq.Sec/ml) over time T. The Patlak equation is a linear equation of the form

 Y
 =
 m
 ∗
 X
 +
 c

 {\displaystyle Y=m*X+c}


Therefore, linear regression is fitted to the data plotted on Y- and X-axis between 4–60 minutes to obtain  m  and  c  values, where  m  is the slope of the regression line representing K i  and  c  is the Y-intercept of the regression line representing V o . [ 52 ]


The calculation of Ki using arterial input function, time-activity curve, and Hawkins model was limited to a small skeletal region covered by the narrow field-of-view of the PET scanner while acquiring a dynamic scan. However, Siddique et al. [ 53 ]  showed in 2012 that it is possible to measure K i  values in bones using static [ 18 F]NaF PET scans. Blake et al. [ 32 ]  later showed in 2019 that the K i  obtained using the Siddique–Blake method has precision errors of less than 10%. The Siddique–Blake approach is based on the combination of the Patlak method, [ 52 ]  the semi-population based arterial input function, [ 54 ]  and the information that V o  does not significantly change post-treatment. This method uses the information that a linear regression line can be plotted using the data from a minimum of two time-points, to obtain  m  and  c  as explained in the Patlak method. However, if V o  is known or fixed, only one single static PET image is required to obtain the second time-point to measure  m , representing the K i  value. This method should be applied with great caution to other clinical areas where these assumptions may not hold true.


The most fundamental difference between SUV and K i  values is that SUV is a simple measure of uptake, which is normalized to body weight and injected activity. The SUV does not take into consideration the tracer delivery to the local region of interest from where the measurements are obtained, therefore, affected by the physiological process consuming [ 18 F]NaF elsewhere in the body. On the other hand, K i  measures the plasma clearance to bone mineral, taking into account the tracer uptake elsewhere in the body affecting the delivery of tracer to the region of interest from where the measurements are obtained. The difference in the measurement of K i  and SUV in bone tissue using [ 18 F]NaF are explained in more detail by Blake et al. [ 34 ]


It is critical to note that most of the methods for calculating K i  require dynamic PET scanning over an hour, except, the Siddique–Blake methods. Dynamic scanning is complicated and costly. However, the calculation of SUV requires a single static PET scan performed approximately 45–60 minutes post-tracer injection at any region imaged within the skeleton.


Many researchers have shown a high correlation between SUV and  K i  values at various skeletal sites. [ 55 ] [ 56 ] [ 57 ]  However, SUV and K i  methods can contradict for measuring response to treatment. [ 45 ]  Since SUV has not been validated against the histomorphometry, its usefulness in bone studies measuring response to treatment and disease progression is uncertain.


Plaque radiotherapy  is a type of  radiation therapy  used to treat  eye  tumors. A thin piece of metal (usually gold) with  radioactive seeds  placed on one side is  sewn  onto the outside wall of the eye with the seeds aimed at the  tumor . It is removed at the end of treatment, which usually lasts for several days.


Iodine-125  is among the isotopes used. [ 1 ]


Positron emission tomography  ( PET ) [ 1 ]  is a  functional imaging  technique that uses radioactive substances known as  radiotracers  to visualize and measure changes in  metabolic processes , and in other  physiological  activities including  blood flow , regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.


For example:


PET is a common  imaging technique , a  medical scintillography  technique used in  nuclear medicine . A  radiopharmaceutical  – a  radioisotope  attached to a drug – is injected into the body as a  tracer . When the radiopharmaceutical undergoes  beta plus decay , a  positron  is emitted, and when the positron interacts with an ordinary electron, the two particles annihilate and two  gamma rays  are emitted in opposite directions. [ 2 ]  These gamma rays are detected by two  gamma cameras  to form a three-dimensional image.


PET scanners can incorporate a  computed tomography scanner  (CT) and are known as  PET-CT scanners . PET scan images can be reconstructed using a CT scan performed using one scanner during the same session.


One of the disadvantages of a PET scanner is its high initial cost and ongoing operating costs. [ 3 ]


PET is both a medical and research tool used in pre-clinical and clinical settings. It is used heavily in the imaging of  tumors  and the search for  metastases  within the field of  clinical oncology , and for the clinical diagnosis of certain diffuse brain diseases such as those causing various types of  dementias . PET is a valuable research tool to learn and enhance our knowledge of the normal human brain, heart function, and support drug development. PET is also used in pre-clinical studies using animals. It allows repeated investigations into the same subjects over time, where subjects can act as their own control and substantially reduces the numbers of animals required for a given study. This approach allows research studies to reduce the sample size needed while increasing the statistical quality of its results. [ citation needed ]


Physiological processes lead to  anatomical  changes in the body. Since PET is capable of detecting biochemical processes as well as expression of some proteins, PET can provide molecular-level information much before any anatomic changes are visible. PET scanning does this by using radiolabelled molecular probes that have different rates of uptake depending on the type and function of tissue involved. Regional tracer uptake in various anatomic structures can be visualized and relatively quantified in terms of injected positron emitter within a PET scan. [ citation needed ]


PET imaging is best performed using a dedicated PET scanner. It is also possible to acquire PET images using a conventional dual-head  gamma camera  fitted with a coincidence detector. The quality of gamma-camera PET imaging is lower, and the scans take longer to acquire. However, this method allows a low-cost on-site solution to institutions with low PET scanning demand. An alternative would be to refer these patients to another center or relying on a visit by a mobile scanner.


Alternative methods of  medical imaging  include  single-photon emission computed tomography  (SPECT), computed tomography (CT),  magnetic resonance imaging  (MRI) and  functional magnetic resonance imaging  (fMRI), and  ultrasound . SPECT is an imaging technique similar to PET that uses  radioligands  to detect molecules in the body. SPECT is less expensive and provides inferior image quality than PET.


PET scanning with the radiotracer  [ 18 F]fluorodeoxyglucose  (FDG) is widely used in clinical oncology. FDG is a  glucose   analog  that is taken up by glucose-using cells and phosphorylated by  hexokinase  (whose  mitochondrial  form is significantly elevated in rapidly growing  malignant  tumors). [ 4 ]   Metabolic trapping  of the radioactive glucose molecule allows the PET scan to be utilized. The concentrations of imaged FDG tracer indicate tissue metabolic activity as it corresponds to the regional glucose uptake. FDG is used to explore the possibility of cancer spreading to other body sites ( cancer   metastasis ). These FDG PET scans for detecting cancer metastasis are the most common in standard medical care (representing 90% of current scans). The same tracer may also be used for the diagnosis of types of  dementia . Less often, other  radioactive tracers , usually but not always labelled with  fluorine-18  ( 18 F), are used to image the tissue concentration of different kinds of molecules of interest inside the body. [ citation needed ]


A typical dose of FDG used in an oncological scan has an effective radiation dose of 7.6  mSv . [ 5 ]  Because the hydroxy group that is replaced by fluorine-18 to generate FDG is required for the next step in  glucose metabolism  in all cells, no further reactions occur in FDG. Furthermore, most tissues (with the notable exception of liver and kidneys) cannot remove the  phosphate  added by hexokinase. This means that FDG is trapped in any cell that takes it up until it decays, since  phosphorylated  sugars, due to their ionic charge, cannot exit from the cell. This results in intense radiolabeling of tissues with high glucose uptake, such as the normal brain, liver, kidneys, and most cancers, which have a higher glucose uptake than most normal tissue due to the  Warburg effect . As a result, FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers, particularly in  Hodgkin lymphoma , [ 6 ]   non-Hodgkin lymphoma , [ 7 ]  and  lung cancer . [ 8 ] [ 9 ] [ 10 ]


A 2020 review of research on the use of PET for Hodgkin lymphoma found evidence that negative findings in interim PET scans are linked to higher  overall survival  and  progression-free survival ; however, the certainty of the available evidence was moderate for survival, and very low for progression-free survival. [ 11 ]


A few other isotopes and radiotracers are slowly being introduced into oncology for specific purposes. For example,  11 C -labelled  metomidate  (11C-metomidate) has been used to detect tumors of  adrenocortical  origin. [ 12 ] [ 13 ]  Also,  fluorodopa  (FDOPA) PET/CT (also called F-18-DOPA PET/CT) has proven to be a more sensitive alternative to finding and also localizing  pheochromocytoma  than the  Iobenguane  (MIBG)  scan . [ 14 ] [ 15 ] [ 16 ]


PET imaging with oxygen-15 indirectly measures blood flow to the brain. In this method, increased radioactivity signal indicates increased blood flow which is assumed to correlate with increased brain activity. Because of its 2-minute  half-life , oxygen-15 must be piped directly from a medical  cyclotron  for such uses, which is difficult. [ 17 ]


PET imaging with FDG takes advantage of the fact that the brain is normally a rapid user of glucose. Standard FDG PET of the brain measures regional glucose use and can be used in neuropathological diagnosis.


Brain pathologies such as  Alzheimer's disease  (AD) greatly decrease brain metabolism of both glucose and oxygen in tandem.  Therefore FDG PET of the brain may also be used to successfully differentiate Alzheimer's disease from other dementing processes, and also to make early diagnoses of Alzheimer's disease. The advantage of FDG PET for these uses is its much wider availability. Some fluorine-18 based radioactive tracers used for Alzheimer's include  florbetapir ,  flutemetamol ,  Pittsburgh compound B  (PiB) and  florbetaben , which are all used to detect  amyloid-beta  plaques, a potential  biomarker  for Alzheimer's in the brain. [ 18 ]


PET imaging with FDG can also be used for localization of "seizure focus". A seizure focus will appear as hypometabolic during an interictal scan. [ 19 ]  Several radiotracers (i.e. radioligands) have been developed for PET that are  ligands  for specific  neuroreceptor  subtypes such as [ 11 C] raclopride , [ 18 F] fallypride  and [ 18 F] desmethoxyfallypride  for  dopamine   D 2 / D 3  receptors; [ 11 C] McN5652  and [ 11 C] DASB  for  serotonin transporters ; [ 18 F] mefway  for serotonin  5HT 1A  receptors ; and [ 18 F] nifene  for  nicotinic acetylcholine receptors  or  enzyme substrates  (e.g. 6- FDOPA  for the  AADC enzyme ). These agents permit the visualization of neuroreceptor pools in the context of a plurality of neuropsychiatric and neurologic illnesses.


