Nuclear Medicine Dosimetry in Paediatric Population

Abstract

Nowadays, the value of paediatric nuclear diagnostic medical imaging has been well established within the medical community. Despite decades of nuclear medicine practice, studies in nuclear medicine to achieve the lowest possible radiation dose to the patient while ensuring the optimized image quality have to be continued. Numerous studies highlighted a long list of objectives, in order to obtain the minimum possible absorbed dose, achieve short scan times and generate images with a high signal to noise ratio (SNR) and spatial/temporal resolution. For the development of guidelines, it is necessary to study the handling of radiopharmaceuticals, the dose splitting processes, the quality control protocols, the plan design of infrastructures, the availability of optimized dose calibrators for the corresponding radiopharmaceuticals, the development of new more sensitive radiopharmaceuticals, and optimized protocols for diagnostic or therapeutical examination of the patient. Anthropomorphic phantoms are used to model paediatric patients, but anatomical models and their pharmacokinetic data are not applied directly to any specific patient. There is a need for the development of personalized dosimetry in children. Factors regarding age, weight and biological and molecular background of the pathology must be included in paediatric personalized dosimetry. The developmental process of the child, as shape, mass, volume, anatomy, physiological indices (metabolism, heart rate, etc.) and variations due to pathologies should be taken under consideration. Corrections of radiation time of the target organ, in relation to neighbouring tissues, blood supply, estimation of residual activity/time and clearance rate are parameters in the calculations of paediatric dosimetry in nuclear medicine. In hybrid imaging examinations with computed tomography modality, the contribution of absorbed dose from CT to the paediatric patient must also be calculated.

1. Introduction

The aim of this chapter is to briefly describe the topic of paediatric dosimetry in nuclear medicine. Paediatric administrated doses are considered, firstly.

Too high administrated activities increased radiation dose without adding diagnostic information but too low activities may not permit an adequate examination. The optimal activity amount gives the desired diagnostic information with the minimum patient radiation exposure.

The next session of this chapter refers to the rules and procedures that are established for the evaluation of quantities as absorbed dose, effective dose or Paediatric Dose Reference Levels (PDRL).

In general, patient-specific dosimetry for a child examination in nuclear medicine differs from that of an adult due to different biodistribution and kinetics and variability of body size. It requires the knowledge of many factors like age, weight, biological and molecular background of the pathology and of the developmental process of the child, shape, mass, volume, anatomy, physiological indices.

Different values of instrumental parameters will be used for personalized dosimetric measurements in planar, SPECT, PET, or hybrid (SPECT/CT, PET/CT) examinations in children’s studies.

Single Photon Emission Computed Tomography (SPECT) is a nuclear medicine imaging modality that generates 3-dimensional pictures of the examined body.

Positron Emission Tomography (PET) investigates areas of abnormal activity by revealing relative glucose metabolic activity in tissues and organs.

SPECT and PET can be combined with Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) producing the so-called “hybrid” imaging.

Nuclear medicine imaging examinations are performed in paediatric patients for diagnosis of diseases or injuries. The necessity of these examinations by radiopharmaceuticals must be ensured and then should be performed securely.

The International Atomic Energy Agency (IAEA) helps medical professionals to improve quality and safety by providing standards and guidelines, training and information resources. Radiation Protection of Patients (RPOP) is also the leading resource for patients and the public on the safe and effective use of radiation in medicine (IAEA, Radiation Protection of Patients).

World Health Organization (WHO) has edited leaflets and posters titled: ‘Nuclear medicine exams in children: what do we need to know?’, for patients and families with many simple advices on what do they need to know about nuclear medicine examinations in children.

The performance of a nuclear examination should be based upon the ‘justification’ radioprotection rule as well as the ‘optimization’ rule. Both are part of responsible and ethical medical practice.

2. International guidelines in pediatric nuclear medicine (EANM, ICRP, IAEA, image gently, SNMMI, ACR)

Paediatric applications of nuclear medicine provide invaluable information in the diagnosis and follow-up of many pathological disorders as well as in therapy.

In North America, the ‘Image Gently’ Campaign encouraged the formation of an expert group to overcome the lack of paediatric guidelines and to look into the possibility of developing paediatric harmonized guidelines. These guidelines were approved by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the Society for Pediatric Radiology (SPR) and the American College of Radiology (ACR).

Although the North American and European Association of Nuclear Medicine (EANM) guidelines use different models, both have concluded in the development of a set of international guidelines, also referred to as “Pediatric Radiopharmaceutical Administration: Harmonization Guidelines” [1].

A modified version of the EANM dosage card incorporating the suggested changes is available online. Data on the biokinetics and dosimetry of commonly used radiopharmaceuticals in paediatric nuclear medicine is missing; an appreciable increase, in obtaining more and better data on image quality and biokinetics, focuses on dosimetry as a basis for further improving the recommended administered activities.

Application of the guidelines will allow many paediatric nuclear medicine patients to receive radiopharmaceutical doses lower than those that are traditionally given, resulting in an overall reduction of radiation exposure in these patients.

Paediatric patients are a particular challenge, as body size and the spatial relationships of individual organs can be very different compared to those of a typical adult.

Effective dose is a useful method for assessing the potential radiationally induced effects as a result from various practices within a population group, or more specifically to children within a similar age group, but attention should be paid used when comparing the radiation risks between the groups considering that the organ-weighting factors are averaged over both age and gender [2].

