Radiation Protection and Dose Optimisation

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A Technologist’s Guide

Produced with the kind Support of

Produced with the kind Support of Editors

Rep, Sebastijan (Ljubljana) Santos, Andrea (Lisbon) Testanera, Giorgio (Milan)

Contributors

Alessio, Adam Bailey, Elizabeth Brusa, Anna Brzozowska, Beata Chiesa, Carlo de Nile, Maria Chiara de Palma, Diego Fahey, Frederic Fragoso Costa, Pedro Gilmore, David Goodkind, Alison Kriszan, Aron Krisztian Lundholm, Lovisa Mira, Marta Ouwens, Marga Rep, Sebastijan Romero, Elizabeth Santos, Ana Isabel Wojcik, Andrzej Zanette, Consuelo

2 Chapter 10 Chapter 9 Chapter 8 Chapter 7 Chapter 6 Chapter 5 Chapter 4 Chapter 3 Chapter 2 Chapter 1 Andrea Santos . 5 Introduction Pedro Fragoso Costa Foreword *Articles were written with the kind support ofandincooperationwiththe support were withthekind written *Articles Table ofContents . 4 Elizabeth Bailey Design. Department Nuclear Medicine Rep Sebastijan Occupational Protection Radiation Diego dePalma, AnaIsabelSantos Paediatric DoseOptimisation Marga Ouwens Dose Optimisation for Radionuclide Therapy. Frederic Fahey, Elizabeth Romero, Adam Alessio DoseOptimisation (*). CT Frederic H.Fahey, AlisonB DoseOptimisation forRadionuclide Diagnostic Procedures (*). Lovisa Lundholm, Andrzej Brzozowska, Beata Wojcik PrinciplesRadiobiology Pedro Fragoso Costa StandardsInternational Saftey Basic Consuelo Zanette, AnnaBrusa ChiaradeNile, Maria Mira, Chiesa,Marta Carlo FundamentalsDosimetry Krizsan Aron Krisztian withMatter ofRadiation Interaction . 6 . Goodkind, David Gilmore .Goodkind, . . . 3 . . 107 99 93 79 71 56 15 46 36 EANM Foreword Pedro Fragoso Costa

Since its inception, more than 20 years ago, most modern internal and external dosime- the EANM Technologist Committee (EANM- try calculation methods and radiological risk TC) has contributed greatly in encouraging assessment and to gain an insight into the professional development and scientific European legal requirements in respect of exchange amongst nuclear medicine tech- protection against ionising radiation . nologists (NMTs) . The Technologist’s Guide series is one of the most successful EANM-TC This brochure is the product of a multidis- endeavours, with an ongoing yearly release ciplinary team of health radiation experts, since 2004 . These brochures have become to whom I am extremely grateful . I would not only a valuable tool in the clinical work- like to thank the EANM Physics Committee, place but also a reference for educational SNMMI-TS (Society of Nuclear Medicine and purposes . Molecular Imaging Technologist Section) and ANZSNM (Australian and New Zealand After a long series of clinical guides, it was Society of Nuclear Medicine) for helping to decided to shift to a more technical, but ensure the outstanding quality of this book . equally important field: Radiation Protection I am very much indebted to Andrea Santos, and Dose Reduction . The major rationale for Sebastijan Rep and Giorgio Testanera for this choice was the fact that NMTs, radiogra- their dedication in reviewing and editing phers and all medical radiation professionals this guide in record time . Finally, thanks are will have radiation protection concerns, in- due to Rick Mills and Sonja Niederkofler for dependently of the specific set-up (i .e . nu- their support in language editing and logis- clear cardiology, PET/CT, conventional NM tics, the EANM Board, the EANM Technologist or therapeutic NM) . Furthermore, the newly Committee and all of those involved in the defined EU Euratom Directive [1] is to take ef- Technologist Guide project . fect in 2018; therefore investing in education and training in the field of radioprotection Pedro Fragoso Costa at this moment is timely and purposeful . Fi- Chair, EANM Technologist Committee nally, this publication presents an excellent opportunity to become acquainted with the

Reference 1 . European Council Directive 2013/59/Euratom on basic safety standards for protection against the dangers arising from exposure to ionising radiation and repealing Directives 89/618/Euratom, 90/ 641/Euratom, 96/29/Euratom, 97/43/ Euratom and 2003/122/ Euratom . Official Journal of the European Union; 2014;L13:1-17 .

4 knowledge requiredknowledge inorder inaccor to act tion andto provide theprofessional withthe ofradiationprotec ontheprinciples overview This year’s Technologist’s Guide aims to give an ratiohas been consideredbenefit/risk should onlybeexposedto the radiationafter eachprocedure ed to andthepatient perform by theradiation need should not be harmed useofradiation. on thecorrect The professional both theprofessional andthepatientdepends nied by great responsibility, since thesafety of The development ofNMhasbeenaccompa decades over theintervening ant advanceshave repeatedly beenachieved – showed great initialpotential andimport applications –diagnostic andtherapeutic been deeplyinvolved inthisprocess safety standards the years, accompaniedby improvements in in medicinehascontinuedto increase over patient care havepurposes beeninvaluable inimproving Ionising radiationprocedures for medical gies inbothpatientsandoperators ed inmany accidents andnumerous patholo the biological effects ofradiation,this result of withthelackofknowledge in conjunction increase material; intheusageofradioactive heal many different diseasesled to arapid es for bothdiagnostic andtherapeuticpurpos ing radiationhasbeenemployed inmedicine Since thebeginning ofthe20 Andrea Santos Introduction . The sources beliefthat radioactive could .Accordingly, theuseofradiation .Nuclearmedicine(NM)has . th century, ionis . . Both .Both ------5 Andrea Santos sation –ATechnologist’s Guide. main actors inproceduresmain actors who alsobearre ofthespecific a description role ofNMTs as protection standards order to ensure compliance with radiation that needto be considered in particularities isdiscussed, inmind the keeping department are covered, andfinallythedesign ofanNM ofoccupationalradiationprotection aspects population.After this,ation inthepaediatric chapter focuses specificallyondoseoptimis radionuclides are explained, andan individual therapeutic procedures involving theuseof cepts ofdoseoptimisationfor diagnostic and and radiobiologyprinciples basicsafety theinternational standardsering damentals ofdosimetry ofradiationwithmatter andthefun action ontheinter withoverviews This bookstarts standardslated and based onrigorous quality used ineachprocedure mustbecarefully calcu theradiation must bejustified;furthermore, There isaconsensusthatallNMprocedures ofdoseoptimisation. is to setout theprinciples dance withtheseprinciples project to helpensure therealisationexpertise ofthis sionals whohave theirtimeand contributed andprofestude to alltheauthors, co-editors closing, to IwouldIn express like my grati protection indailypractice forsponsibility theapplicationofradiation : Radiation ProtectionRadiation - Optimi andDose .Eachchapter includes It continuesby cov .It A further intention intention .Afurther . . The basiccon .