PET may also be used for the diagnosis of  hippocampal sclerosis , which causes epilepsy. FDG, and the less common tracers  flumazenil  and  MPPF  have been explored for this purpose. [ 20 ] [ 21 ]  If the sclerosis is unilateral (right hippocampus or left hippocampus), FDG uptake can be compared with the healthy side. Even if the diagnosis is difficult with MRI, it may be diagnosed with PET. [ 22 ] [ 23 ]


The development of a number of novel probes for  non-invasive ,  in-vivo  PET imaging of neuroaggregate in human brain has brought amyloid imaging close to clinical use. The earliest  amyloid  imaging probes included [ 18 F]FDDNP [ 24 ]  developed at the  University of California, Los Angeles  and  Pittsburgh compound B  (PiB) [ 25 ]  developed at the  University of Pittsburgh . These probes permit the visualization of amyloid plaques in the brains of Alzheimer's patients and could assist clinicians in making a positive clinical diagnosis of AD pre-mortem and aid in the development of novel anti-amyloid therapies. [ 11 C] polymethylpentene  (PMP) is a novel radiopharmaceutical used in PET imaging to determine the activity of the acetylcholinergic neurotransmitter system by acting as a substrate for  acetylcholinesterase . Post-mortem examination of AD patients have shown decreased levels of acetylcholinesterase. [ 11 C]PMP is used to map the acetylcholinesterase activity in the brain, which could allow for  premortem  diagnoses of AD and help to monitor AD treatments. [ 26 ]   Avid Radiopharmaceuticals  has developed and commercialized a compound called florbetapir that uses the longer-lasting  radionuclide  fluorine-18 to detect amyloid plaques using PET scans. [ 27 ]


To examine links between specific psychological processes or disorders and brain activity.


Numerous compounds that bind selectively to neuroreceptors of interest in biological psychiatry have been radiolabeled with C-11 or F-18. Radioligands that bind to  dopamine receptors  ( D 1 , [ 28 ]  D 2 , [ 29 ] [ 30 ]  reuptake transporter),  serotonin receptors  ( 5HT 1A ,  5HT 2A , reuptake transporter),  opioid receptors  ( mu  and  kappa ),  cholinergic receptors  (nicotinic and  muscarinic ) and other sites have been used successfully in studies with human subjects. Studies have been performed examining the state of these receptors in patients compared to healthy controls in  schizophrenia ,  substance abuse ,  mood disorders  and other psychiatric conditions. [ citation needed ]


PET can also be used in  image guided surgery  for the treatment of intracranial tumors, arteriovenous malformations and other surgically treatable conditions. [ 31 ]


Cardiology ,  atherosclerosis  and vascular disease study: FDG PET can help in identifying  hibernating myocardium . However, the  cost-effectiveness  of PET for this role versus  SPECT  is unclear. FDG PET imaging of  atherosclerosis  to detect patients at risk of  stroke  is also feasible. Also, it can help test the efficacy of novel anti-atherosclerosis therapies. [ 32 ]


Imaging infections with  molecular imaging  technologies can improve diagnosis and treatment follow-up. Clinically, PET has been widely used to image bacterial infections using FDG to identify the infection-associated inflammatory response. Three different PET  contrast agents  have been developed to image bacterial infections in vivo are [ 18 F] maltose , [ 33 ]  [ 18 F]maltohexaose, and [ 18 F]2-fluorodeoxy sorbitol  (FDS). [ 34 ]  FDS has the added benefit of being able to target only  Enterobacteriaceae .


In pre-clinical trials, a new drug can be radiolabeled and injected into animals. Such scans are referred to as biodistribution studies. The information regarding drug uptake, retention and elimination over time can be obtained quickly and cost-effectively compare to the older technique of killing and dissecting the animals. Commonly, drug occupancy at a purported site of action can be inferred indirectly by competition studies between unlabeled drug and radiolabeled compounds to bind with specificity to the site. A single radioligand can be used this way to test many potential drug candidates for the same target. A related technique involves scanning with radioligands that compete with an  endogenous  (naturally occurring) substance at a given receptor to demonstrate that a drug causes the release of the natural substance. [ 35 ]


A miniature animal PET has been constructed that is small enough for a fully conscious  rat  to be scanned. [ 36 ]  This RatCAP (rat conscious animal PET) allows animals to be scanned without the confounding effects of  anesthesia . PET scanners designed specifically for imaging  rodents , often referred to as microPET, as well as scanners for small  primates , are marketed for academic and pharmaceutical research. The scanners are based on microminiature scintillators and amplified  avalanche photodiodes  (APDs) through a system that uses single-chip silicon  photomultipliers . [ 1 ]


In 2018 the  UC Davis School of Veterinary Medicine  became the first veterinary center to employ a small clinical PET scanner as a scanner for clinical (rather than research) animal diagnosis. Because of cost as well as the marginal utility of detecting cancer metastases in companion animals (the primary use of this modality), veterinary PET scanning is expected to be rarely available in the immediate future. [ citation needed ]


PET imaging has been used for imaging muscles and bones. FDG is the most commonly used tracer for imaging muscles, and  NaF-F18  is the most widely used tracer for imaging bones.


PET is a feasible technique for studying  skeletal muscles  during exercise. [ 37 ]  Also, PET can provide muscle activation data about deep-lying muscles (such as the  vastus intermedialis  and the  gluteus minimus ) compared to techniques like  electromyography , which can be used only on superficial muscles directly under the skin. However, a disadvantage is that PET provides no timing information about muscle activation because it has to be measured after the exercise is completed. This is due to the time it takes for FDG to accumulate in the activated muscles. [ 38 ]


Together with [ 18 F]sodium floride,  PET for bone imaging  has been in use for 60 years for measuring regional bone metabolism and blood flow using static and dynamic scans. Researchers have recently started using [ 18 F]sodium fluoride to study bone metastasis as well. [ 39 ]


PET scanning is non-invasive, but it does involve exposure to  ionizing radiation . [ 3 ]  FDG, which is now the standard radiotracer used for PET neuroimaging and cancer patient management, [ 40 ]  has an effective radiation dose of 14  mSv . [ 5 ]


The amount of radiation in FDG is similar to the effective dose of spending one year in the American city of  Denver, Colorado  (12.4 mSv/year). [ 41 ]  For comparison, radiation dosage for other medical procedures range from 0.02 mSv for a  chest X-ray  and 6.5–8 mSv for a CT scan of the chest. [ 42 ] [ 43 ]  Average civil aircrews are exposed to 3 mSv/year, [ 44 ]  and the whole body occupational dose limit for nuclear energy workers in the US is 50 mSv/year. [ 45 ]  For scale, see  Orders of magnitude (radiation) .


For PET-CT scanning, the radiation exposure may be substantial—around 23–26 mSv (for a 70 kg person—dose is likely to be higher for higher body weights). [ 46 ] [ 47 ]


Radionuclides are incorporated either into compounds normally used by the body such as  glucose  (or glucose analogues),  water , or  ammonia , or into molecules that bind to receptors or other sites of drug action. Such labelled compounds are known as  radiotracers . PET technology can be used to trace the biologic pathway of any compound in living humans (and many other species as well), provided it can be radiolabeled with a PET isotope. Thus, the specific processes that can be probed with PET are virtually limitless, and radiotracers for new target molecules and processes are continuing to be synthesized. As of this writing there are already dozens in clinical use and hundreds applied in research. In 2020 by far the most commonly used radiotracer in clinical PET scanning is the carbohydrate derivative FDG. This radiotracer is used in essentially all scans for oncology and most scans in neurology, thus makes up the large majority of radiotracer (>95%) used in PET and PET-CT scanning.


Due to the short half-lives of most positron-emitting radioisotopes, the radiotracers have traditionally been produced using a cyclotron in close proximity to the PET imaging facility. The half-life of fluorine-18 is long enough that radiotracers labeled with fluorine-18 can be manufactured commercially at offsite locations and shipped to imaging centers. Recently  rubidium-82  generators have become commercially available. [ 49 ]  These contain strontium-82, which decays by  electron capture  to produce positron-emitting rubidium-82.


The use of positron-emitting isotopes of metals in PET scans has been reviewed, including elements not listed above, such as lanthanides. [ 50 ]


The isotope  89 Zr has been applied to the tracking and quantification of molecular antibodies with PET cameras (a method called "immuno-PET"). [ 51 ] [ 52 ] [ 53 ]


The biological half-life of antibodies is typically on the order of days, see  daclizumab  and  erenumab  by way of example. To visualize and quantify the distribution of such antibodies in the body, the PET isotope  89 Zr is well suited because its physical half-life matches the typical biological half-life of antibodies, see table above.


To conduct the scan, a short-lived radioactive tracer  isotope  is injected into the living subject (usually into blood circulation). Each tracer atom has been chemically incorporated into a biologically active molecule. There is a waiting period while the active molecule becomes concentrated in tissues of interest. Then the subject is placed in the imaging scanner. The molecule most commonly used for this purpose is FDG, a sugar, for which the waiting period is typically an hour. During the scan, a record of tissue concentration is made as the tracer decays.


As the radioisotope undergoes  positron emission  decay (also known as positive  beta decay ), it emits a positron, an  antiparticle  of the  electron  with opposite charge. The emitted positron travels in tissue for a short distance (typically less than 1 mm, but dependent on the isotope [ 54 ] ), during which time it loses kinetic energy, until it decelerates to a point where it can interact with an electron. [ 55 ]  The encounter annihilates both electron and positron, producing a pair of  annihilation  ( gamma )  photons  moving in approximately opposite directions. These are detected when they reach a  scintillator  in the scanning device, creating a burst of light which is detected by photomultiplier tubes or silicon avalanche photodiodes (Si APD). The technique depends on simultaneous or coincident detection of the pair of photons moving in approximately opposite directions (they would be exactly opposite in their  center of mass frame , but the scanner has no way to know this, and so has a built-in slight direction-error tolerance). Photons that do not arrive in temporal "pairs" (i.e. within a timing-window of a few nanoseconds) are ignored.