The International Commission on Radiological Protection (ICRP) has published numerous reports addressing the issue of radiation dose with respect to administrated activities in diagnostic nuclear medicine procedures. ICRP Publication 17, published in 1971 and updated in ICRP Publications 53, 80 and 106, address the absorbed dose for various used radiopharmaceuticals. In more details, these reports represent a collection of available data that may be used to estimate radiation dose, expressed as radiation dose to specified target organs, as well as the effective dose, to a population of patients to whom a specific radiopharmaceutical has been administered. They provide conversion factors for the administered activity to effective dose (in mSv/MBq) based on models of patients of different ages, such as 1, 5, 10 and 15 years-old, as well as adults).

Efforts of standardizing and optimising administered activities of radiopharmaceuticals in paediatric nuclear medicine produced fruitful results. Two major guidelines providing administered activities recommended for children, have been developed: one in Europe and the other one in North America.

The European Association of Nuclear Medicine (EANM) issued guidelines for administered activities in children that included a dosage card which provides recommended administered activities for a variety of diagnostic nuclear medicine procedures and radioisotopes correspondingly. EANM’s dosage card aim is to secure similar radiation dose levels for all patients undergoing a particular type of nuclear medicine procedure. Therefore, for each radiopharmaceutical, recommended administered activities were calculated (Figure 1) so that patients in various age groups receive similar estimated effective doses.

Figure 1.

EANM dosage card- Radiopharmaceutical activities are calculated for administration to paediatric patients by weight coefficient in all age groups. Effective doses are estimated for various diagnostic examinations.

Effective Doses in paediatric PET examinations are included in the following (Figure 2), per age group in mSv/MBq.

Figure 2.

Effective doses in paediatric PET examinations by common PET radiopharmaceuticals for age groups 5-, 10-, and 15- (ICRP publications).

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) of North America, the American College of Radiology (ACR), the Society of Pediatric Radiology (SPR) and the Image Gently campaign developed also guidelines for dose optimization by identifying best practices [3]. The North American harmonic so-called guidelines are strictly weight-based for 10 out of the 12 procedures included in the guideline, with recommended administered activities corrected for patient size (expressed as mCi/kg or MBq/kg). Consequently, for each nuclear medicine procedure, these guidelines tend to result in similar levels of image noise and thus image quality, for patients of all sizes.

European and North American guidelines differ due to the different models used to develop them. In addition, for some radiopharmaceuticals, there are considerable variances between the two guidelines in the reference adult administered activities, which are used in order to calculate children’s activities.

Differences in the effective doses resulting between the two ‘schools’ were more pronounced in younger patients. For ages 1 year or 5-year olds, the EANM’s administered activities result in an estimated effective dose at least 20% greater than that provided by the North American guidelines.

The critical organ is independent of the administered activity of radiopharmaceuticals. The most common critical organ is the urinary bladder. At the administered activities recommended by the two guidelines, the highest radiation absorbed doses to other critical organs are those produced by Tc99m-MDP to bone and I123-MIBG to the liver. Normal renal function is assumed when dose estimates are calculated. Age-specific or disease-specific alteration in organ function can change the biokinetics of a radiopharmaceutical and thus change radiation exposure.

The ICRP allows an adjustment for abnormal renal function or for unilateral ureteral blockage when calculating the absorbed radiation dose from renal imaging agents. For example, infants with biliary atresia have an underdeveloped or absent gallbladder, so the gallbladder is unlikely to be the critical organ during a performance of hepatobiliary scintigraphy in these children.

2.1 Image gently

The Image Gently Alliance was formed to help change practice and increase awareness about radiation exposure to children by medical imaging. The effort of Image Gently Alliance was supported by SNMMI, the SPR and the ACR.

A Nuclear Medicine Working Group has assisted to standardize radiopharmaceutical administered activities in the practice of paediatric nuclear medicine across North America and to harmonize these practices with those in Europe.

The Nuclear Medicine Global Initiative project (NMGI) was formed in 2012 by 13 international organizations to promote human health by advancing the field of nuclear medicine and molecular imaging. The first project focused on the standardization of administered activities in paediatric nuclear medicine and resulted in two articles [4, 5].

Guidelines have a positive effect on the practice of many nuclear medicine departments dealing with children. Resources useful for radiation dose estimation of paediatric nuclear medicine examinations can be obtained in Paediatric Injected Activity Tool (SNMMI) for estimation of injected activity in children and Nuclear Medicine Radiation Dose Tool (SNMMI) for an approximate effective dose estimation either by ICRP185, 2015 model or by RADAR model 2017 in various paediatric nuclear medicine examinations.

3. Paediatric dose phantoms

Paediatric model-derived pharmacokinetics to compare absorbed dose and effective dose estimates for F18−FDG in paediatric patients, using S values generated from two different geometries of computational phantoms; Cristy-Eckerman stylized phantoms (C−E) and University of Florida/National Cancer Institute (UF/NCI) hybrid computational phantoms.

Time−integrated activity coefficients of F18−FDG in brain, lungs, heart wall, kidneys and liver, retrospectively, were calculated. The absorbed dose calculation was performed in accordance with the Medical Internal Radiation Dose (MIRD) method using S values generated from the UF/NCI hybrid phantoms. The effective dose was computed using tissue−weighting factors from ICRP publication 60 and 103 for the C−E and UF/NCI, respectively.