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EANM Chapter 1: Interaction of Radiation with Matter Aron Krisztian Krizsan

This chapter provides information on the with the target object (e .g . human tissue) electromagnetic radiation interactions of or even result in total absorption of the ra- significance for medical imaging, especially diation . There are three radiation wavelength for nuclear medicine applications, and also ranges where the absorption characteristics offers a glimpse into the practical knowledge can be used for the purpose of medical im- required by technologists working in this aging: the X-ray window (used in CT, planar field . When describing interactions of radi- X-ray, PET, gamma cameras and SPECT), the ation (electromagnetic and acoustic) with radiofrequency window (used in MRI) and matter, it is necessary to consider whether the ultrasound window (used in ultrasonog- the wavelength will cause any interaction raphy) (Fig . 1) .

Figure 1: Attenuation of electromagnetic radiation by human tissue for a wide spectrum of wavelengths . The X-ray window is used in CT, planar X-ray, PET, gamma cameras and SPECT while the radiofrequency window is used in MRI . Acoustic radiation is strongly absorbed for wavelengths below 1 mm and therefore is only useful for medical imaging purposes in the ultrasound window [1] . UV, Ultraviolet; IR, infrared; MW, microwave

6 isation; therefore, radiation withanenergy 13 .6eV, radiationisnotableto induceion- least oneelectron .Below anenergy limitof at An atom becomesionisedwhenitejects = 1.6×10 tential difference of1 1eV volt (numerically electron gains when it travels through a po by definition the amount of energy that an energy units of toOn theatomic usethe scaleitispractical goandwhathappenstothey theirenergy where willsurvive, focus isonwhichparticles the classicalmodelisapplicablesince withinthischapter particles, tions between tum electrodynamic explanationsofinterac- difference the classical and quan- between range) andneutrons cles are thephotons (intheadequate energy - ionisingparti and any othernuclei .Indirectly (electrons), protons nuclei), betaparticles (helium the alpha particles ticles comprise . Directly ionisingpar (uncharged particles) andindirectly ionisingparticles particles) between isdrawnrespect to ionisation,a distinction energy, charge momentumandelectric quantities include total tion . Such conserved referred to intheinterac asbeingconserved - . the interaction These quantitiesare often some quantitiesremain thesamefollowing before reveals theinteraction and after that single system . ofthesystemThe comparison Let asa usconsideraradiationinteraction bremsstrahlung Ionisation, excitation and Chapter 1:Interaction withMatter ofRadiation -19 (charged directly ionisingparticles . J) , which is electron volt (eV) . While there isadefinite . With - - . 7 with anouter shell electron (Fig isfilled number elements, andthevacancy K-shell electron inthecaseofhigheratomic ofthe an incidentelectron willcauseejection as excitation . There isthenaprobability that enters an “excited” state, aprocess referred to is raised to a higher energy level, the atom fromejected the atom by the radiation but number (hydrogen) . When anelectron isnot tron oftheelementwithsmallestatomic least energy required theK-shell to eject elec- is callednon-ionising. This (i.e radiation withanenergy lower than13.6eV higher than13.6eViscalledionisingwhile characteristic forcharacteristic theelement, X-ray photons as electromagnetic radiationthatisreferred to shellsisemittedof thetwo intheform of this processDuring the energy difference energy difference theelectron shells between X-rays are emitted inaccordance withthe to fill the inner shell vacancy, characteristic Figure 2: When an outer shell electron moves characteristic X-ray sincetheenergy is 6 eV) isthe .136eV) .2)

EANM of different energy being emitted according of acceleration, it would . Two typical X-ray to the characteristics of the electron shells of emission spectra with 80 kV and 120 kV ap- the atom . The incident electrons may only be plied on the X-ray tube are displayed in Fig . 3 . repelled by the nucleus, and while they are continuously accelerated in the electric field The integral of the functions displayed in Fig . of the nucleus, electromagnetic radiation 3 (and therefore the total X-ray photon num- is emitted in the X-ray spectrum . This is the ber) is proportional to the electric current so-called bremsstrahlung process . The clas- and to the square of the voltage applied on sical electromagnetic explanation derives the X-ray tube . The number of X-ray photons from the fact that an electric charge moving correlates strongly with the image quality in with constant velocity would not emit elec- the case of CT imaging . tromagnetic radiation, whereas in the event

Figure 3: X-ray spectra with different voltages applied on the X-ray tube (120 kV and 80 kV) . Peaks in the spectrum represent X-ray photons originating from the characteristic X-ray process, while the wide spectrum is the result of the bremsstrahlung effect . (By courtesy of Dr . Laszlo Balkay)

8 Chapter 1: Interaction of Radiation with Matter

Radioactive decay and characteristics of between different nucleon arrangements in- radiation volve discrete and exact amounts of energy The nuclide of an atom can be unstable in and therefore can result (in the direction of the presence of a certain ratio of protons the ground state) in emission of particles or and neutrons, leading to an emission pro- γ-rays . The energy difference between the cess called radioactive decay . Radioactive states determines the γ-ray energy . Even a β- decay has three major forms: alpha (α), beta emission with a metastable daughter nucle- (β) and gamma (γ) . In the case of α-emission, us can result in a final γ-ray emission [2] . An- expulsion of a helium nucleus from the atom other route for γ-photon emission is through occurs, that consists of two neutrons and a β+ decay, when the ejected positron loses two protons . Alpha decay occurs primarily kinetic energy by inelastic interactions with among heavy elements that are of little in- atomic electrons . Then, a temporary particle terest in nuclear medicine . Beta decay can called the positronium is formed with a final EANM occur in two forms: β- and β+ . During β- decay electron . This is followed by the annihilation a neutron in the nucleus is converted into process, while the mass of the positron and a proton and an electron, followed by ejec- the electron are converted into two 511-keV tion of the electron together with a neutrino γ-photons, which are emitted simultaneously (ν) . The electron in this case is referred to as at about 180° with respect to each other [3] . a β- particle while the neutrino is a “particle” that has no mass or electric charge . In the Interaction of γ-rays and X-rays with case of β+ decay, a proton in the nucleus is matter transformed into a neutron and the so-called As described in the preceding sections, the dif- positron, which is the anti-particle of the ference between X-rays and γ-rays derive from electron . This process is followed by emis- their origin and are not necessarily observable sion of the positron together with a neutri- in their energy . Both are forms of electromag- no . We sometimes refer to α- and β-particles netic radiation and have a certain probability as charged particles because they carry an of passing through different processes based electric charge . Gamma emission can occur on their energy . The energy of X-rays and in several ways . The atom may have three γ-rays in nuclear medicine applications regu- different states: the most stable arrangement larly causes three kinds of interactions: photo- of the nucleons, called the ground state; a electric absorption, Compton scatter and pair very unstable state with only a transient exis- production . The last-mentioned occurs when tence, which is termed the excited state; and a photon interacts with the electric field of a a further unstable state that, however, has a charged particle and the photon disappears life-time longer than 10-12 s and is called the while its energy is used to create a positive– metastable state [2] . The nuclear transitions negative electron pair (an electron and a