The most significant fraction of electron–positron annihilations results in two 511 keV gamma photons being emitted at almost 180 degrees to each other. Hence, it is possible to localize their source along a straight line of coincidence (also called the  line of response , or  LOR ). In practice, the LOR has a non-zero width as the emitted photons are not exactly 180 degrees apart. If the resolving time of the detectors is less than 500  picoseconds  rather than about 10  nanoseconds , it is possible to localize the event to a segment of a  chord , whose length is determined by the detector timing resolution. As the timing resolution improves, the  signal-to-noise ratio  (SNR) of the image will improve, requiring fewer events to achieve the same image quality. This technology is not yet common, but it is available on some new systems. [ 56 ]


The raw data collected by a PET scanner are a list of 'coincidence events' representing near-simultaneous detection (typically, within a window of 6 to 12 nanoseconds of each other) of annihilation photons by a pair of detectors. Each coincidence event represents a line in space connecting the two detectors along which the positron emission occurred (i.e., the line of response (LOR)).


Analytical techniques, much like the reconstruction of  computed tomography  (CT) and  single-photon emission computed tomography  (SPECT) data, are commonly used, although the  data set  collected in PET is much poorer than CT, so reconstruction techniques are more difficult. Coincidence events can be grouped into projection images, called  sinograms . The sinograms are sorted by the angle of each view and tilt (for 3D images). The sinogram images are analogous to the projections captured by CT scanners, and can be reconstructed in a similar way. The statistics of data thereby obtained are much worse than those obtained through transmission tomography. A normal PET data set has millions of counts for the whole acquisition, while the CT can reach a few billion counts. This contributes to PET images appearing "noisier" than CT. Two major sources of noise in PET are scatter (a detected pair of photons, at least one of which was deflected from its original path by interaction with matter in the field of view, leading to the pair being assigned to an incorrect LOR) and random events (photons originating from two different annihilation events but incorrectly recorded as a coincidence pair because their arrival at their respective detectors occurred within a coincidence timing window).


In practice, considerable pre-processing of the data is required – correction for random coincidences, estimation and subtraction of  scattered  photons, detector  dead-time  correction (after the detection of a photon, the detector must "cool down" again) and detector-sensitivity correction (for both inherent detector sensitivity and changes in sensitivity due to angle of incidence).


Filtered back projection  (FBP) has been frequently used to reconstruct images from the projections. This algorithm has the advantage of being simple while having a low requirement for computing resources. Disadvantages are that  shot noise  in the raw data is prominent in the reconstructed images, and areas of high tracer uptake tend to form streaks across the image. Also, FBP treats the data deterministically – it does not account for the inherent randomness associated with PET data, thus requiring all the pre-reconstruction corrections described above.


Statistical, likelihood-based approaches : Statistical, likelihood-based  [ 57 ] [ 58 ]  iterative  expectation-maximization algorithms  such as the Shepp–Vardi algorithm [ 59 ]  are now the preferred method of reconstruction. These algorithms compute an estimate of the likely distribution of annihilation events that led to the measured data, based on statistical principles. The advantage is a better noise profile and resistance to the streak artifacts common with FBP, but the disadvantage is greater computer resource requirements. A further advantage of statistical image reconstruction techniques is that the physical effects that would need to be pre-corrected for when using an analytical reconstruction algorithm, such as scattered photons, random coincidences, attenuation and detector dead-time, can be incorporated into the likelihood model being used in the reconstruction, allowing for additional noise reduction. Iterative reconstruction has also been shown to result in improvements in the resolution of the reconstructed images, since more sophisticated models of the scanner physics can be incorporated into the likelihood model than those used by analytical reconstruction methods, allowing for improved quantification of the radioactivity distribution. [ 60 ]


Research has shown that  Bayesian  methods that involve a Poisson likelihood function and an appropriate  prior probability  (e.g., a smoothing prior leading to  total variation regularization  or a  Laplacian distribution  leading to

 ℓ

 1

 {\displaystyle \ell _{1}}

 -based regularization in a  wavelet  or other domain), such as via  Ulf Grenander 's  Sieve estimator [ 61 ] [ 62 ]  or via Bayes penalty methods [ 63 ] [ 64 ]  or via  I.J. Good 's roughness method [ 65 ] [ 66 ]  may yield superior performance to expectation-maximization-based methods which involve a Poisson likelihood function but do not involve such a prior. [ 67 ] [ 68 ] [ 69 ]


Attenuation correction : Quantitative PET Imaging requires attenuation correction. [ 70 ]  In these systems attenuation correction is based on a transmission scan using  68 Ge rotating rod source. [ 71 ]


Transmission scans directly measure attenuation values at 511 keV. [ 72 ]  Attenuation occurs when  photons  emitted by the radiotracer inside the body are absorbed by intervening tissue between the detector and the emission of the photon. As different LORs must traverse different thicknesses of tissue, the photons are attenuated differentially. The result is that structures deep in the body are reconstructed as having falsely low tracer uptake. Contemporary scanners can estimate attenuation using integrated x-ray CT equipment, in place of earlier equipment that offered a crude form of CT using a  gamma ray  ( positron  emitting) source and the PET detectors.


While attenuation-corrected images are generally more faithful representations, the correction process is itself susceptible to significant artifacts. As a result, both corrected and uncorrected images are always reconstructed and read together.


2D/3D reconstruction : Early PET scanners had only a single ring of detectors, hence the acquisition of data and subsequent reconstruction was restricted to a single transverse plane. More modern scanners now include multiple rings, essentially forming a cylinder of detectors.


There are two approaches to reconstructing data from such a scanner:


3D techniques have better sensitivity (because more coincidences are detected and used) hence less noise, but are more sensitive to the effects of scatter and random coincidences, as well as requiring greater computer resources. The advent of sub-nanosecond timing resolution detectors affords better random coincidence rejection, thus favoring 3D image reconstruction.


Time-of-flight (TOF) PET : For modern systems with a higher time resolution (roughly 3 nanoseconds) a technique called "time-of-flight" is used to improve the overall performance. Time-of-flight PET makes use of very fast gamma-ray detectors and data processing system which can more precisely decide the difference in time between the detection of the two photons. It is impossible to localize the point of origin of the annihilation event exactly (currently within 10 cm). Therefore, image reconstruction is still needed. TOF technique gives a remarkable improvement in image quality, especially signal-to-noise ratio.


PET scans are increasingly read alongside CT or MRI scans, with the combination ( co-registration ) giving both anatomic and metabolic information (i.e., what the structure is, and what it is doing biochemically). Because PET imaging is most useful in combination with anatomical imaging, such as CT, modern PET scanners are now available with integrated high-end multi-detector-row CT scanners (PET-CT). Because the two scans can be performed in immediate sequence during the same session, with the patient not changing position between the two types of scans, the two sets of images are more precisely  registered , so that areas of abnormality on the PET imaging can be more perfectly correlated with anatomy on the CT images. This is very useful in showing detailed views of moving organs or structures with higher anatomical variation, which is more common outside the brain.


At the  Jülich  Institute of Neurosciences and Biophysics, the world's largest PET-MRI device began operation in April 2009. A 9.4- tesla  magnetic resonance tomograph (MRT) combined with a PET. Presently, only the head and brain can be imaged at these high magnetic field strengths. [ 73 ]


For brain imaging, registration of CT, MRI and PET scans may be accomplished without the need for an integrated PET-CT or PET-MRI scanner by using a device known as the  N-localizer . [ 31 ] [ 74 ] [ 75 ] [ 76 ]


The minimization of radiation dose to the subject is an attractive feature of the use of short-lived radionuclides. Besides its established role as a diagnostic technique, PET has an expanding role as a method to assess the response to therapy, in particular, cancer therapy, [ 77 ]  where the risk to the patient from lack of knowledge about disease progress is much greater than the risk from the test radiation. Since the tracers are radioactive, the elderly [ dubious  –  discuss ]  and pregnant are unable to use it due to risks posed by radiation.


Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to produce the short-lived radionuclides for PET scanning and the need for specially adapted on-site chemical synthesis apparatus to produce the radiopharmaceuticals after radioisotope preparation. Organic radiotracer molecules that will contain a positron-emitting radioisotope cannot be synthesized first and then the radioisotope prepared within them, because bombardment with a cyclotron to prepare the radioisotope destroys any organic carrier for it. Instead, the isotope must be prepared first, then the chemistry to prepare any organic radiotracer (such as FDG) accomplished very quickly, in the short time before the isotope decays. Few hospitals and universities are capable of maintaining such systems, and most clinical PET is supported by third-party suppliers of radiotracers that can supply many sites simultaneously. This limitation restricts clinical PET primarily to the use of tracers labelled with fluorine-18, which has a half-life of 110 minutes and can be transported a reasonable distance before use, or to rubidium-82 (used as  rubidium-82 chloride ) with a half-life of 1.27 minutes, which is created in a portable generator and is used for  myocardial   perfusion  studies. In recent years a few on-site cyclotrons with integrated shielding and "hot labs" (automated chemistry labs that are able to work with radioisotopes) have begun to accompany PET units to remote hospitals. The presence of the small on-site cyclotron promises to expand in the future as the cyclotrons shrink in response to the high cost of isotope transportation to remote PET machines. [ 78 ]  In recent years the shortage of PET scans has been alleviated in the US, as rollout of  radiopharmacies  to supply radioisotopes has grown 30%/year. [ 79 ]


Because the half-life of fluorine-18 is about two hours, the prepared dose of a radiopharmaceutical bearing this radionuclide will undergo multiple half-lives of decay during the working day. This necessitates frequent recalibration of the remaining dose (determination of activity per unit volume) and careful planning with respect to patient scheduling.