Differences in anatomical modelling features among computational phantoms used to perform Monte Carlo−based photon and electron transport simulations for F18, effect internal organ dosimetry computations for paediatric nuclear medicine studies.

Paediatric pharmacokinetic data are collected for diagnostic imaging agents, relevant to paediatric studies and the field conversions from older stylized phantoms to more detailed computation hybrid phantoms were created. The effective doses, computed by the UF/NCI hybrid phantom S values, were different than those seen using the C−E stylized phantoms for newborns, 1-year-old and 5 years old, Figures 3 and 4 [6].

Figure 3.

Three-D visualization of Cristy-Eckerman (C-E) stylized phantoms [6].

Figure 4.

Three-D visualization of University of Florida/National Cancer Institute (UF/NCI) hybrid computational phantoms for various age groups [6].

Since hermaphrodite Cristy-Eckerman phantoms are used to represent the newborn, 1-year-old and 5-year-old anatomies, the OLINDA/EXM (Organ Level INternal Dose Assessment/EXponential Modelling) code developed by the Radiation Dose Assessment Resource (RADAR) Task Group of the Society of Nuclear Medicine, output for these age groups provides organ−absorbed doses for both paediatric male and female tissues.

In contrast, the University of Florida hybrid phantoms are gender-specific and these tissues are specifically modelled age-wise. The dose estimates for breast and ovaries obtained by the University of Florida F/NCI hybrid phantom were higher for newborn, 1-year-old and 5-year-old ages. The effective dose coefficient computed by OLINDA/EXM version 1.0 uses an effective dose coefficient that is based on radiation and tissue weighting factors specified in ICRP Publication 60 (1991). Later publication 103 (2007), readjusted the tissue weighting factor for breast from 0.05 to 0.12 and for gonads from 0.20 to 0.08.

The understanding of transitioning from the older phantoms and tissue−weighting factors to the most recently updated phantoms that are now being adopted by ICRP is essential (OLINDA/EXM version 2.0).

The OLINDA/EXM has standardized dose calculations for diagnostic and therapeutic radiopharmaceuticals. The previous generation of anthropomorphic phantoms based on the Oak Ridge models, employed geometrical shapes in order to define the body and its organs.

Nowadays, these models have been replaced with realistic, Non-Uniform Rational B-Spline (NURBS) type models based on the recent standardized masses defined by the ICRP in its Publication 89. NURBS is a mathematical model using B-splines that is commonly used in computer graphics for representing curves and surfaces.

These and other new models have been implemented in a new version of the OLINDA/EXM 2 code. The new generation of models is now available in the OLINDA/EXM code and represents a significant improvement in standardized dose calculations. OLINDA/EXM version 2.0 employs realistic NURBS-style phantoms [7].

ICRP in Publication 143, Paediatric Computational Reference Phantoms, 2020, has adopted a set of reference phantoms that were derived from the University of Florida phantoms. ICRP phantoms will be used to calculate ICRP dose coefficients. The publication is supported by a series of annexes. The last annex gives a description of the electronic files available for download and use of each of the 10 paediatric reference computational phantoms.

A reference set of phantoms and dose coefficients for external exposures and intakes of radionuclides will promote consistency in the assessment of doses.

4. Paediatric dose estimations

4.1 RADAR—OLINDA/EXM 2

Based on the OLINDA/EXM version 2.0 software and on 2007 recommendations of the ICRP, a new generation of voxel-based, realistic human computational phantoms was developed by the RADAR committee of the SNMMI.

It was used to develop the dose estimates as well as the most recent biokinetic models. These estimates will be made available in electronic form and can be modified and updated, as models are changed and new radiopharmaceuticals are added, MIRD Pamphlet No. 21 [8].

RADAR Dose Estimates Report in 2018 based on OLINDA/EXM Version 2.0 for Radiopharmaceutical Dose Estimates [9].

• The MIRD method uses the term A˜ (cumulated activity) for the time–activity integral and presents the dose factor by the S factor.

• RADAR uses the terms N (number of disintegrations) and dose factor, respectively.

The ICRP has a method for internal dose calculations, originally described in ICRP Publication 30. This schema has been repeated, with modifications, several times, the latest being in ICRP Publication 130.

In many ICRP documents, slightly different names are given to some terms, but all the concepts are identical [8, 9].

OLINDA/EXM 2.0 used biokinetic models for 100 radioisotopes and adult and paediatric phantoms in order to develop dose estimate tables. Data within the ICRP task group on radiopharmaceutical dosimetry was considered. Tables for males and females were generated for 1-y olds, 5-y olds, 10-y olds, 15-y olds and adults.

The dose estimate tables give male and female dose values for approximately 25 target organs, as well as sex-averaged values for the five phantom-ages considered (1-y olds, 5-y olds, 10-y olds, 15-y old and adults). In these estimations, individual organ doses are given in units of equivalent dose (e.g., mSv) and not of absorbed dose (e.g., mGy), as quality factors applied may be non-unity for some emitters. For example, OLINDA/EXM 2.0 uses:

• for emissions a default radiation weighting factor.