9 positron) . Because both the positron and the photon energy is available . A schematic rep- electron have a rest mass equivalent to 0 .511 resentation of PEA is shown in Fig . 4 . MeV, the minimum photon energy necessary for pair production is 1 .022 MeV . In nuclear During Compton scattering (CS) the incident medicine applications this photon energy is photon interacts with a loosely bound outer rarely used, and therefore we focus below on shell orbital electron . In this case the energy the other two interactions . of the incident photon greatly exceeds the binding energy; the photon will not disap- During the photoelectric effect or photoelec- pear, but after it has been deflected with a tric absorption (PEA), the target atom absorbs scattering angle (θ) some of its energy is the total energy of the incident photon . While transferred to a recoil electron . This interac- the photon disappears, this energy is used to tion looks somewhat like a collision between eject one of the orbital electrons, which is a photon and a “free” electron . The scattering therefore called a photoelectron. The kinetic angle distribution depends largely on the in- energy of the photoelectron is equal to the cident photon energy [2] . The process of CS difference between the incident photon en- is depicted schematically in Fig . 5 . ergy and the binding energy of the electron shell from which it was ejected [2] . The kinetic These interactions (PEA and CS) do not cause energy of the photoelectron is deposited in ionisation directly as do the charged-particle the near site of the interaction during exci- interactions, but the ejection of orbital elec- tation and ionisation processes . Photoelec- trons and the creation of positive–negative tron ejection from the innermost electron electrons will cause ionisation and, therefore, shell is most probable if sufficient incident result in radiobiological effects .

Figure 4: Schematic representation of Figure 5: Schematic representation of photoelectric absorption (PEA) Compton scattering (CS)

10 Chapter 1: Interaction of Radiation with Matter

Attenuation in tissues attenuation by the tissue, and µ is the attenu- Both PEA and CS lead to missing or misplaced ation coefficient . The formula in Eq . 1 applies information when using nuclear medicine for both X-ray and γ-ray photon energies . imaging techniques . The true signal is there- Therefore, the eµx factor gives the probabili- fore attenuated and the final image data ty that an attenuating interaction will occur need to be corrected for this attenuation . In throughout the tissue length x . The thickness general, the absorption of any radiation can of an absorber (e .g . body tissue) that decreas- be described as follows: es the original intensity of radiation (I0) by one-half is called the half-value layer (HVL) .

μx In some radiation protection applications I0 ~ Ix e (such as shielding) it is useful to calculate the tenth-value layer (TVL), i .e . the thickness Eq . 1 of the absorber that decreases the radiation EANM intensity by the factor of 10 [2] . The total at- where I0 is the intensity of the radiation tenuation of a certain tissue is the sum of the impinging on the tissue, x is the length of PEA and CS attenuation coefficients and var- tissue through which the radiation has to ies based on the photon energy . This effect penetrate, Ix is the intensity of radiation after is displayed in Fig . 6 for bone and muscle

Figure 6: Dependence of total, photoelectric and Compton scatter attenuation coefficient on photon energy for bone and muscle tissues (courtesy of Dr . Nicola Belcari)

11 density tissues . It can be observed that PEA ergy to SPECT energy) and resolution scaling . becomes less dominant at around 50 keV and that most of the interactions are CS for In a PET system the coincidence events reg- higher photon energies . istered during data acquisition derive not only from true coincidences; rather, they are In the CT energy range (20–140 keV) both also biased by the so-called scattered and the CS and the PEA effect are present, but random events . The γ-photons (originating above 30–40 keV CS is dominant . For most from the annihilation process) with 511-keV single-photon emission computed tomog- energy have a very low probability for PEA raphy (SPECT) examinations, too, the photon but a significant probability of undergoing energy results mainly in CS . During SPECT, CS (over 95%) (Fig . 8) . This scatter can occur collimators are used to eliminate at least a in the body, changing the direction of the portion of the events scattered in the body; γ-photon while the coincidence is assigned however, the missing signals result in a need to a misleading line of response (LOR) . for attenuation correction (Fig . 7) . In modern During 3D PET a very large number of single hybrid SPECT/CT systems, the CT images of γ-photons reach the detector ring, includ- the patient are used for the purpose of atten- ing from sections of the body outside of the uation correction . This procedure includes field of view . Because the coincidence time co-registration, energy scaling (from CT en- window is not infinitely narrow (usually be-

Figure 7: Schematic diagram of single-photon emissions and detection . The detected signal needs to be corrected for PEA and CS

12 Chapter 1: Interaction of Radiation with Matter

tween 5 and 10 ns), there is a high likelihood signal and therefore have a great impact that two single photons from two different on the image data . Because of the geome- annihilation events will arrive during the giv- try of the patient, these interactions cause en coincidence time window, resulting in a severe attenuation that is more prominent random coincidence event . These random in the inner parts of the body and lower at events then contribute to the noise level of the surface . As discussed above, the results of the final images . The final detected count these interactions are the removal of primary rate will consist of the count rates mentioned photons from a given LOR and the potential above as: detection of scattered photons in a different LOR . Thus, attenuation and scatter are side effects of the same physical process . Cor- M ~ Atten × T + S + R rections are necessary and include removal of the estimated scatter fraction from the EANM Eq . 2 . LORs . Moreover, it is necessary subsequently to correct each LOR for the fraction of events where M is the measured count rate, Atten missing from that LOR . is the attenuation effect, T is the true count rate, S is the scatter count rate and R is the The probability that a γ-photon will escape random count rate . Random events, atten- the body depends on the distance between uation and CS will result in a distorted PET the annihilation site and the surface (x) mul-

Figure 8: Attenuation probability of a given Line of response (LOR): because of the coincidence detection, the probability of detection of both photons (p = p1 × p2) depends on the attenuation coefficient (µ) and the diameter (D) along the LOR and is independent of the distance of the annihilation site from the surface (x)

13 tiplied by the attenuation coefficient of the raw data of PET images . It must be empha- tissue (µ) . The probability of detecting both sised that all corrections will contribute to photons is the product of the individual the overall noise characteristics of the recon- probabilities that one of the photons will es- structed images, while the average image cape the body [4] . Therefore, only the diame- pixel values will be unbiased and will refer ter (D) of the patient along the LOR contrib- more closely to the true signal . utes to the equation of this probability (Eq . 3), regardless of the distance of the annihilation Acknowledgements. The author would like site from the surface: to express his gratitude to Dr . Laszlo Balkay for his advice and thoughtful conversations

-μ(D-x) -μx -μD during the writing process, and to Dr . Nicola p = p2× p1 = e × e = e Belcari for his help in the figure presentations .