The concept of emission and transmission  tomography  was introduced by  David E. Kuhl , Luke Chapman and Roy Edwards in the late 1950s. Their work would lead to the design and construction of several tomographic instruments at  Washington University School of Medicine  and later at the  University of Pennsylvania . [ 80 ]  In the 1960s and 70s tomographic imaging instruments and techniques were further developed by  Michel Ter-Pogossian ,  Michael E. Phelps ,  Edward J. Hoffman  and others at  Washington University School of Medicine . [ 81 ] [ 82 ]


Work by Gordon Brownell, Charles Burnham and their associates at the  Massachusetts General Hospital  beginning in the 1950s contributed significantly to the development of PET technology and included the first demonstration of annihilation radiation for medical imaging. [ 83 ]  Their innovations, including the use of light pipes and volumetric analysis, have been important in the deployment of PET imaging. In 1961, James Robertson and his associates at Brookhaven National Laboratory built the first single-plane PET scan, nicknamed the "head-shrinker." [ 84 ]


One of the factors most responsible for the acceptance of positron imaging was the development of radiopharmaceuticals. In particular, the development of labeled 2-fluorodeoxy-D-glucose (FDG-firstly synthethized and described by two Czech scientists from  Charles University  in Prague in 1968) [ 85 ]  by the Brookhaven group under the direction of Al Wolf and Joanna Fowler was a major factor in expanding the scope of PET imaging. [ 86 ]  The compound was first administered to two normal human volunteers by  Abass Alavi  in August 1976 at the University of Pennsylvania. Brain images obtained with an ordinary (non-PET) nuclear scanner demonstrated the concentration of FDG in that organ. Later, the substance was used in dedicated positron tomographic scanners, to yield the modern procedure.


The logical extension of positron instrumentation was a design using two 2-dimensional arrays. PC-I was the first instrument using this concept and was designed in 1968, completed in 1969 and reported in 1972. The first applications of PC-I in tomographic mode as distinguished from the computed tomographic mode were reported in 1970. [ 87 ]  It soon became clear to many of those involved in PET development that a circular or cylindrical array of detectors was the logical next step in PET instrumentation. Although many investigators took this approach, James Robertson [ 88 ]  and  Zang-Hee Cho [ 89 ]  were the first to propose a ring system that has become the prototype of the current shape of PET. The first multislice cylindrical array PET scanner was completed in 1974 at the  Mallinckrodt Institute of Radiology  by the group led by Ter-Pogossian. [ 90 ]


The PET-CT scanner, attributed to David Townsend and Ronald Nutt, was named by  Time  as the medical invention of the year in 2000. [ 91 ]


As of August 2008,  Cancer Care Ontario  reports that the current average incremental cost to perform a PET scan in the province is CA$1,000–1,200 per scan. This includes the cost of the radiopharmaceutical and a stipend for the physician reading the scan. [ 92 ]


In the United States, a PET scan is estimated to be US$1500-$5000.


In England, the  National Health Service  reference cost (2015–2016) for an adult outpatient PET scan is £798. [ 93 ]


In Australia, as of July 2018, the  Medicare Benefits Schedule Fee  for whole body FDG PET ranges from A$953 to A$999, depending on the indication for the scan. [ 94 ]


The overall performance of PET systems can be evaluated by quality control tools such as the  Jaszczak phantom . [ 95 ]


Prophylactic cranial irradiation  ( PCI ) is a technique used to combat the occurrence of  metastasis  to the brain in highly aggressive  cancers  that commonly metastasize to brain, most notably  small-cell lung cancer . [ 1 ]   Radiation therapy is commonly used to treat known tumor occurrence in the brain, either with highly precise  stereotactic radiation  or therapeutic cranial irradiation.  By contrast, PCI is intended as preemptive treatment in patients with no known current intracranial tumor, but with high likelihood for harboring occult microscopic disease and eventual occurrence. [ 2 ]   For small-cell lung cancer with limited [ 3 ] [ 4 ]  and select cases of extensive disease, [ 5 ]  PCI has shown to reduce recurrence of brain metastases and improve overall survival in complete remission.


During the fervor to develop treatments for pediatric leukemia in the 1960s, there was initial experimentation with PCI for children with  ALL.   Although advances in  chemotherapy  had been able to successfully treat tumor throughout the body, there remained an alarming incidence of brain metastasis following systemic chemotherapy. A theory was developed that the brain was likely a pharmacologic sanctuary where sub-clinical metastases were protected from  cytotoxic drugs  by the  blood–brain barrier .  Oncologists hypothesized that treatment of this sub-clinical disease with radiation therapy may stamp out the malignant process before it could advance to cause symptoms.  Indeed, subsequent studies showed that an increased rate of disease-free survival and overall survival in those children treated with PCI.  Due to successes with pediatric blood cancers, the concept of PCI was enlisted for the treatment of other types of cancers.


Over time, there has slowly been a shift away from PCI due to incidence of long-term side effects and secondary cancers, as well as evidence of equivalent control with alternate forms of treatment such as long-term  intrathecal chemotherapy . [ 6 ]   For ALL, PCI had been reserved only for high-risk cases; however, a 2009 study by Ching-Hon et al. reporting on the results of clinical trial NCT00137111 suggesting that PCI is unwarranted even in high-risk cases. [ 7 ]    Despite changing recommendations for ALL, PCI continues to play an important role in treatment of small-cell lung cancer.


Early trials for PCI in ALL utilized high-dose treatments, up to 24 Gy cumulative dose, that resulted in significant toxicity.  Further experiments showed that lower-dose treatments (12–18 Gy) [ 8 ] [ 9 ]  administered in smaller fractions provide equivalent benefit with lower neuro-toxicity.


Proton computed tomography (pCT) , or  proton CT , is an imaging modality first proposed by  Cormack  in 1963  [ 1 ]  and initial experiment explorations identified several advantages over conventional  X-ray CT  (xCT).  However, particle interactions such as multiple  Coulomb scattering  (MCS) and (in)elastic nuclear scattering events deflect the  proton  trajectory, resulting in nonlinear paths which can only be approximated via  statistical assumptions , leading to lower  spatial resolution  than  X-ray tomography .  Further experiments were largely abandoned until the advent of proton  radiation therapy  in the 1990s which renewed interest in the topic due to the potential benefits of imaging and treating patients with the same particle.


Proton computed tomography (pCT) uses measurements of a proton's position/ trajectory  and  energy  before and after traversing an object to reconstruct an image of the object where each  voxel  represents the  relative stopping power  (RSP) of the material composition of the corresponding region of the object.  The deviations of a proton's path inside the object are primarily due to interactions between the  Coulomb fields  of the  proton  and the  nuclei  in the absorbing material, resulting in many small-angle deflections as it passes through the object.   Statistical models  of the effect of MCS on the trajectory of a proton were developed to calculate the most likely path (MLP) of a proton given its entry and exit position/ trajectory  and corresponding uncertainty at intermediate depths within the object. [ 2 ] [ 3 ]   Additional (in)elastic nuclear scattering events can also occur which cause larger angle deviations, which cannot easily be modeled, but these are fairly easy to identify and remove from consideration in the image reconstruction process.


With an approximate path of a proton through the object, one can then identify the voxels through which the proton passed, and the difference between entry and exit energy indicates the energy collectively deposited in these voxels.  Assuming there are

 J

 {\displaystyle J}

  voxels in the image, the distance,

 Δ

 l

 j

 {\displaystyle \Delta l_{j}}

 , the proton travels through each voxel

 j
 ∈
 J

 {\displaystyle j\in J}

  varies along the path and the amount of energy deposited in each voxel,

 Δ

 E

 h

 {\displaystyle \Delta E_{h}}

 , depends on this and the voxel's RSP,

 x

 j

 {\displaystyle x_{j}}

 .  The total energy loss

 E

 {\displaystyle E}

  is the  line integral  of RSP scaled by the intersection length, or


E
 =
 ∫

 x

 j

 Δ

 l

 j

 {\displaystyle E=\int x_{j}\Delta l_{j}}


A  PSMA scan  is a  nuclear medicine  imaging technique used in the  diagnosis  and  staging  of prostate cancer. It is carried out by injection of a  radiopharmaceutical  with a  positron  or  gamma  emitting  radionuclide  and a  prostate-specific membrane antigen  (PSMA) targeting  ligand . After injection, imaging of positron emitters such as  gallium-68  ( 68 Ga),  copper-64  ( 64 Cu), and  fluorine-18  ( 18 F) is carried out with a  positron emission tomography  (PET) scanner. For gamma emitters such as  technetium-99m  ( 99m Tc) and  indium-111  ( 111 In)  single-photon emission computed tomography  (SPECT) imaging is performed with a  gamma camera .


As well as the diagnosis and staging of prostate cancer, PSMA imaging can also be used to assess suitability for and plan treatment with  external beam radiotherapy  and PSMA-targeted  radionuclide therapy . [ 1 ] [ 2 ]


Attempts have been made to target the overexpression of PSMA in prostate cancer cells for several decades, although PSMA is also found in other tissue. PSMA targeting molecules have included antibodies, aptamers, peptides, and small-molecule inhibitors. [ 3 ] [ 4 ]  Initially, development focussed on the antibody capromab. Later research has focussed on small molecule  ligands  that bind to the extracellular active centre of PSMA, such as PSMA-11. [ 5 ]  These ligands for PSMA-scanning target the large extracellular region of the PSMA  glycoprotein . [ 6 ]


PSMA however is also over-expressed in non prostate cancer cells, including kidney, salivary gland, lacrimal gland and duodenal mucosa, where physiological uptake may be seen on imaging. [ 7 ]


European Association of Urology  (EAU) guidelines recognise that PSMA can provide accurate staging, however there is a lack of outcome data to inform further management. [ 8 ]  The  American Society of Clinical Oncology  (ASCO) guidelines for imaging of advanced prostate cancer also recommend PSMA imaging (among other PET radiopharmaceuticals), while acknowledging that these are not FDA approved and therefore limited to a clinical trial or other controlled research setting. [ 9 ]  A 2024 overview of reviews published in Seminars of Nuclear Medicine concluded that while evidence gaps remain for some outcomes and most systematic reviews are at high or unclear risk of bias, the evidence base is broadly supportive of 18-F PSMA PET/CT in patients with high-risk prostate cancer or biochemical recurrence  [ 10 ]


In part thanks to the wide range of similar PSMA radiopharmaceuticals, [ 4 ] [ 16 ]  approval by regulatory authorities is at varying stages. Even so, use has been widespread in some areas, particularly as part of  clinical trials . For example,   European Association of Urology  (EAU) guidelines have included recommendations to perform PSMA PET scans in certain circumstances since 2018, and there has been widespread agreement of the utility of PSMA scanning for several years. [ 17 ] [ 18 ] [ 19 ] [ 20 ]