• variable radiation weighting factors adjusted by the user.

• effective doses that are expressed in the same units as equivalent doses, by applying individual tissue weighting factors.

• a bone model that is the same as that used in OLINDA/EXM versions 1.0 and 1.1.

• unlike the Cristy-Eckerman phantoms, no breast tissue that was assigned in children 10 years old or younger.

• several new organs that have been defined in the RADAR phantoms.

Biokinetic models for nearly 100 radiopharmaceuticals can be used with the OLINDA/EXM 2.0 paediatric phantoms to develop dose estimate tables. Male and female tables for 1-year-olds, 5-year-olds, 10-year-olds, 15-year-olds can be generated.

In ICRP Publication 103, a sex-averaged rule is described for the development of relative data.

Individual organ doses are given in units of equivalent dose (mSv) and not in units of absorbed dose (mGy).

5. Paediatric diagnostic reference levels (PDRLs)

The International Commission on Radiological Protection (ICRP) Publication 73 was first to introduce the term ‘Diagnostic Reference Level’ (DRL) in 1996, a concept that was further developed further. The DRL has been proven to be an effective tool towards the optimisation of protection in the medical exposure of patients in diagnostic procedures.

5.1 Planar-SPECT imaging procedures

For planar nuclear medicine imaging, DRLs have been set either by administered activity (MBq) or by administered activity per body weight (MBq/kg).

For SPECT imaging procedures, DRL values should be used in the same way as for planar nuclear medicine procedures. DRL values for SPECT studies are usually slightly higher than for the same radiopharmaceuticals used for planar imaging.

5.2 Positron emission tomography (PET)

Specific radiopharmaceuticals are used for PET imaging, depending on the scope of the study. F18-fluorodeoxyglucose (F18-FDG) is used for diagnosing, staging and assessing therapeutical schemes in cancer, inflammation, viable myocardium and brain diseases by revealing relative glucose metabolic activity in tissues and organs. N13-ammonia or Rb82-chloride assesses myocardial perfusion. Ga68-DOTATATE and DOTATOC in neuroendocrine tumours reflecting the status of somatostatin receptors. As the physical half-lives of radionuclides and biological half-times of radiopharmaceuticals are different, DRL values have to be set for each one.

European guidelines provide a calculation system according to body weight, image acquisition method (two-, or three-dimensional), scan speed (minutes per table position) and table overlap during the following PET acquisitions.

5.3 Hybrid imaging (PET-CT, SPECT-CT and PET-MRI, SPECT-MRI)

PET and SPECT have been combined with the modality of CT generating the so-called hybrid systems of PET-CT and SPECT-CT accordingly. Nowadays, they have been combined with the Magnetic Resonance Imaging (MRI) modality too, as these combinations increase diagnostic accuracy by providing both functional and anatomical images of the body.

The acquisition of accurately co-registered anatomical and functional images is a major strength of combined modality (hybrid imaging) devices. The patient dose from a PET-CT or SPECT-CT examination is the combination of the radiation exposures caused by the radiopharmaceutical and by the CT study via the exposure to ionising radiation.

The MRI component of PET/MRI or SPECT/MRI does not increase the patient dose considering that it uses non-ionising radiation, so from a radiation protection point of view, this hybrid imaging is preferable in paediatric examinations.

In the framework of a PET/CT or SPECT/CT, the CT portion of the examination consists of a localiser radiograph and the helical CT scan. If a CT is solely performed for attenuation correction and co-localisation, the acquisition parameters (tube current, voltage, slice thickness, rotation time, and pitch) should be selected in order to minimise the patient’s radiation exposure. A low-dose CT used in hybrid imaging is sufficient for attenuation correction and anatomic localisation and proper for paediatric examinations.

5.4 Paediatric diagnostic reference level of examinations in nuclear medicine (PDRL)

Establishing Dose Reference Level values for children is more challenging than for adults, due to the broad range of sizes of paediatric patients. Weight in children can vary by a factor of more than 100 from a premature infant to an obese adolescent. The amounts of radiation used for examinations of children can vary extremely due to the great difference in children’s size and weight.

Patient age groups have been used in the past in order to establish Paediatric DRL values. However, it has been recognized that age alone is not a representative parameter. Weight categories have to be included and should be used whenever possible. The difference in patient dose due to patient weight is expected and therefore weight ranges are recommended for establishing Paediatric DRL values.

Age groups around the ages of 0, 1, 5, 10 and 15 years can be used if age is the only available quantity. For examinations including the head, age grouping is recommended for establishing PDRL values. In paediatric imaging, sufficient data is an issue and therefore it has been suggested that the DRL quantity could be a function of patient’s weight.

For nuclear medicine imaging, the DRL quantities and DRL values are set as administered activity per body weight (MBq/kg) as a practical and simple approach.

Activities for administration should be adjusted based on size or weight associated factors.

When regional or national DRL values, relevant for paediatrics, are not available, the local practice may be compared with appropriate available published data.

For CT used in a hybrid system SPECT/CT or PET/CT, the DRL quantities are Computed Tomography Dose Index (CTDIvol) and Dose Length Product (DLP), based on calibration with a 32-cm-diameter phantom for body examinations and a 16-cm-diameter phantom for head examinations.