Eq . 3 References

Attenuation of the signal from a given LOR 1 . Ernst R, Bodenhausen G, Wokaun A . Principles of nuclear magnetic resonance in one and two dimensions . can be measured with different algorithms Oxford: Oxford Science Publications; 1990 . from CT or MR images of the same patient . 2 . Cherry SR, Sorenson JA, Phelps ME . Physics in nuclear This so-called µ-map is generated using a medicine . 3rd ed . Philadelphia: Saunders; 2003 . bilinear scaling method in the case of CT im- 3 . Hendee WR, Ritenour ER . Medical imaging physics . 4th ages . For MRI, segmentation algorithms are ed . New York: Wiley-Liss; 2002 . routinely employed, using a Dixon sequence . 4 . Cherry SR, Dahlbom M . PET: physics, instrumentation Besides attenuation correction, scatter and and scanners . In: Phelps ME, ed . PET, molecular imaging random corrections are performed on the and its biological applications . Berlin Heidelberg New York: Springer; 2004 .

14 fined usingaradiation W weighting factor examinations, thedoseequivalent Hwasde the publicorpatientsundergoing diagnostic radiation protection membersof ofworkers, regimen a low-dose (up to 0 .1grays)In for more pronounced adverse biological effects er thanby X-rays orgammarays results in delivered rath- by neutrons oralphaparticles that, for instance, doseD thesameabsorbed fact into to account the observed take etry quantitieswere introducedOther into dosim- cal entity ological effects are mainly related to thisphysi ofD The importance . Eq in thatmass: defined as theamount of energy posure to ionisingradiation.DinamassMis measure dose D following theabsorbed ex isthedisciplinewhichaimsto Dosimetry different applications Different dosimetricapproaches for Consuelo Nile, Zanette ChiaraDe andAnnaBrusa Maria Mira, Chiesa,Marta Carlo Technologists: inRadionuclide Therapy Dosimetry FundamentalsChapter 2:Dosimetry for

W . Eq (LET) oftheradiation,i.e (LET) R isrelated to thelinearenergy transfer 1 2 [joule] /M[kg] D [gray] =E[joule] [sievert] =W H [sievert] .D isapurely [1]. physical quantity

arises fromthatbi arises thefact the density ofener .thedensity R D[gray] E deposited

R : - - - - - .

15 beam hasaW be below 5%. should planning andverification,inaccuracy nal beamradiotherapy, i.e figure of30%isquite anoptimistic an inaccuracy and interval, a relatively large uncertainty dosearetimates ofabsorbed calculated with regimens, low-dose to theapplication.In es- differs required according racy indosimetry isalsoto benoted thatthedegreeIt ofaccu- protection versus therapeutic applications in radiation varies of RBE for alpha particles intole energy account[3]. istaken The value - cisely ifitsdependenceonincidentα-partic RBE equals5orcanbeevaluated more pre therapy, RBEis1.1,whilefor alphaparticles gray into thebiological effect .For proton of 20,whiletheW and gamma rays have a path.X-raysgy deposited along theparticle role similarto W (RBE)isused;RBEhasa biological efficacy treatment planning, theconceptofrelative radiation protection in radiotherapy, i .e regimen (grays), ahigh-dose forIn patient the biological . effects ofirradiation physical quantity, asitrequires of knowledge dose, thedose equivalentisnotapurely for theabsorbed details[2]).Note that,unlike 2.5and20(seeICRPpublication103 tween oftheirenergy,ous function witharangebe ticles (hadrons) have ahigherW By contrast, in the context of exter contrast, in the context . By R of 2 and alpha particles, aW of2andalphaparticles, R in converting thephysical inconverting R ofneutrons isacontinu- W during treatment .during R Heavy par of 1 . Heavy R .Aproton . in . - - - - R

EANM In low-dose regimens, in order to compare livered when we enter the field of radiation the risk deriving from different practices, a therapy, where absorbed doses are of the third dosimetric variable was introduced, order of tens of grays . Deterministic effects named effective dose (ED) . ED depends on in this field include all kinds of radio-induced the dose equivalent of each tissue (HT) . For an toxicity, as well as lesion responses . Dosime- exposed individual, the risk of radio-induced try in radiotherapy aims to predict or to pre- cancer or hereditary effects is the sum of the vent such deterministic effects . risks to each organ, given by the product of the tissue weighting factor WT and the dose In internal dosimetry for radionuclide ther- equivalent HT . WT is a risk weighting factor apy a distinction can be drawn between defined in ICRP 60 and updated in ICRP 103 safety-oriented dosimetry and efficacy-ori- [3] . It accounts for the fact that the same dose ented dosimetry . The former aims to prevent equivalent to different tissues entails a differ- adverse events in relation to healthy organs . ent risk of deterministic effects . Misleadingly, Historically, the most common kind of tox- ED is expressed in the same unit as the dose icity is acute and reversible haematological equivalent, i .e . sieverts, but ED is a completely toxicity, or myelodepression, consisting in different concept . ED is a measure of the bio- a reduction in white blood cell and platelet logical risk of inducing mutations in cells of an counts . In radiopeptide therapy with yttri- exposed body; it is not a physical quantity . ED um-90 labelled DOTATOC (90Y-DOTATOC), was conceived in order to permit comparison irreversible kidney impairment has been of risks . It should not be used to compute an observed, while in radioembolisation, liver absolute number of deaths from a practice, decompensation leading to death has been since it is based on the linear, no-threshold reported [4, 5] . Efficacy-oriented dosimetry risk curve, which could be too conservative attempts to plan the treatment in order to [3] . ED focusses on the probability of an effect, achieve a treatment response . i .e . on stochastic effects (cancer induction or gene mutation in gonad cells) . For these rea- Dosimetry for therapeutic applications: sons, ED is applied in a dose range at which legal requirements deterministic effects are not observable, i .e . in The legal requirements with regard to dosim- the low-dose regimen . In radiotherapy, H and etry in any radiotherapeutic exposure derive ED should not be used . Here the absorbed from Council Directive 97/43, as translated dose D, potentially weighted with RBE, is the into national legislation . Council Directive quantity to be adopted . 2013/59 [6] repeals the previous Directive and must be converted into national laws Dosimetry for radiation therapy by 6 February 2018 . It contains three items A completely different range of doses is de- strictly relating to nuclear medicine therapy:

16 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

as to negate the therapeutic effect of the 1. Definition 81: “radiotherapeutic” means treatment . pertaining to radiotherapy, including nuclear medicine for therapeutic purposes. Article 57, a real novelty, remarks on the legal responsibility for ensuring compliance with 2 . Article 56 (the Optimisation principle ap- the optimisation principle . plied to radiotherapy): For all medical exposure of patients for radiotherapeutic For a number of historical and practical purposes, exposures of target volumes reasons, the activity to be administered in shall be individually planned and their radionuclide therapy is at present chosen delivery appropriately verified taking into using empirical or raw dosimetric methods . account that doses to non-target volumes Pre-treatment dosimetry (treatment plan- and tissues shall be as low as reasonably ning) is only seldom applied . The same can achievable and consistent with the intend- be said for peri-treatment dosimetry (verifi- EANM ed radiotherapeutic purpose of the expo- cation) . sure. Note that radionuclide therapy is often de- 3 . Article 57: Responsibilities: livered in a series of administrations . This is the case in treatments of thyroid cancer with 1. Member States shall ensure that: radioiodine and of neuroendocrine tumours (a) any medical exposure takes place under the with radiolabelled somatostatin analogues clinical responsibility of a practitioner; (radiopeptides) or iodine-131 metaiodoben- (b) the practitioner, the medical physics expert zylguanidine (131I-mIBG) . Verification dosim- and those entitled to carry out practical as- etry performed during the first administra- pects of medical radiological procedures are tion can be used as treatment planning for involved, as specified by Member States, in the subsequent administrations, with the the optimisation process. limitation that a variation in tumour uptake following one administration (therapeutic It is therefore clearly stated that nuclear med- response) will also alter the normal organ icine treatments: uptake . • cannot be considered different from external beam radiation therapy (EBRT); Dosimetry methods • should be planned (and verified) Although “dosimetry” literally means “mea- individually, through dosimetry of target surement of the dose”, internal dosimetry is and non-target volumes; always a rather indirect dose calculation . For • should be optimised, i .e . delivered with this purpose, three main methods have been reasonably low dosage, but not so low developed:

17 1 . The Medical Internal Radiation Dose (MIRD) The Medical Internal Radiation Dose (MIRD) schema [7–10] schema for organ dosimetry 2 . Convolution methods (MIRD pamphlet 17 [8]) The simplest dosimetry method was pro- 3 .Patient-specific Monte Carlo-based meth- posed by the MIRD Committee [7–10] . De- ods spite its apparently complicated formalism, we try here to develop its main concepts in These methods are characterised by in- a non-rigorous but didactic way, following a creasing levels of accuracy and complexity . paper by Mike Stabin [11] . We also use the However, their basic needs are the same: most popular and historical nomenclature quantitative evaluations of the activity (MIRD Primer 1991) [7], though a new, official, content in metabolically active tissues or but still unused nomenclature was published perfused volumes and of the variations in in MIRD pamphlet 21 (2009) [8] . this activity over time . This represents a pro- found difference from EBRT dosimetry . The The schema was originally conceived to eval- dose distribution from an accelerator beam uate mean absorbed dose at organ level and or from a sealed source (brachytherapy) can was based on the classification of an organ as be simulated, using as input data a CT scan source or target . A source organ is perfused of the patient and the beam or the source or displays uptake of the radioactive agent, characteristic . In radionuclide therapy, the while target organs passively receive irradi- activity biodistribution and its physiologi- ation from source organs . Within this frame- cal variation over time must be studied by work, it is important to distinguish between sequential patient data collection . This may two kinds of radiation: include thyroid uptake measurements, images, blood sampling, whole body counts, • Non-penetrating radiation, which is and collection of urine samples, depending incapable of going beyond the borders of on the injected radiopharmaceutical and the source organ to reach other organs . the aim of dosimetry . The frequency and Such radiation is typically charged particles time framework of data collection depend (beta particles, positrons, alpha particles) . on the nature of the treated disease and on • Penetrating radiation, capable of the clearance of the used agent . The conse- transferring energy from a source to a quence may be a non-negligible workload target organ . Such radiation is typically for both the patient and the division . This gamma rays or X-rays . argument, often used in the past against internal dosimetry, is weak when one consid- Two important points should be noted . ers that a complete EBRT treatment requires First, the MIRD schema has been extended daily irradiation for weeks . from the organ level down to the cellular

18 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

level, where the source region may be the maximum of 42% if we consider the largest cell membrane, and the target region, the source for the standard 73-kg male, i .e . its nucleus . In this case, the classification of whole body, uniformly filled by radioiodine . charged particles as “non-penetrating radi- If, on the other hand, 177Lu is considered, the ation” should be revised, since any of these low photon abundance means that 96% of particles can reach the cell nucleus from the the liver dose is due to beta rays, and only membrane . Second, remaining at the or- 4% to gamma rays . Therefore, for beta-gam- gan level, consider, for instance, 131I thyroid ma emitters in clinical use, the highest ab- uptake . Here, 94% of the absorbed dose is sorbed dose is delivered to source organs by attributable to beta rays and only 6% to 364- beta particles . This fact is highly relevant in keV photons . For liver uptake of the same understanding the implications of the MIRD isotope, the contribution of gamma rays schema in the following different situations increases to 25% . The relative amount of of increasing complexity . EANM absorbed dose from gamma rays reaches a

Figure 1: images of hepatocarcinoma treated with 90Y microspheres Upper left: diagnostic CT arterial phase; Upper right: lobe volumetry on portal phase Lower left: 99mTc SPECT-CT slice; Lower right: microsphere 90Y PET

19 Consider as an example an organ subject to Since 90Y microspheres are permanently self-irradiation only from non-penetrating trapped, the time-activity curve (TACT curve) radiation: a liver lobe injected with 90Y mi- in the lobe is given by the mono-exponential crospheres (Fig . 1) . Such devices are perma- decay curve of the administered activity A0 of 90 nently trapped in capillaries and release their Y, with a half-life T1/2 = 64 .2 h and a decay beta energy in tissue until complete decay constant λ = ln2 / T1/2: has occurred . At each time instant, the lobe dose rate dD/dt (Gy/min) is proportional to the activity burden . Let us introduce the pro- A(t) = A0 exp(- l t) portionality constant, called S: Eq . 6

dD/dt = S A(t) The integral in eq . (5) can be easily solved:

Eq . 3 ∫ A(t) dt = ∫ A0 exp(- l t) =

A0 ∫ exp(- l t) = A0 / l The differential absorbed dose to the organ during a small interval of time dt, during Eq . 7 which the activity can be considered constant, is given by the dose rate times dt: Finally the absorbed dose is given by:

dD = S A(t) dt D = S A0 / l

Eq . 4 Eq . 8

The total absorbed dose is given by the sum The integral in eq . (7) has a simple physical of all the time intervals, from the zero time meaning . The activity A(t) is by definition the (administration) to infinite time . A sum of dif- number of decays per second . A(t) multiplied ferential terms is mathematically performed by the time dt in eq . (4) gives the number of by an integral: decays during the interval dt . The integral [eq . (7)] is therefore the total number of decays (NDs) of 90Y nuclides in the liver lobe, D = S ∫ A(t) dt from the administration to infinite time:

Eq . 5

20 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

We now have all the parameters needed to compute the absorbed dose to the injected ∫ A(t) dt = NDs portion of liver with mass M liver from 90Y microspheres: Eq . 9

Then D = 933 keV / M × A0 / l

Eq . 13 D = S × NDs This can be approximated, compacting the Eq . 10 physical constant into a formula: EANM

It is no surprise that the absorbed dose is proportional to the number of decays in the D [Gy] = 50 / M [kg] × A0 [GBq] organ . Eq . 14 The problem now is the value of the parameter S . This, too, can be easily calculated (in this The multiplication symbol “×” was intention- first easy case) . Solving eq . (10) for S, we have: ally inserted . It refers to the basic splitting of the MIRD dose calculation into two factors (eq . 10) . The absorbed dose in eq . (13) is the S = D / NDs product of two independent terms: the first one (50/M), i .e . the S term, accounts for the Eq . 11 isotope emitted energy and organ geometry (mass), while the second in this case is simply S is the absorbed dose per one decay . From the injected activity . the definition of absorbed dose, it can be in- ferred that this quantity is given by the mean Note that for an accurate dosimetric estima- beta energy (933 keV) emitted by 90Y divided tion, the organ or the perfused portion mass by the perfused region mass M: M should be carefully evaluated (Fig . 1 upper left, Fig . 2) . This is usually done by contouring the organ under study or its portions on CT S = 933 keV / M slices . This necessary step is performed by technologists in a number of centres . For a Eq . 12 more accurate determination, a first raw vol-

21 ume of interest (VOI) is created around the Absorbed dose to an organ from non- organ . Then the true organ volume is de- penetrating radiation in the presence of fined by applying a Hounsfield acceptance biological clearance window; for example, for the kidney in the A slight complication arises if the agent arterial phase, this can be chosen as [0, 400] . displays both physical decay and biologi- For liver lobe contouring, the technologist cal clearance, which is the case for almost usually asks for advice and supervision from all radiopharmaceuticals used in nuclear the radiologist who performed the injection medicine diagnosis and therapy . We keep under angiographic guidance . Knowledge as an example the liver after administration of the angiographic study together with the of 90Y-DOTATOC . Eq . (7) cannot be solved simulation with technetium-99m macroag- as easily as for the mono-exponential TACT, gregated albumin (99mTc-MAA) SPECT is use- but there are several mathematical methods ful in defining the actually perfused portion . to obtain the value of the integral . The value The CT portal phase is used since the medial of the integral represents the area under the suprahepatic vein defines the border be- curve (AUC) . Absorbed dose is therefore al- tween the right and the left lobe . The mass of ways directly proportional to the NDs, corre- the organ is given by its CT volume times the sponding to the AUC . This quantity is defined soft tissue density (1 .03 g/cc) . as cumulated activity Ã:

Ã = ∫ A(t) dt = NDs

Eq . 15

Ã is usually expressed in MBq h, but this is simply a strange way of saying that Ã is the number of decays occurring in the organ . In order to have a variable which is independent

of the administered activity A0, we divide

the cumulated activity (MBq h) by A0 (MBq), obtaining a time (h) . This variable is named Figure 2: Mass determination on CT slices of residence time τ . This name is misleading . Do kidney in radiopeptide therapy not think that once the residence time has elapsed, the organ is free from radioactivity . τ is just the cumulated activity divided by the injected activity . τ allows comparison of the

22 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

absorbed dose per unit activity . For any given apeutic administration, since tumour mass isotope, the higher is τ, the higher will be the and uptake may be reduced owing to ther- absorbed dose per unit activity . apy . For the pure beta emitter 90Y, the TACT in organs is derived from a sequence of scintigrams taken after the administration of the t = Ã / A0 same molecule labelled with a gamma emitter, in radiopeptide therapy the 177Lu isotope

Eq . 16 (Fig . 3) . TACT can be derived by drawing ROIs on the liver . Examples of such curves for the The basic MIRD equation is: livers of different patients are shown in Fig . 4 .

D = S × Ã EANM

Eq . 17

The simplicity of the MIRD methodology is evident in this product . For 90Y only, S is given by eq . (12) . The second term depends on the liver clearance, i .e . on organ biokinetics, which is an individual characteristic . Other, probably more familiar examples of biokinet- Figure 3: the sequence of 177Lu-DOTATOC ics in diagnostics are the kidney TACT curves whole body anterior images obtained at 1, in a dynamic study . 18, 40 and 65 h post injection .

Here we confront the key point concerning the need for individualised dosimetry: Every Absorbed dose from non-penetrating individual shows his or her own clearance and penetrating radiations curve (TACT) in his or her organs and for each As long as non-penetrating radiations are con- injected radiopharmaceutical. This implies sidered, the dosimetric calculation is relatively that in order to achieve complete dosimetry, simple, since for each source organ eq . (17) i .e . optimised radionuclide therapy, the TACT can be applied . The use of penetrating radia- of each source organ has to be determined tions (gamma emitters) introduces two com- in each individual patient . This is usually done plications . Consider the liver with an uptake with a sequence of scans . Biokinetics may of 177Lu-DOTATOC . First, only a fraction of the change even for the same patient after a ther- gamma energy emitted in the liver is depos-

0.40

0.35

0.30

0.25 minimum residence 0.20 time = 0.55 h maximum residence 0.15 time = 68 h 0.10

0.05

Fraction of injected activity 0.00 0 24 48 72 t(h)

Figure 4: TACT curve in liver after 177Lu-DOTATATE administration . The two patients with minimum and maximum residence time studied in National Cancer Institue of Milan were chosen, corresponding to a non metastatic versus a heavily metastatic liver . The huge difference in AUC between these two patients is evident . ited in the liver itself . The S value computation all these S values (Snyder’s factors) were cal- becomes non-trivial . Second, another fraction culated by the MIRD committee using Mon- of gamma energy is deposited out of the liv- te Carlo simulations . These values are now er, irradiating all the other target organs . The available in tables for many isotopes . They notation Ss←s (S “from source to source”) is in- are also available online [12] . Therefore, con- troduced for the self-irradiation, and we have sidering again eq . (17), the main advantage a large set of St←s values (S “from source s to of the MIRD method is that S values are avail- target t”) for cross-irradiation . An additional op- able . Clinical dosimetrists have to measure erational complexity arises from the fact that the biokinetics only, and to determine Ã for after a 177Lu-DOTATOC administration, there are all source organs, i .e . only the second term several source organs, primarily liver, spleen, in eq . (17) . The basic data required for calcu- kidney and circulating activity . We need the set lation of the S value, used to determine the of St←s for any possible cross-irradiation . absorbed fraction for self- and cross-irradiation, are the total energy emission for each The often mentioned simplicity of the MIRD isotope (physical isotope properties) and the schema is apparently lost . This is false, since organ geometry .