A kit for manufacture of a  68 Ga-PSMA-11 product, branded Illucix, was approved by Australia's  Therapeutic Goods Administration  (TGA) in 2021. [ 21 ]


A  marketing authorisation  application for  68 Ga-PSMA-11  ( INN  Gallium (68Ga) gozetotide), under the brand name Illucix, was made to the  Danish Medicines Agency , on behalf of several EU countries and the UK. Approval is expected in 2022. [ 22 ] [ 23 ]


In 2022 a marketing authorisation application was made by the manufacturer of  18 F-DCFPyL  (branded Pylclari) to the  European Medicines Agency . [ 12 ]


Polish manufacturer and distributor of radiopharmaceutical procuts, Polatom, has been granted a US patent for a  99m Tc-PSMA-T4 kit. [ 24 ] [ 25 ]  In the UK, Tc-99m labelled PSMA has product authorisation but lacks funding. [ 26 ]


A new drug submission was made to  Canada's regulator  in 2021, for  68 Ga-PSMA-11. [ 27 ]


The first approved PSMA imaging agent was  indium-111  ( 111 In) capromab pendetide (branded Prostascint). It received  Food and Drug Administration  (FDA) approval in 1996. [ 15 ]  However, the agent had poor sensitivity and saw little widespread use. [ 19 ]


The first PET PSMA imaging agent,  68 Ga-PSMA-11, was approved by the FDA in 2020. [ 28 ]  Listed indications include suspected metastasis prior to initial treatment, and recurrence of prostate cancer (based on elevated serum  prostate-specific antigen  (PSA) level). [ 29 ]  This was followed by two further  68 Ga-PSMA-11 agents in 2021 and 2022 (branded Illucix and Locametz). [ 30 ] [ 31 ]  Listed indications for Lucametz additionally includes selection of patients prior to  177 Lu-PSMA  radionuclide therapy. [ 32 ]


An  18 F-PSMA agent ( 18 F-DCFPyL) (branded Pylarify) was approved by the FDA in 2021. [ 33 ]  Indications are as for  68 Ga-PSMA-11. [ 34 ] [ 35 ]


Another  18 F-PSMA agent ( 18 F-rhPSMA-7.3) (branded Posluma) was approved by the FDA in 2023. [ 36 ]


68 Ga-PSMA-11 (Illucixwas) was granted initial authorisation in 2021, with full approval expected in 2022. [ 37 ] [ 38 ]


A  radiation burn  is a damage to the  skin  or other  biological tissue  and organs as an  effect of radiation . The radiation types of greatest concern are  thermal radiation , radio frequency energy,  ultraviolet light  and  ionizing radiation .


The most common type of radiation  burn  is a  sunburn  caused by UV radiation. High exposure to  X-rays  during diagnostic  medical imaging  or  radiotherapy  can also result in radiation burns. As the ionizing radiation interacts with  cells  within the body—damaging them—the body responds to this damage, typically resulting in  erythema —that is, redness around the damaged area. Radiation burns are often discussed in the same context as  radiation-induced cancer  due to the ability of ionizing radiation to interact with and damage  DNA , occasionally inducing a cell to become cancerous.  Cavity magnetrons  can be improperly used to create surface and internal burning. Depending on the  photon   energy ,  gamma radiation  can cause deep  gamma burns , with  60 Co  internal burns common.  Beta burns  tend to be shallow as  beta particles  are not able to penetrate deeply into a body; these burns can be similar to sunburn.  Alpha particles  can cause internal  alpha burns  if inhaled, with external damage (if any) being limited to minor erythema.


Radiation burns can also occur with high power  radio transmitters  at any frequency where the body absorbs radio frequency energy and converts it to heat. [ 1 ]  The U.S.  Federal Communications Commission  (FCC) considers 50 watts to be the lowest power above which radio stations must evaluate emission safety. Frequencies considered especially dangerous occur where the human body can become  resonant , at 35 MHz, 70 MHz, 80-100 MHz, 400 MHz, and 1 GHz. [ 2 ]  Exposure to  microwaves  of too high intensity can cause  microwave burns .


Radiation dermatitis  (also known as  radiodermatitis ) is a  skin disease  associated with prolonged exposure to ionizing radiation. [ 3 ] : 131–2   Radiation dermatitis occurs to some degree in most patients receiving radiation therapy, with or without chemotherapy. [ 4 ]


There are three specific types of radiodermatitis: acute radiodermatitis, chronic radiodermatitis, and eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy. [ 3 ] : 39–40   Radiation therapy can also cause radiation cancer. [ 3 ] : 40


With interventional fluoroscopy, because of the high skin  doses  that can be generated in the course of the intervention, some procedures have resulted in early (less than two months after exposure) and/or late (two months or more after exposure) skin reactions, including necrosis in some cases. [ 5 ] : 773


Radiation dermatitis, in the form of intense erythema and  vesiculation  of the skin, may be observed in radiation ports. [ 3 ] : 131


As many as 95% of patients treated with radiation therapy for cancer will experience a skin reaction. Some reactions are immediate, while others may be later (e.g., months after treatment). [ 6 ]


Acute radiodermatitis  occurs when an "erythema dose" of ionizing radiation is given to the skin, after which visible erythema appears up to 24 hours after. [ 3 ] : 39    Radiation dermatitis generally manifests within a few weeks after the start of radiotherapy. [ 4 ] : 143    Acute radiodermatitis, while presenting as red patches, may sometimes also present with  desquamation  or blistering. [ 7 ]   Erythema may occur at a dose of 2  Gy  radiation or greater. [ 8 ]


Chronic radiodermatitis  occurs with chronic exposure to "sub-erythema" doses of ionizing radiation over a prolonged period, producing varying degrees of damage to the skin and its underlying parts after a variable latent period of several months to several decades. [ 3 ] : 40    In the past this type of radiation reaction occurred most frequently in  radiologists  and  radiographers  who were constantly exposed to ionizing radiation, especially before the use of  X-ray filters . [ 3 ] : 40    Chronic radiodermatitis, squamous and
basal cell carcinomas may develop months to years after radiation exposure. [ 7 ] : 130  [ 9 ]   Chronic radiodermatitis presents as atrophic indurated plaques, often whitish or yellowish, with telangiectasia, sometimes with  hyperkeratosis . [ 7 ] : 130


Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy  is a skin condition that occurs most often in women receiving cobalt radiotherapy for internal cancer. [ 3 ] : 39–40


Radiation-induced  erythema multiforme  may occur when  phenytoin  is given prophylactically to neurosurgical patients who are receiving whole-brain therapy and systemic steroids. [ 3 ] : 130


Radiation acne  is a cutaneous condition characterized by comedo-like  papules  occurring at sites of previous exposure to therapeutic ionizing radiation, skin lesions that begin to appear as the acute phase of radiation dermatitis begins to resolve. [ 10 ] : 501


Radiation recall reactions  occur months to years after radiation treatment, a reaction that follows recent administration of a chemotherapeutic agent and occurs with the prior radiation port, characterized by features of radiation dermatitis. [ 3 ] [ 11 ]   Restated, radiation recall dermatitis is an inflammatory skin reaction that occurs in a previously irradiated body part following drug administration. [ 12 ]   There does not appear to be a minimum dose, nor an established radiotherapy dose relationship. [ 12 ]


"Alpha burns"  are caused by  alpha particles , which can cause extensive tissue damage if inhaled. [ 13 ]  Due to the keratin in the  epidermal layer  of the skin, external alpha burns are limited to only mild reddening of the outermost layer of skin. [ 14 ]


"Beta burns" —caused by  beta particles —are shallow surface burns, usually of skin and less often of  lungs  or  gastrointestinal tract , caused by beta particles, typically from  hot particles  or dissolved  radionuclides  that came to direct contact with or close proximity to the body. They can appear similar to sunburn. Unlike gamma rays, beta emissions are stopped much more effectively by materials and therefore deposit all their energy in only a shallow layer of tissue, causing more intense but more localized damage. On cellular level, the changes in skin are similar to radiodermatitis.


The dose is influenced by relatively low penetration of beta emissions through materials. The  cornified   keratine  layer of  epidermis  has enough stopping power to absorb beta radiation with energies lower than 70 keV. Further protection is provided by clothing, especially shoes. The dose is further reduced by limited retention of radioactive particles on skin; a 1 millimeter particle is typically released in 2 hours, while a 50 micrometer particle usually does not adhere for more than 7 hours. Beta emissions are also severely attenuated by air; their range generally does not exceed 6 feet (1.8 m) and intensity rapidly diminishes with distance. [ 15 ]


The  eye lens  seems to be the most sensitive organ to beta radiation, [ 16 ]  even in doses far below maximum permissible dose.  Safety goggles  are recommended to attenuate strong beta. [ 17 ]


Careful washing of exposed body surface, removing the radioactive particles, may provide significant dose reduction. Exchanging or at least brushing off clothes also provides a degree of protection.


If the exposure to beta radiation is intense, the beta burns may first manifest in 24–48 hours by itching and/or burning sensation that last for one or two days, sometimes accompanied by  hyperaemia . After 1–3 weeks burn symptoms appear; erythema, increased  skin pigmentation  (dark colored patches and raised areas), followed by  epilation  and  skin lesions . Erythema occurs after 5–15  Gy , dry desquamation after 17 Gy, and  bullous   epidermitis  after 72 Gy. [ 15 ]   Chronic radiation keratosis  may develop after higher doses. Primary erythema lasting more than 72 hours is an indication of injury severe enough to cause chronic radiation dermatitis. Edema of  dermal papillae , if present within 48 hours since the exposition, is followed by transepidermal  necrosis . After higher doses, the  malpighian layer  cells die within 24 hours; lower doses may take 10–14 days to show dead cells. [ 18 ]  Inhalation of beta radioactive isotopes may cause beta burns of lungs and  nasopharyngeal  region, ingestion may lead to burns of gastrointestinal tract; the latter being a risk especially for  grazing  animals.