The CTDIvol and the DLP are common methods to estimate a patient’s radiation exposure from a CT procedure. The exposures are the same regardless of patient size, but the size of the patients is a factor in the overall patient’s absorbed dose.

The unit of CTDIvol is the gray (Gy) and it can be used in conjunction with patient size to estimate the absorbed dose. The CTDIvol and absorbed dose may differ by more than a factor of two for small patients such as children. On the other hand, DLP measured in mGy.cm is a measure of CT tube’s radiation output/exposure. It is related to volume CT Dose Index (CTDIvol). CTDI_vol represents the dose through a slice of an appropriate phantom and DLP accounts for the length of radiation output along the long axis of the patient. DLP = (CTDI_vol) [in units: mGy.cm]. DLP does not take into account the size of the patient and is not a measure of absorbed dose or the patient’s effective dose.

The effective dose depends on factors including patient size and the region of the body being scanned. Values for these quantities should be obtained from patient examinations. Most CT scanners permit the determination of effective diameter or patient equivalent thickness. This is an additional improvement for setting Paediatric DRL values.

Size Specific Dose Estimate (SSDE) measured in mGy, is a method of estimating CT radiation dose that takes a patient’s size into account. SSDE may be used in addition to the recommended DRL quantities as an extra source of information for the evaluation of the absorbed dose value.

Results from the largest international dose survey in paediatric computed tomography (CT) in 32 countries are included in ICRP Publication 135 where international DRL for Paediatric computed tomography were established [10]. Patient data were recorded among four age groups: <1 year, 1–5 years, <5–10 years and <10–15 years.

5.5 Views related to paediatric DRLs

The risk of harmful radiation effects is greater in children than in adults and optimisation of paediatric imaging is of particular importance because they have a longer life expectancy during which these effects may appear.

The amount of radiation used for examinations of children can vary greatly due to the excessive difference in patient size and weight from neonates to adult-sized adolescents.

Variation in patient radiation dose for two paediatric patients with the same size, same exposed area of anatomy should be the minimum. If not, this could be due to poor technique, or failure to adapt imaging protocols to account for both paediatric diseases and paediatric patient sizes. Weight or size-adjusted paediatric DRL values are therefore particularly important in optimization.

A number of factors need to be considered when communicating the development of DRL values for children. Some parameters are the same for adults and children. These include the choice of DRL quantities, the percentile of the distribution of the DRL quantity and whether to collect data from patient examinations or from measurements with phantoms.

DRL values for children, there cannot be as a single standard patient due to the large size range of paediatric patients [11].

Weight in children can vary by a factor of more than 100, from that of a premature infant.

Within the first 6 months of life, a typical baby’s body weight doubles, and during the first year, it increases 3-fold. Ideally, five or more size ranges should be established between premature to infants (newborn, >1, >5, >10 and >15 years) [12].

It is preferable creation of groups based on paediatric patient body size and that body size be determined for individual patients before performing diagnostic imaging procedures by radiation sources.

In 1999, the European Commission issued Radiation Protection 109 (RP 109) with the title: ‘Guidance on diagnostic reference levels (DRLs) for medical exposure’. This document indicates the critical need of establishing DRLs for high-dose medical examinations of patients sensitive to radiation, such as children. This work used average-sized adult phantom or standard size phantoms.

However, the same approach has not been considered appropriate for children due to the wide variation in body habitus.

DRL values for paediatric patients are only available for some common radiological examinations and there is a need to generate appropriately more.

The European Commission recognized this need and approved the 27-month tender project, European Diagnostic Reference Levels for Paediatric Imaging (PDRL) on the establishment of European DRLs for paediatric patients in December 2013. PDRL is coordinated by the European Society of Radiology (ESR, Eurosafe Imaging), Figure 5 [12].

Figure 5.

The calculated PDRLs may help in the standardization of the appropriate activity in paediatric nuclear medicine [18].

The Japanese Society of Nuclear Medicine (JSNM) in 2014 has published the consensus guidelines for paediatric nuclear medicine. JSNM proposes dose optimization in paediatric nuclear medicine studies and widely discusses imaging techniques for the appropriate conduct of paediatric nuclear medicine procedures, considering the features of children imaging in order to produce harmonic PDRL [13].

Scientists in nuclear medicine departments must be familiar with

• the increased radiosensitivity of children,

• the risks of low dose radiation,

• the patterns of dedicated clinical results when radiation activities in paediatric patients are minimized.

Regarding the reduction of radiation exposure to paediatric patients, continuous education and thoughtful application of techniques for radiation dose management may lead to the improvement of risk-benefit ratios when performing diagnostic imaging in children by radiopharmaceuticals.

Technology provides options such as new software and new hardware (collimators, computer components, etc.) for reducing radiation exposure while maintaining image quality driving to a minimum variation in PDRL values, globally.

6. Radiobiology in nuclear medicine and molecular imaging

Paediatric patients are referred to nuclear medicine from nearly all paediatric specialities including urology, oncology, cardiology, gastroenterology or orthopaedics. Radiation exposure is associated with a potential small risk of inducing cancer in the patient, later in life; this danger is higher in younger patients.

In the field of nuclear medicine imaging, which uses very small amounts of radioactive substances (radiopharmaceuticals) to diagnose and treat disease, the radiopharmaceuticals injected into the patient’s body are detected in very precise images of the part of the body being imaged.