24 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

This simplicity has a price . S factors were not manual summing, ad hoc calculation codes determined in real patients . A virtual phan- have been developed, of which OLINDA/ tom was drawn, and S factors were derived EXM version 1 .1 is the most popular [13] . This for that geometric object (Fig . 5) . Actually, code needs as input data first, the choice of several phantoms of different size were used . the phantom among those available, then, This allowed the above-mentioned simplicity the choice of the injected isotope among to be achieved, but at the expense of accura- 814 available, and, finally, the patient-specific cy . When we perform organ MIRD dosimetry, biokinetics data, i .e . the residence times of we evaluate absorbed doses to a phantom, the source organs (Fig . 6) . It then proceeds not our real patient . by making τ × S multiplications and sums . It needs to be mentioned here that individualised organ masses may be used instead of the standard phantom organ masses . EANM

Figure 5: the phantom used to determine the S factors of the MIRD schema

A demanding task still remains . For each considered target organ, for instance lungs, we need to sum all the contributions deriving from source organs (liver, spleen, kidneys, circulating activity) . This step has to be repeated for all target organs . In order to avoid Figure 6: The OLINDA input panels (choice of the phantom, biokinetic data)

25 The main limitation of present MIRD do- apy can be designed to deliver the maximum simetry at the organ level is the use of a tolerable activity (MTA) on an individualised phantom geometry instead of a real patient basis . If we were adequately organised to geometry . To improve this point, the new routinely accomplish planning of this nature S value calculations are based on an an- in all three of these patient classes in Europe, thropomorphic CT-based virtual phantom . most of the oncological nuclear medicine Another approximation is the evaluation of treatments in Europe would partially fulfil only mean organ and tumour doses, since the optimisation principle . The term “partial- the uptake in organs or lesions is non-ho- ly” is used here because the MTA approach is mogeneous . The voxel dosimetry approach a maximisation: rigorous optimisation would was introduced to account for non-homo- require also lesion dosimetry, for which im- geneous uptake . aging would be necessary .

In the particular case of OLINDA 1 .1, the tu- Thyroid Graves’ disease mour is modelled only as an ideal sphere . In the case of Graves’ disease, efficacy-ori- Moreover, differently from normal organs, ented thyroid dosimetry can be performed the tumour is not considered for the cross-ir- without the need for scintigraphic imag- radiation: the tumour dose is calculated for ing, provided that the mass of the organ is self-irradiation only . Nevertheless, all these measured on scintigrams or with ultrasound approximations have only a minor impact images . The detector is a scintillation probe since, as we have seen, the higher dose with a fixed probe–thyroid distance . This al- contribution derives from non-penetrating lows one to obtain the uptake and the TACT particles, which are exactly accounted for in of the organ . The number and the time in- source organs in OLINDA calculations . terval for thyroid counting can be chosen according to the desired accuracy [14, 15] . Easy cases of MIRD dosimetry, feasible without imaging Blood and red marrow dosimetry for agents In many situations dosimetry can provide without specific marrow uptake sufficient information to plan a treatment Bone marrow is the organ at risk in most nu- even without imaging . The main fields of ap- clear medicine systemic therapies, including plication of this methodology are the treat- treatment of thyroid cancer with radioiodine, ment of Graves’ disease, the treatment of 131I-mIBG therapy, treatment with monoclo- metastatic thyroid cancer and 131I-mIBG treat- nal antibodies and the use of bone-seeking ments . While the first of these cases involves agents for bone pain palliation (as employed a benign pathology, in the others we are prior to the introduction of 223Ra chloride) . dealing with safety-oriented dosimetry . Ther- If the injected radioactivity binds to neither

26 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

bone nor red marrow nor blood particles, an of the whole body is obtained, and a whole- easy method of dosimetry for blood or red body dose is calculated as: marrow is possible provided that the TACT of the activity concentration in blood sam- D = S × Ã ples and the whole-body activity burden are whole body whole body ← whole body measured [16, 17] . The necessary instrumentation is a gamma counter to count blood Eq . 18 samples and a spectroscopic probe or Gei- ger counter to count the patient body, with a SPECT imaging for internal dosimetry reproducible patient–detector distance . Data Kidneys are another example of an organ collection should last several days, and ide- at risk . Renal impairment has seldom been ally up to the 6th day for blood sampling in observed in treatments with radiopeptides radioiodine therapy . labelled with 90Y . Prevention of such damage EANM requires imaging-based dosimetry . The mean 131I-mIBG whole-body dosimetry dose MIRD approach presented above has This method was developed as a simpli- an additional limitation if the adopted imag- fication of red marrow dosimetry to treat ing methodology is planar (2D) . Overlapping neuroblastoma in children, in whom repeat- of activity from different organs can be only ed blood withdrawal is inappropriate . In partially corrected by background subtraction . 131I-mIBG therapy of paediatric patients, the This problem arises, for example, in radiopep- whole-body dose has been demonstrated tide treatment, where intestinal activity over- to correlate with haematological toxicity laps with kidney activity, or in radioimmuno- [18] . A limit of 2 Gy whole-body absorbed therapy using labelled antibodies, which circu- dose is generally accepted . Since this kind late for days with negligible excretion (Fig . 7) . of therapy is based on repeated administrations, peri-therapeutic dosimetry after the In these situations, the organ or lesion mean first administration can be used to plan the dose can be more accurately determined subsequent administrations . The dosimetric if a sequence of SPECT scans is performed method is based on a sequence of whole- (Fig . 8) . Dosimetry requires attenuation cor- body counts (minimum two per day) taken rection, which can be done in SPECT with a during the hospitalisation for therapy using co-registered CT . The increase in the number a Geiger counter fixed on the ceiling above of SPECT-CT systems in recent years rep- the patient’s bed or a portable counter at a resents a step in this direction . fixed distance from the patient . Usually the geometric mean G = √A P of anterior A and Attenuation correction is less demanding in posterior P counts is considered . The TACT planar imaging . A planar transmission scan

27 Figure 7: the problem of overlapping sources in planar dosimetry . Anterior and posterior WB images after 177Lu-DOTATOC administration . In radiopeptides treatment, the critical organ activity (kidney) is often overlapped to intestinal activity . for the purpose of attenuation correction can converted to the energy of the injected iso- be easily done by placing a flood source 57( Co tope (MIRD dose estimate report no . 20 [8]) . or 99mTc) on the lower gamma camera head, below the patient couch (Fig . 9) . The most In 3D dosimetry, an additional problem still accurate attenuation correction is obtained under study is the mutual co-registration if the radial distance of the lower gamma of the SPECT image sequence needed to camera head from the couch is maximal . A produce the TACT in each studied region . blank scan without the patient is acquired; A possible approximated simplification of then, with an identical setting, a transmis- the method is so-called 2 .5 D dosimetry, or sion scan is performed on the non-injected hybrid dosimetry [19] . One SPECT examina- patient . ROIs are drawn on images recorded tion and a sequence of planar images are by the upper gamma camera head . The ratio acquired, with one planar scan at the same between ROI counts in the transmission scan time as the SPECT . Quantification is derived and counts in the blank scan gives a number, on the 3D image, while the TACT is derived whose square root is the attenuation correc- from the sequence of planar images . tion factor at the energy of the isotope used for transmission scan . This should then be

28 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

and not only for dosimetric purposes [21] .