Lost hair begins regrowing in nine weeks and is completely restored in about half a year. [ 19 ]


The acute dose-dependent effects of beta radiation on skin are as follows: [ 20 ]


According to other source: [ 21 ]


As shown, the dose thresholds for symptoms vary by source and even individually. In practice, determining the exact dose tends to be difficult.


Similar effects apply to animals, with fur acting as additional factor for both increased particle retention and partial skin shielding. Unshorn thickly wooled sheep are well protected; while the epilation threshold for sheared sheep is between 23 and 47 Gy (2500–5000  rep ) and the threshold for normally wooled face is 47–93 Gy (5000–10000 rep), for thickly wooled (33 mm hair length) sheep it is 93–140 Gy (10000–15000 rep). To produce skin lesions comparable with  contagious pustular dermatitis , the estimated dose is between 465 and 1395 Gy. [ 22 ]


The effects depend on both the intensity and the energy of the radiation. Low-energy beta (sulfur-35, 170 keV) produces shallow ulcers with little damage to dermis, while  cobalt-60  (310 keV),  caesium-137  (550 keV),  phosphorus-32  (1.71 MeV),  strontium-90  (650 keV) and its daughter product  yttrium-90  (2.3 MeV) damage deeper levels of the  dermis  and can result in  chronic  radiation dermatitis. Very high energies from  electron beams  from  particle accelerators , reaching tens of megaelectronvolts, can be deeply penetrating. Conversely, megavolt-scale beams can deposit their energy deeper with less damage to the dermis; modern radiotherapy electron beam accelerators take advantage of this. At yet higher energies, above 16 MeV, the effect does not show significantly anymore, limiting the usefulness of higher energies for radiotherapy. As a convention, surface is defined as the topmost 0.5 mm of skin. [ 23 ]  High-energy beta emissions should be shielded with plastic instead of lead, as  high-Z  elements generate deeply penetrating gamma  bremsstrahlung .


The electron energies from  beta decay  are not discrete but form a continuous spectrum with a cutoff at maximum energy. The rest of the energy of each decay is carried off by an  antineutrino  which does not significantly interact and therefore does not contribute to the dose. Most energies of beta emissions are at about a third of the maximum energy. [ 17 ]  Beta emissions have much lower energies than what is achievable from particle accelerators, no more than few megaelectronvolts.


The energy-depth-dose profile is a curve starting with a surface dose, ascending to the maximum dose in a certain depth d m  (usually normalized as 100% dose), then descends slowly through depths of 90% dose (d 90 ) and 80% dose (d 80 ), then falls off linearly and relatively sharply though depth of 50% dose (d 50 ). The extrapolation of this linear part of the curve to zero defines the maximum electron range, R p . In practice, there is a long tail of weaker but deep dose, called "bremsstrahlung tail", attributable to  bremsstrahlung . The penetration depth depends also on beam shape, narrower beam tend to have less penetration. In water, broad electron beams, as is the case in homogeneous surface contamination of skin, have d 80  about E/3 cm and R p  about E/2 cm, where E is the beta particle energy in MeV. [ 24 ]


The penetration depth of lower-energy beta in water (and soft tissues) is about 2 mm/MeV. For a 2.3 MeV beta the maximum depth in water is 11 mm, for 1.1 MeV it is 4.6 mm. The depth where maximum of the energy is deposited is significantly lower. [ 25 ]


The energy and penetration depth of several isotopes is as follows: [ 26 ]


For a wide beam, the depth-energy relation for dose ranges is as follows, for energies in  megaelectronvolts  and depths in millimeters. The dependence of surface dose and penetration depth on beam energy is clearly visible. [ 24 ]


Radiation burns are caused by exposure to high levels of radiation. Levels high enough to cause burn are generally lethal if received as a whole-body dose, whereas they may be treatable if received as a shallow or local dose.


Fluoroscopy  may cause burns if performed repeatedly or for too long. [ 10 ]


Similarly, X-ray  computed tomography  and traditional  projectional radiography  have the potential to cause radiation burns if the exposure factors and exposure time are not appropriately controlled by the operator.


A study of radiation-induced skin injuries [ 27 ] [ 28 ]  has been performed by the  Food and Drug Administration  (FDA) based on results from 1994, [ 29 ]  followed by an advisory to minimize further fluoroscopy-induced injuries. [ 30 ]  The problem of radiation injuries due to fluoroscopy has been further investigated in review articles in 2000, [ 31 ]  2001, [ 32 ] [ 33 ]  2009 [ 34 ]  and 2010. [ 35 ] [ 36 ] [ 37 ]


Beta burns are frequently the result of exposure to  radioactive fallout  after  nuclear explosions  or  nuclear accidents . Shortly after the explosion, the  fission products  have very high beta activity, with about two beta emissions per each gamma photon.


After the  Trinity test , the fallout caused localized burns on the backs of  cattle  in the area downwind. [ 38 ]  The fallout had the appearance of small flaky dust particles. The cattle showed temporary burns, bleeding, and loss of hair. Dogs were also affected; in addition to localized burns on their backs, they also had burned paws, likely from the particles lodged between their toes as hoofed animals did not show problems with feet. About 350–600 cattle were affected by superficial burns and localized temporary loss of dorsal hair; the army later bought 75 most affected cows as the discolored regrown hair lowered their market value. [ 39 ]  The cows were shipped to Los Alamos and Oak Ridge, where they were observed. They healed, now sporting large patches of white fur; some looked as if they had been scalded. [ 40 ]


The fallout produced by the  Castle Bravo  test was unexpectedly strong. A white snow-like dust, nicknamed by the scientists "Bikini snow" and consisting of contaminated crushed  calcined   coral , fell for about 12 hours upon the  Rongelap Atoll , depositing a layer of up to 2 cm. Residents developed beta burns, mostly on the backs of their necks and on their feet, [ 38 ]  and were resettled after three days. After 24–48 hours their skin was itching and burning; in a day or two the sensations subsided, to be followed after 2–3 weeks by epilation and ulcers. Darker-colored patches and raised areas appeared on their skin, blistering was uncommon. Ulcers formed dry scabs and healed. Deeper lesions, painful, weeping and ulcerated, formed on more contaminated residents; the majority healed with simple treatment. In general, the beta burns healed with some cutaneous  scarring  and depigmentation. Individuals who bathed and washed the fallout particles from their skin did not develop skin lesions. [ 20 ]  The fishing ship  Daigo Fukuryu Maru  was affected by the fallout as well; the crew suffered skin doses between 1.7 and 6.0 Gy, with beta burns manifesting as severe skin lesions, erythema,  erosions , sometimes necrosis, and skin  atrophy . Twenty-three U.S. radar servicemen of the 28-member weather station on  Rongerik [ 41 ]  were affected, experiencing discrete 1–4 mm skin lesions which healed quickly, and ridging of  fingernails  several months later. Sixteen crew members of the aircraft carrier  USS  Bairoko  received beta burns, and there was an increased cancer rate. [ 15 ]


During the Zebra test of the  Operation Sandstone  in 1948, three men had beta burns on their hands when removing sample collection filters from  drones  flying through the  mushroom cloud ; their estimated skin surface dose was 28 to 149 Gy, and their disfigured hands required  skin grafts . A fourth man showed weaker burns after the earlier Yoke test. [ 42 ]


The  Upshot–Knothole Harry  test at the  Frenchman Flat  site released a large amount of fallout. A significant number of sheep died after grazing on contaminated areas. The  AEC  however had a policy to compensate farmers only for animals showing external beta burns, so many claims were denied. Other tests on the Nevada Test Site also caused fallout and corresponding beta burns to sheep, horses and cattle. [ 43 ]  During the  Operation Upshot–Knothole , sheep as far as 50 miles (80 km) from the test site developed beta burns to their backs and nostrils. [ 42 ]


During  underground nuclear testing  in Nevada, several workers developed burns and skin ulcers, in part attributed to exposure to  tritium . [ 44 ]


Beta burns were a serious medical issue for some victims of the  Chernobyl disaster ; from 115 patients treated in Moscow, 30% had burns covering 10–50% of body surface, 11% were affected on 50–100% of skin; the massive exposure was often caused by clothes drenched with radioactive water. Some firefighters developed beta burns of lungs and nasopharyngeal region after inhalation of massive amounts of radioactive  smoke . Out of 28 deaths, 16 had skin injuries listed among the causes. The beta activity was extremely high, with beta/gamma ratio reaching 10–30  [ clarification needed ]  and beta energy high enough to damage  basal layer  of the skin, resulting in large area portals for  infections , exacerbated by damage to  bone marrow  and weakened  immune system . Some patients received skin dose of 400–500 Gy. The infections caused more than half of the acute deaths. Several died of fourth degree beta burns between 9–28 days after dose of 6–16 Gy. Seven died after dose of 4–6 Gy and third degree beta burns in 4–6 weeks. One died later from second degree beta burns and dose 1-4 Gy. [ 44 ]  The survivors have atrophied skin which is  spider veined  and with underlying  fibrosis . [ 15 ]


The burns may manifest at different times at different body areas. The  Chernobyl liquidators ' burns first appeared on wrists, face, neck and feet, followed by chest and back, then by knees, hips and buttocks. [ 45 ]


Industrial radiography  sources are a common source of beta burns in workers.


Radiation therapy sources can cause beta burns during exposure of the patients. The sources can be also lost and mishandled, as in the  Goiânia accident , during which several people had external beta burns and more serious gamma burns, and several died. Numerous accidents also occur during radiotherapy due to equipment failures, operator errors, or wrong dosage.