6.1 The role of radiobiology in nuclear medicine

In 2021, the EANM published a position paper on the role of radiobiology in nuclear medicine [14]. For that paper, a group of EANM radiobiology, physics and dosimetry experts summarized the main issues concerning radiobiology in nuclear medicine. The position of the EANM is that radiobiology will contribute to the optimization of radiotherapy to ensure that they are effective and safe for each individual patient, considering age and weight.

There is a need to generate and apply more radiobiologic knowledge specific to nuclear medicine diagnostic and therapeutic procedures, as DNA damage induction and repair strongly because of the comparatively low dose rates varying over time with physical decay and kinetic clearance.

While the role of radiobiology for diagnostics remains to be clarified, its role in the benefits of radiopharmaceuticals in therapy is clear.

It is expected that a better understanding of radiobiological parameters can contribute to fully exploiting the abilities of new and existing nuclear medicine applications; how can be effective and safe for each individual patient, child or adult. Radiobiology plays an important role in supporting optimizations, in an increase of the use of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine.

A better understanding of radiobiologic parameters will enhance the capabilities of new and existing nuclear medicine applications in adults and paediatric patients. There is a need to better define the dose-effect relationships of radiopharmaceutical radiation in tumours and normal tissue. To reach this target, the EANM recommends a strong link between all scientists involved (Radiobiologists, radiochemists, radiopharmacists, medical physicists, and physicians). So, an improved understanding of the biological processes, with special regard to the effects of ionizing radiation to normal tissues and tumours, for any living matter, will be gained.

When ionizing radiation interrupts living matter, it deposits energy along its path leading to atomic ionization, thereby damaging biological molecular structures (Figure 6).

Figure 6.

Interaction of ionizing radiation with cellular matter- DNA and others. DNA and other cell elements are potential targets for ionizing radiation damage. Ionizing radiation also influences cell signalling pathways like oxidative stress, cell death and survival pathways, premature ageing and inflammation [14].

DNA damage induced by radiation is considered critical. DNA, as well as proteins, lipids and metabolites can potentially be modified by ionizing radiation. As first action, absorption of ionizing radiation will occur at the site of the atoms of the cellular molecules. Following ionization events may cause the breakage of chemical bonds. It may also convert atoms and molecules into free radicals with very sensitive unpaired electrons that can further interact with close molecules, after which a damaging sequence may occur.

6.2 Molecular imaging: how it works

Molecular imaging provides detailed images at the molecular and cellular levels. Molecular imaging indicates how the body is functioning and gives the prospect to measure its chemical and biological processes. It offers exclusive insights into the human body that patients can obtain personalized care. In diagnostic molecular imaging, diseases are identified in the earliest stages and the exact location can be determined, avoiding more invasive procedures such as biopsy or surgery.

When disease occurs, the biochemical activity of cells begins to change. Cancer cells may multiply at a much faster rate and are more energetic than normal cells. As the disease progresses, this abnormal cellular activity begins to affect body tissue and structures, causing anatomical changes; Cancer cells may form a mass or tumour. Molecular imaging detects cellular changes early in the course of the disease. A variety of imaging agents are used to visualize cellular activity, such as the chemical processes involved in metabolism, oxygen use or blood flow. The imaging agent in the body accumulates in a target organ or attaches to specific cells. The distribution pattern of the agent helps to distinguish how well organs and tissues are functioning.

6.3 Radiosensitivity of children

Children are more radiosensitive as the organs and cells in children are undergoing constant self-renewal, therefore are more sensitive to radiation. Measurement of DNA synthesis by PET Radiopharmaceuticals that identify increased DNA synthesis can be used to identify increased cellular proliferation in tumours.

Children, due to increased mitotic activity and longer life expectancy, are more radiosensitive than middle-aged adult by a factor of up to 10 and girls are considered more radiosensitive than boys [12].

Radiosensitivity decreases with age, exhibiting lifetime attributable cancer mortality risks per unit dose as a function of age at a single acute exposure. This was estimated by the Committee on the Biological Effects of Ionizing Radiations (BEIR) [15, 16] and the International Commission on Radiological Protection (ICRP) [17].

Children are two to three times more susceptible to radiation for the development of leukaemia. Adults exposed to radiation during childhood have an increased likelihood of emerging breast or thyroid cancer.

The National Academy of Sciences BEIR V committee and the ICRP report 60 have estimated the lifetime cancer mortality risks per unit dose at a single acute exposure as a function of age. They have shown a rapid increase in lifetime risk with decreasing age at exposure (Figure 7).

Figure 7.

The above risk estimate is an average for a population comprised of all ages. It is apparent that the risk varies dramatically with age (from Eric J. Hall, 2002), [15].

This indicates that radiosensitivity decreases with age. Neonates are more radiosensitive than infants, infants are more radiosensitive than children and children are more radiosensitive than adolescents.

6.4 Radiation life-time risk

Radiation-induced cancers tend to appear at the same age as spontaneous cancers of the same type. So, it takes half a century or more to judge the impact of radiation exposure, especially when children are included in the exposed individuals.

Exposed to radiation individuals in their first decade of life, the risk is approximately 15% per Sv, while for adults in their late middle age, the risk drops to 1 or 2%/Sv. There is also a clear gender difference, especially at early ages, with girls being more radiosensitive than boys (Figure 7).

7. Paediatric patient-specific dosimetry

7.1 Individualized dosimetry

Paediatric Dose Reference Levels (PDRLs) must be established, especially in a national level and then effective dose estimations from images data can be obtained. The calculated PDRLs may help in the standardization of the appropriate activity in paediatric nuclear medicine.

Individualized dosimetry and iterative algorithms may reduce further the administered dose resulting in safer children’s examinations.

To limit radiation exposure to children from diagnostic nuclear medicine procedures to the lowest levels consistent with quality imaging, a study has been established [18] to correlate administered activity/weight- to an effective dose in paediatric nuclear medicine imaging.

In radiopharmaceutical schedules for children, fractions of adult administered amounts and formulae based on the child’s body parameters are used. Recommended activities could also be obtained by EANM dosage-card or North American Guidelines.

The paediatric administered activities are determined by the formula that reduces adult administered activity as:

Paediatric dosage [MBq] = (Child Weight [Kg] x Adult Reference Activity [MBq])/70.

Radiopharmaceutical dosages for five diagnostic radiopharmaceuticals (Tc99m-DMSA, Tc99m-DTPA, Tc99m-MAG3, Tc99m-MDP & I123-MIBG) were calculated for 100 paediatric imaging procedures and administered in terms of activity/kg.

Knowledge of physical and biological parameters is required for the calculation of the absorbed dose.

Absorbed dose is the average deposition of energy in the tissue from the administered radiopharmaceutical.

The radioactive elements, used in the diagnosis, are distributed to the human body following the rules of pharmacokinetics & pathophysiology (Figure 8).

Figure 8.

The absorbed dose depends on: The administered activity. The active time of its stay in an organ. The parameters fixed in time, that is: radioisotope characteristics, shape and size of the radiating organ (source), the irradiated organ (target) and the distance and mass of the target) [18].

The RADAR dosimetry program was used by Plousi et al [18] in order to estimate the effective dose per child per weight/age for various radioisotopes, with reduced reference adult activity being incorporated, Figure 9.

Figure 9.

The absorbed dose in neonates is extremely higher (because the activity is distributed over smaller volumes). Significant differences -about a factor of two and sometimes three in activity and effective dose were measured between underweight, average weight and corpulent children of the same age [18].

Weighting Factor of administered activities per weight (kg) were varied from (0.1–0.86%) for 3Kg weight of a neonate to 40Kg weight of an adult.

For neonates and infants’ cases, a minimum administered activity is applied considering that the use of a fraction of the administered activity of adults would result in an uncompleted study. Planar whole-body and SPECT imaging studies were performed on a γ-camera equipped with a high-resolution collimator.

Regarding I123-MIBG, the lower limit [30 MBq for neonatal] and upper limit [110 MBq] was established to give the least effective dose with the best quality imaging.

For newborn cases, it is necessary to apply a minimum activity, as the activity calculated according to weight is less than the recommended minimum activity. When the suggested weight-based administered activities are used, the resulting effective doses range in ages 1–10 years old are, Figure 10.

Figure 10.

Effective doses for ages between 1 and 10 years old.

Activities for Tc99m-DMSA for planar and 3D imaging are lowering as filtering and iterative reconstruction methods were used. In dynamic studies of paediatric patients, the SNMMI/EANM Guidelines for Diuresis Renography in infants and children were followed [19]. The lowest burden is estimated for Tc99m-MAG3.

Optimal protocols, with improved image reconstruction methods and advanced instrumentation, facilitate the dosage reduction and provide the maximum image quality at a minimum of effective dose [20].

A graphic relation of Administered Activity versus weight of all patient groups, from neonates to adolescents, is presented in Figure 11A.

Figure 11.

(A) Administered Activity (MBq) to patient. Weight in Kg/from neonates to adolescents. (B) Positive relation of the effective dose (mSv) with patients’ age (0–26 years). No differences were observed between boys and girls of the same age [18].

In Figure 11B, a positive correlation of the effective dose (mSv) with patient ages (0–26years) is shown. No differences were observed between boys and girls of the same age [18].

7.2 Dosimetry aspects in hybrid molecular imaging applications in paediatric patients

Dose reduction in PET/CT and SPECT/CT studies with children can be achieved by optimized CT parameters and the administered activity of the radiopharmaceutical, without compromising the diagnostic information needed for high-quality examination. Effective doses to the paediatric patient examined by PET/CT or SPECT/CT depend on the CT protocol of the accompanying CT scan. The co-registered CT scan can be optimized to meet the patient’s diagnostic needs and may be performed either as a diagnostic-type CT scan or as an attenuation-correction only [21].

The hybrid molecular imaging examination by PET or SPECT and the CT should be acquired without child-patient movement. Attention to the respiratory phase during the CT imaging for PET/CT is also of a semantic point.

High-quality biokinetic data must be known for the calculation of dose estimates of new PET radiopharmaceuticals. Then, standardized dosimetry codes as OLINDA/EXM can provide information of doses to organs and effective doses [22].

In addition to the molecular imaging agents ¹⁸F-FDG (PET) and ¹²³I-MIBG (SPECT) that are frequently used in children, other PET and SPECT imaging agents may have promise for molecular imaging in children.