Electron beam sources and particle accelerators can be also sources of beta burns. [ 46 ]  The burns may be fairly deep and require skin grafts, tissue  resection  or even  amputation  of fingers or limbs. [ 47 ]


Radiation burns should be covered by a clean, dry dressing as soon as possible to prevent infection.  Wet dressings are not recommended. [ 48 ]  The presence of combined injury (exposure to radiation plus trauma or radiation burn) increases the likelihood of generalized sepsis. [ 49 ]  This requires  administration of systemic antimicrobial  therapy. [ 50 ]


Radiation colitis  is injury to the  colon  caused by  radiation therapy .   It is usually associated with treatment for  prostate cancer  or  cervical cancer . [ 1 ]   Common symptoms are  diarrhea , a  feeling of being unable to empty the bowel , [ 2 ]  gastrointestinal bleeding, and abdominal pain. [ 1 ]


If symptoms of radiation colitis onset within 60 days of exposure to radiation, it is referred to as acute; otherwise, it is classified as chronic.  Acute radiation colitis may onset within a few hours of radiation exposure, and may clear up within two or three months after radiation ends. Between 5 and 15% of individuals who receive radiation to the pelvis may have chronic radiation colitis. [ 1 ]  Radiation therapy can also affect the  bowel  at the  small intestine  ( radiation enteritis ) or the  rectum  ( radiation proctitis ). [ 2 ]


Tenesmus  or  diarrhea  appear to be the most common symptoms in patients with radiation colitis. Patients may also exhibit perforation or obstruction. [ 2 ]


Radiation colitis is typically brought on by  radiation therapy  administered to the pelvis for prostate, cervix, uterus, anus, rectum, or bladder cancers. [ 3 ]


Radiation primarily harms rapidly dividing cells by causing  DNA  strand loss that results in irreversible DNA changes. Consequently, the G2/M phase of the cell cycle, when the  DNA strands  are arranged into well-defined  chromatin  pairs and prepared for division into two  daughter cells , is when radiation damage is greatest. [ 4 ]   Colocytes , the cells that divide quickly that make up the  epithelium  lining the colon, undergo regeneration every five to six days. Its quick regeneration also makes it more vulnerable to radiation-related damage. [ 5 ]


Genetic and  cytokine  interactions are necessary for the active process of  programmed cell death  known as  apoptosis . Research on animals has demonstrated a significant increase in intestinal crypt apoptosis following low-dose radiation exposure. [ 6 ]


Through its strong fibrogenic and proinflammatory effects,  TGF-β  also plays a significant role in the pathogenesis of chronic radiation colitis.  TGF-β  levels in irradiated tissues are significantly higher and stay elevated in smooth muscle cells, vascular endothelial cells, and  fibrocytes  for up to 26 weeks. [ 7 ]


Radiation colitis is characterized histologically by stromal injury followed by progressive  fibrosis  that results in epithelial  atrophy  and persistent mucosal  ischemia . [ 3 ]


Radiation enteropathy  is a  syndrome  that may develop following abdominal or pelvic  radiation therapy  for  cancer . [ 1 ] [ 2 ]  Many affected people are  cancer survivors  who had treatment for  cervical cancer  or  prostate cancer .  It has also been termed  pelvic radiation disease  with  radiation proctitis  being one of its principal features [ 3 ]  and  radiation-induced lumbar plexopathy (RILP)  being a rare consequence. [ 4 ]


People who have been treated with  radiotherapy  for pelvic and other abdominal cancers frequently develop gastrointestinal symptoms. [ 3 ] [ 1 ] [ 2 ]


These include:


Gastrointestinal symptoms are often found together with those in other systems including  genitourinary disorders  and  sexual dysfunction . The burden of symptoms substantially impairs the patients'  quality of life . [ citation needed ]


Nausea, vomiting, fatigue, and diarrhea may happen early during the course of radiotherapy.  Radiation enteropathy represents the longer-term, chronic effects that may be found after a latent period most commonly of 6 months to 3 years after the end of treatment.  In some cases, it does not become a problem for 20–30 years after successful curative therapy. [ 1 ]


A large number of people receive abdominal and or pelvic  radiotherapy  as part of their cancer treatment with 60–80% experiencing gastrointestinal symptoms. [ 1 ]   This is used in standard therapeutic regimens for  cervical cancer ,  prostate cancer ,  rectal cancer ,  anal cancer ,  lymphoma  and other abdominal malignancies.  Symptoms can be made worse by the effects of surgery, chemotherapy or other drugs given to treat the cancer. [ 5 ]   Improved methods of radiotherapy have reduced the exposure of non-involved tissues to radiation, concentrating the effects on the cancer.  However, as the parts of the intestine such as the  ileum  and the  rectum  are immediately adjacent to the cancers, it is impossible to avoid some radiation effects. [ 1 ]   Previous intestinal surgery, obesity, diabetes, tobacco smoking and vascular disorders increase the chances of developing enteropathy. [ 1 ]


Early radiation enteropathy is very common during or immediately after the course of radiotherapy.  This involves cell death, mucosal  inflammation  and epithelial barrier dysfunction. This injury is termed  mucositis  and results in symptoms of nausea, vomiting, fatigue, diarrhea and abdominal pain. [ 1 ] [ 6 ]   It recovers within a few weeks or months.


The delayed effects, found 3 months or more after radiation therapy, produce pathology which includes  intestinal   epithelial  mucosal  atrophy , vascular  sclerosis , and progressive  fibrosis  of the  intestinal wall , among other changes in intestinal  neuroendocrine  and immune cells and in the  gut microbiota . [ 1 ] [ 6 ]  These changes may produce  dysmotility , strictures,  malabsorption  and bleeding.  Problems in the terminal ileum and rectum predominate. [ citation needed ]


Multiple disorders are found in patients with radiation enteropathy, so guidance including an algorithmic approach to their investigation has been developed. [ 5 ] [ 7 ]   This includes a holistic assessment with investigations including  upper endoscopy ,  colonoscopy , breath tests and other nutritional and gastrointestinal tests.  Full investigation is important as many cancer survivors of radiation therapy develop other causes for their symptoms such as  colonic polyps ,  diverticular disease  or  hemorrhoids . [ 8 ]


Prevention of radiation injury to the small bowel is a key aim of techniques such as  brachytherapy , field size, multiple field arrangements, conformal radiotherapy techniques and intensity-modulated radiotherapy.  Medications including  ACE inhibitors ,  statins  and  probiotics  have also been studied and reviewed. [ 2 ] [ 9 ]


In people presenting with symptoms compatible with radiation enteropathy, the initial step is to identify what is responsible for causing the symptoms. Management is best with a multidisciplinary team including gastroenterologists, nurses, dietitians, surgeons and others. [ 1 ]  Medical treatments include the use of  hyperbaric oxygen  which has beneficial effects in  radiation proctitis  or anal damage. [ 10 ]  Nutritional therapies include treatments directed at specific malabsorptive disorders such as low fat diets and  vitamin B12  or  vitamin D  supplements, together with  bile acid sequestrants  for  bile acid diarrhea  and possibly antibiotics for  small intestinal bacterial overgrowth . [ 2 ]  Probiotics have all been suggested as another therapeutic avenue. [ 11 ]


Endoscopic therapies including  argon plasma coagulation  have been used for bleeding  telangiectasia  in radiation proctitis and at other intestinal sites, although there is a rick of perforation. [ 2 ]


Surgical treatment may be needed for  intestinal obstruction ,  fistulae , or perforation, which can happen in more severe cases. [ 12 ]   These can be fatal if patients present as an emergency, but with improved radiotherapy techniques are now less common. [ citation needed ]
A systematic review has found there is some promising evidence for non-surgical interventions for late rectal damage, however due to low quality evidence no conclusions could be drawn. [ 13 ]  Optimal treatment usually produces significant improvements in quality of life. [ 3 ]


An increasing number of people are now surviving cancer, with improved treatments producing cure of the malignancy ( cancer survivors ).  There are now over 14 million such people in the US, and this figure is expected to increase to 18 million by 2022. [ 14 ]   More than half are survivors of abdominal or pelvic cancers, with about 300,000 people receiving abdominal and pelvic radiation each year.  It has been estimated there are 1.6 million people in the US with post-radiation intestinal dysfunction, a greater number than those with  inflammatory bowel disease  such as  Crohn's disease  or  ulcerative colitis . [ 1 ]


New agents have been identified in animal studies that may have effects on intestinal radiation injury. [ 1 ]   The research approach in humans has been reviewed. [ 15 ]


A  radiation oncologist  is a specialist physician who uses  ionizing radiation  (such as  megavoltage X-rays  or  radionuclides ) in the treatment of  cancer .  Radiation oncology is one of the three primary specialties, the other two being surgical and medical oncology, involved in the treatment of cancer.  Radiation can be given as a curative modality, either alone or in combination with surgery and/or chemotherapy. It may also be used palliatively, to relieve symptoms in patients with incurable cancers. A radiation oncologist may also use radiation to treat some  benign  diseases, including benign tumors.  In some countries (not the United States), radiotherapy and chemotherapy are controlled by a single  oncologist  who is a "clinical oncologist". Radiation oncologists work closely with other physicians such as  surgical oncologists ,  interventional radiologists ,   internal medicine  subspecialists, and medical oncologists, as well as  medical physicists  and technicians as part of the multi-disciplinary cancer team. [ 1 ]  Radiation oncologists undergo four years of oncology-specific training whereas oncologists who deliver chemotherapy have two years of additional training in cancer care during fellowship after internal medicine residency in the United States.


In the United States, radiation oncologists undergo four years of residency (in addition to an internship), which is more dedicated to oncology training than any other medical specialty. During the four years of post-graduate training, residents learn about clinical oncology, the physics and biology of ionizing radiation, and the treatment of cancer patients with radiation.  After completion of this training, a radiation oncologist may undergo certification by the  American Board of Radiology  (ABR). Board certification includes three written tests and an oral examination which is given only once per year. The written tests include separate exams in radiation physics, and radiobiology, clinical oncology, which is followed by an eight-part oral examination given in the late spring one year into practice. Successfully passing these tests leads to the granting of a time-limited board certification. Recertification is obtained via a series of continuing medical education and practice qualifications including a written exam, clinical practice parameter evaluation, continuing medical education credits, and meeting community practice standards. [ citation needed ]


Radiotherapy training in India encompasses the treatment of solid tumors in terms of  Chemotherapy ,  radiation therapy , and  palliative care  in most states. Postgraduate MD degree is awarded after 3 years of post-MBBS in-service comprehensive training and a final university level exam. MD Radiation oncology practitioners are the most proficient oncologists in India delivering radiotherapy and chemotherapy. The first Radiotherapy department of Asia was set up in 1910 at  Calcutta Medical College  in the state of West Bengal and is still a leading oncology training center of India. [ citation needed ]


Radiation Oncology training in Canada is very similar to the United States. Radiation oncologists directly enter radiation oncology residencies of 5 years duration, with the first year as an internship year. During the next four years, residents complete intensive training in clinical oncology, in radiophysics and radiobiology, and in the treatment planning and delivery of radiotherapy. [ 2 ]  Most radiation oncologists also pursue a fellowship after their residency, examples of which include  brachytherapy ,  intensity modulated radiation therapy  (IMRT), gynecologic radiation oncology, and many others.  Radiation oncologists in Canada commonly treat two or three different anatomic sites, such as head and neck, breast, genitourinary, hematologic, gynecologic, central nervous system, or lung cancer.