• C-11-methionine by PET has been shown in several studies to better depict paediatric brain tumours when compared to FDG.

• SPECT/CT may be used to localize sites of abnormal I-131 uptake in thyroid cancer patients who are post-thyroidectomy or

• Tc-99m-HMPAO-labeled white blood cells may be used with SPECT/CT to localize areas of inflammation [21].

PET/MRI use in children with systemic malignancies may benefit from the reduced radiation exposure offered by PET/MRI. The effective dose of a PET/MRI scan is only about 20% that of the equivalent PET/CT examination. Simultaneous acquisition of PET and MRI data combines the advantages of the two previously separate modalities. One disadvantage of PET/MRI is that in order to have an effect, a significantly longer examination time is needed than with PET/CT. PET/MRI has turned out to be a stable hybrid imaging modality, which generates paediatric safe diagnostic studies [23].

7.3 Foetal doses from nuclear medicine examinations

Doses are provided for “early pregnancy” (dose to the nongravid uterus in the RADAR reference adult female model) and doses to the foetus at 3, 6, and 9 months of gestation (OLINDA/EXM 2.0 software).

Uncertainties in using these estimates for a specific subject are noteworthy, both in the physiology of the radiopharmaceutical kinetics and in the assumed geometry of the maternal and foetal organs [23].

Foetal whole-body doses from common nuclear medicine examinations in early pregnancy as well as at terms have been calculated by Russell and Stabin using ICRP 53 and ICRP 80.

For Example:

1. A pregnant woman at 4 months’ gestation is administered 370 MBq of 18FDG. The estimated foetal dose at 3 months is 4.8 mGy and at 6 months is 3.1mGy. An estimate of 5 mGy is reasonable and conservative [24].

2. Foetal thyroid doses are much higher than foetal whole-body doses, 5–15 mGy/MBq for ¹²³I and 0.5–1.1 Gy/MBq for ¹³¹I (Figure 12).

Figure 12.

Foetal thyroid doses for 30MBq ¹²³I or 0.55 MBq ¹³¹I in early pregnancy and at 9 months.

8. Discussion

8.1 Dosimetry in paediatric nuclear medicine: from acquisition to image processing, image gently

The radiation burden in nuclear medicine depends principally on the administered radiopharmaceutical properties and the biological parameters-pharmacokinetics properties of the radiopharmaceutical within the patient. So,

• Activity determination is one of the fundamental bases in nuclear medicine dosimetry.

• The calculation of effective dose in a paediatric patient varies also due to anatomical differences.

• The basic schema for dosimetry calculations involved in the MIRD formalism for radiopharmaceutical dosimetry.

• The ICRP models underlying the application of dosimetry.

• Imaging value in dosimetry is the best conversion of image data to absolute values of uptake.

To limit radiation exposure to children from diagnostic nuclear medicine procedures to the lowest levels with reliable qualitative imaging, a correlation of administered activity with weight-effective dose in radiopharmaceutical imaging is valued.

Administered activities in paediatric subjects are distributed over smaller volumes generating higher absorbed doses. In diagnostic examinations, fractions of adult administered amounts and formulae based on child’s body parameters are used. Recommended activities could be obtained by EANM dosage-card or North American Guidelines—Paediatric dosage card.

Cumulated activity calculation from the time-activity curve will lead to a total number of disintegrations. Absorbed dose algorithms and image processing determine the radiation transport, energy deposition and the radiation burden of the subject; Advanced approaches such as Monte-Carlo modelling in nuclear medicine for imaging and dosimetry are successfully used.

For newborn subjects, it is necessary to apply the minimum dose, because the activity calculated according to newborn weight is less than the recommended minimum activity, resulting to worsen diagnostic imaging quality.

8.2 Optimization—Conclusion

Optimization in medical imaging is the balancing of the amount of ionizing radiation and image quality. The minimum radiation dose for the paediatric patient must assure that the image quality provides satisfactory information to meet the clinical requirement. Optimization involves both the imaging systems as testing and quality control as well as imaging body parameters and administered activity [25].

Optimal protocols, with improved image reconstruction methods and advanced instrumentation, facilitate the dosage reduction and provide the maximum image quality at a minimum effective dose. Optimization of imaging protocols and establishment of diagnostic reference levels achieve the goals of good quality images at reduced radiation doses. Standardized methods for performing dose calculations for radiopharmaceuticals by various steps in the process and models for calculating time–activity integrals as urinary bladder or intestines can be used [26].

In hybrid imaging PET/CT or SPECT/CT, deep learning-based reconstruction (DLR) may facilitate CT radiation dose reduction in children. Lower-dose DLR images were compared with standard-dose iterative reconstruction images. DLR use at 80-kVp results in substantial dose reduction with preserved or even improved image quality. So, the use of DLR allows greater dose reduction for paediatric CT than current image reconstruction techniques [27].

Clinical dosimetry in targeted radionuclide therapy in children supports the treatment decisions and should be a strong indication that treatment results are dependent on the absorbed dose delivered to the treated organ as well as to the critical organs.

Acknowledgments

D.A. Verganelakis gratefully acknowledges all support provided by the ‘ELPIDA’ Association of Friends of Children with Cancer and the Oncology Clinic “Marianna V. Vardinoyiannis” at Children’s hospital “Aghia Sophia” in Athens.