In the United Kingdom, clinical oncologists, who practise radiotherapy are also fully qualified to administer chemotherapy. After completion of their basic medical degree, all oncologists must train fully in general internal medicine and pass the  MRCP  exam, normally 3–4 years after qualification. Following this, 5 years of Specialist Registrar (SpR) training is required in all non-surgical aspects of oncology in a recognised training program. During this time, the trainee must pass the  FRCR  examination in order to qualify for specialist registration as a clinical oncologist. A significant proportion of trainees will extend their time to undertake an academic fellowship, MD, or PhD. Almost all consultant clinical oncologists in the UK are Fellows of the  Royal College of Radiologists , the governing body of the specialty. Whilst most oncologists will treat a selection of common general oncology cases, there is increasing specialisation, with the expectation that consultants will specialise in one or two subsites.


In Australia and New Zealand,  The Royal Australian and New Zealand College of Radiologists  (RANZCR  Home | RANZCR ) awards a Fellowship (FRANZCR) to trainees after a 5-year program and several sets of exams and modules. As in other countries, radiation oncologists tend to subspecialize although generalists will always exist in smaller centres. Although trained in the delivery of chemotherapy, radiation oncologists in Australia and New Zealand rarely prescribe it.


In Iran, radiation oncologists, who are trained in non-surgical aspects of oncology (including radiation therapy) directly enter a 5-year residency program after completion of 7 years of training in general medicine and acceptance in national comprehensive residency exam.


In  Nepal , only  Bir Hospital  runs residency program on Radiation Oncology, under NAMS. It's a 3 years residency program, and the main domains are Chemotherapy, Radiotherapy and Palliative Care.


In Spain Radiation Oncology Specialists undertake a 4 year specialization program and are recognized to apply both ionizing radiation therapies and chemotherapy. Most fellows follow the policies emerged from leading national society SEOR (Sociedad Española de Oncología Radioterápica).


The Radiation oncologist is responsible for preparing the treatment plan where the radiation is required.  Some of the treatment methods are radioactive implantations, external beam radiotherapy, hyperthermia, and combined modality therapy such as radiotherapy with surgery, chemotherapy, or immunotherapy. [ 3 ]


To provide the treatment correctly, a series of equipment is needed which will help to complement it. First, a simulator and treatment preparation must be carried out. This consists of locating the area where the tumor is located to know where exactly the patient will be exposed at the time of treatment. The equipment used to perform this work is a computed tomography (CT) scan, a Magnetic resonance imaging (MRI), and W x-ray. Subsequently, the site targeted for treatment is marked and an immobilizer is created which helps to limit exposure another body area to the radiation. To complement this immobilizer staff will employ tape, foam sponges, headrests, molds and plaster casts. When treatment is in the head and neck area a thermoplastic mask is employed. This mask is precisely molded to the patient's shape and secured it to fasteners on the treatment table. This improves patient stability. When the treatment plan is complete, the patient will be assigned (depending upon the type of cancer and its stage) appointments to perform the therapy and monitoring. [ 4 ]


Radiation proctitis  or  radiation proctopathy  is a condition characterized by damage to the rectum after exposure to  x-rays  or other  ionizing radiation  as a part of  radiation therapy . [ 1 ]  Radiation proctopathy may occur as acute inflammation called  "acute radiation proctitis"  (and the related  radiation colitis ) or with chronic changes characterized by  radiation associated vascular ectasiae (RAVE) and chronic radiation proctopathy . [ 2 ] [ 1 ]   Radiation proctitis most commonly occurs after pelvic radiation treatment for  cancers  such as  cervical cancer ,  prostate cancer ,  bladder cancer , and  rectal cancer . RAVE and chronic radiation proctopathy involves the lower  intestine , primarily the  sigmoid colon  and the rectum, and was previously called chronic radiation proctitis,  pelvic radiation disease  and  radiation enteropathy . [ 3 ]


Acute radiation proctopathy often causes pelvic pain, diarrhea, urgency, and the urge to defecate despite having an empty colon (tenesmus). [ 4 ]  Hematochezia and fecal incontinence may occur, but are less common. [ 4 ]  Chronic radiation damage to the rectum (>3 months) may cause rectal bleeding, incontinence, or a change in bowel habits secondary. Severe cases may lead to with strictures or fistulae formation. [ 5 ] [ 4 ]  Chronic radiation proctopathy can present at a median time of 8-12 months following radiation therapy. [ 4 ]


Acute radiation proctopathy occurs due to direct damage of the lining ( epithelium ) of the colon. [ 1 ]  Rectal biopsies of acute radiation proctopathy show superficial depletion of epithelial cells and acute inflammatory cells located in the lamina propria. [ 4 ]  By contrast, rectal biopsies of RAVE and chronic radiation proctopathy demonstrates ischemic endarteritis of the submucosal arterioles, submucosal fibrosis, and neovascularization. [ 4 ]


Where chronic radiation proctopathy or RAVE is suspected, a thorough evaluation of symptoms is essential. Evaluation should include an assessment of risk factors for alternate causes of proctitis, such as  C. difficile colitis ,  NSAID use , and travel history. [ 6 ]  Symptoms such as diarrhea and painful defecation need to be systematically investigated and the underlying causes each carefully treated. [ 7 ]  Testing for parasitic infections ( amebiasis ,  giardiasis ) and sexually transmitted infections ( Neisseria gonorrhoeae  and  herpes simplex virus ) should be considered. [ 6 ]  The location of radiation treatment is important, as radiation directed at regions of the body other than the pelvis (eg brain, chest, etc) should  not  prompt consideration of radiation proctopathy. [ 6 ]


Endoscopy is the mainstay of diagnosis for radiation damage to the rectum, with either  colonoscopy  or  flexible sigmoidoscopy . RAVE is usually recognized by the macroscopic appearances on endoscopy characterized by vascular ectasias. [ 8 ]  Mucosal biopsy may aid in ruling out alternate causes of proctitis, but is not routinely necessary and may increase the risk of fistulae development. [ 6 ]   Telangiectasias  are characteristic and prone to bleeding. [ 3 ]  Additional endoscopic findings may include pallor (pale appearance), edema, and friability of the mucosa.


Radiation proctitis can occur a few weeks after treatment, or after several months or years:


Several methods have been studied in attempts to lessen the effects of radiation proctitis. Acute radiation proctitis usually resolves without treatment after several months. When treatment is necessary, symptoms often improve with hydration, anti-diarrheal agents, and discontinuation of radiation. [ 4 ]   Butyrate   enemas  may also be effective. [ 9 ] [ 10 ]


In contrast, RAVE and chronic radiation proctopathy usually is not self-limited and often requires additional therapies. [ 4 ]  These include  sucralfate ,  hyperbaric oxygen therapy ,  corticosteroids ,  metronidazole ,  argon plasma coagulation ,  radiofrequency ablation  and  formalin  irrigation. [ 1 ] [ 3 ] [ 11 ]  The average number of treatment sessions with argon plasma coagulation to achieve control of bleeding ranges from 1 to 2.7 sessions. [ 4 ]


In rare cases that do not respond to medical therapy and endoscopic treatment, surgery may be required.  Overall, less than 10 percent of individuals with radiation proctopathy require surgery. [ 4 ]  In addition, complications such as obstruction and fistulae may require  surgery .


Up to 30 percent of individuals who receive pelvic radiation therapy for cancer may develop radiation proctopathy. [ 4 ]


In  radiotherapy ,  radiation treatment planning  ( RTP ) is the process in which a team consisting of  radiation oncologists ,  radiation therapist ,  medical physicists  and  medical dosimetrists  plan the appropriate external beam radiotherapy or internal  brachytherapy  treatment technique for a patient with  cancer .


In the early days of radiotherapy planning was performed on 2D  x-ray  images, often by hand and with manual calculations. Computerised treatment planning systems began to be used in the 1970s to improve the accuracy and speed of dose calculations. [ 1 ]


By the 1990s  CT scans , more powerful computers, improved dose calculation algorithms and  Multileaf collimators  (MLCs) lead to 3D conformal planning (3DCRT), categorised as a Level 2 technique by the European Dynarad consortium. [ 2 ] [ 3 ]  3DCRT uses MLCs to shape the radiotherapy beam to closely match the shape of a target tumour, reducing the dose to healthy surrounding tissue. [ 4 ]


Level 3 techniques such as  IMRT  and  VMAT  utilise inverse planning to provide further improved dose distributions (i.e. better coverage of target tumours and sparing of healthy tissue). [ 5 ] [ 6 ]  These methods are growing in use, particularly for cancers in certain locations which have been shown to derive the greatest benefits. [ 7 ] [ 8 ]


Typically,  medical imaging  is used to form a  virtual patient  for a computer-aided design procedure. A  CT scan  is often the primary image set for treatment planning while  magnetic resonance imaging  provides excellent secondary image set for soft tissue contouring.  Positron emission tomography  is less commonly used and reserved for cases where specific uptake studies can enhance planning target volume delineation. [ 9 ]  Modern treatment planning systems provide tools for multimodality image matching, also known as image coregistration or fusion. Treatment simulations are used to plan the geometric, radiological, and dosimetric aspects of the therapy using radiation transport simulations and  optimization . For  intensity modulated radiation therapy  ( IMRT ), this process involves selecting the appropriate beam type (which may include photons, electrons and protons), energy (e.g. 6, 18  megaelectronvolt  (MeV) photons) and physical arrangements. In  brachytherapy  planning involves selecting the appropriate catheter positions and source dwell times
 [ 10 ] [ 11 ]
(in HDR brachytherapy) or seed positions (in LDR brachytherapy).