Convolution and direct Monte Carlo methods Convolution methods go beyond the evaluation of organ mean dose . They aim to compute the absorbed dose point by point, at any location in the studied object . Voxel dosimetry and dose point kernel dosimetry are similar in that the dose from a point or voxel Figure 8: SPECT-CT dosimetry after 177Lu- source to the surroundings is calculated . This DOTATOC administration .critical organ activity calculation is repeated for all source voxels, EANM (kidney) is often overlapped to intestinal adding the contribution of each source vox- activity . el to all target voxels . This process is termed convolution . It overcomes the phantom geometry limits of the MIRD approach . Snyder PET imaging for internal dosimetry (S) factors from voxel to voxel are also avail- PET imaging is now a routine in dosimetry able . Commercial software can be employed [20], especially after 90Y radioembolisation for dosimetry using convolution methods . (Fig . 1, lower right) . Here the problem is the infinitesimal positron emission from90 Y (32 Convolution methods can be successfully per million decays), which requires acquisi- applied to homogeneous tissues, while in tion times of 15 min per bed position with inhomogeneous tissues or at organ–organ two bed positions to cover the liver and interfaces (e .g . bone–tissue or liver–lung), results in unavoidably noisy images despite direct Monte Carlo simulation is the most the long acquisition time . The huge advan- reliable, though also the most demanding tage in radioembolization dosimetry derives calculation . It is based on the simulation of from the permanent trapping of micro- each single radionuclide decay, following spheres: just one scan is sufficient since TACT the history of the emitted beta and gamma is given by the physical decay of 90Y . rays, with their probabilistic interactions . The deposited energy from each interaction is The enhanced image quality in comparison recorded . The process is repeated with a dif- with SPECT is outstanding in iodine imaging . ferent random fate for some ten millions of Iodine-124 PET should be used for accurate decays, obtaining a 3D inhomogeneous ab- staging after thyroidectomy, given the low sorbed dose distribution . diagnostic sensitivity of 131I whole-body scan,

29 Figure 9: Attenuation correction in planar imaging: operational setting

30 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

Figure 10: Pre therapy SPECT-CT dosimetry in radioembolization of hepatocarcinoma . Voxel EANM dosimetry map (left) and corresponding integral Dose Volume Histogram (DVH) (right) .

From a practical point of view, for dosime- histograms are still under investigation in ra- try in a real patient, both convolution and dionuclide therapy (Fig . 10), while in external Monte Carlo methods need as input a 3D beam radiotherapy, voxel dosimetry is rou- nuclear imaging sequence of images (SPECT tinely applied . or PET), accompanied by and co-registered with the morphological patient data (CT Segmentation scan) . The problem of mutual co-registration Segmentation is the process of contouring of the 3D image sequence of a non-rigid organs or lesions to define regions of inter- body requires elastic deformation co-reg- est (ROIs) or volumes of interest (VOIs) . This istration . In addition, when we go down to procedure is necessary to obtain counts in the voxel level, the problem of image noise VOIs, which are related to the activity in VOIs . arises . Voxel counts (and then voxel absorbed It is also necessary to determine the object dose) have an intrinsic indetermination due volume, i .e . its mass . Segmentation is not a to noise, which is given by the Poisson noise, trivial step in the dosimetric calculation, and with additional noise introduced by the re- it can introduce a non-negligible uncertain- construction algorithm . Absorbed dose and ty . Difficulties may especially arise during activity in each voxel are therefore subject to liver volume determination in patients with an intrinsic uncertainty . For this problem and abnormal liver anatomy following hepatic re- for the partial volume effect problem, typical section . Another problematic situation is the of nuclear medicine imaging, dosimetry at presence of infiltrative liver tumours, whose the voxel level and the use of dose volume borders cannot be defined even on CT . Ow-

31 ing to the need for segmentation, dosimetry The quantification on images is more com- is dependent on the skills of the operator . plex . In contrast to PET scanners, gamma The optimal threshold for segmenting an ob- cameras were not conceived to be quantita- ject in order to obtain quantitatively accurate tive . Only the last model of a producer was information is a general problem in nuclear developed ad hoc, with new hardware and medicine, an example being segmentation software, in order to provide quantitative for FDG PET target volume delineation for ra- SPECT, and then only for 99mTc . PET scanners diotherapy treatment planning [22] . are usually considered quantitative, but issues arise when non-conventional isotopes Segmentation requires knowledge of basic are employed, such as 90Y [23] or 124I . anatomy . For this reason, technologists can be usefully employed in this activity . During Quantitative imaging requires the imple- this work they are usually supervised by an mentation of all the possible corrections for experienced radiologist . physical effects (attenuation, scatter, dead time, partial volume effect, resolution recov- Quantification ery and, for PET, random correction and time Regardless of the kind of dosimetry, the of flight) . A system calibration is then nec- amount of activity in source regions (organs essary, to convert the count rate in a VOI to or voxels) needs to be determined . The first activity . This requires a phantom containing requirement is an accurate dose calibrator a known activity: such a phantom can be a to measure the administered activity and point source or an extended phantom, or its residue . In whole-body dosimetry, quan- a hot insert in a water phantom . If a phan- tification is immediate since the first body tom is used, an absolute system calibration count is taken immediately after the adminis performed . In some particular situations, istration, before urinary bladder voiding . Set- each patient can be the “calibration phan- ting the correspondence between obtained tom” for him- or herself . In the case of liver initial whole body counts and the known radioembolisation, the known activity can be injected activity allows one to proportionally imaged on one SPECT or PET scan and can calculate the activity burden in subsequent be set in correspondence with the obtained counts . This is called “patient relative calibra- counts (patient relative calibration method, tion” . Calibration of the gamma counter is cf . above) . Technologists can play a useful required to convert the blood sample count role in the calibration process owing to their rate in a tube into activity, with a correction technical competence on scanners and their for non-linearity effects . authorisation to handle radioactivity .

32 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

The necessity of the technologist in Disclosure clinical dosimetry Carlo Chiesa received honoraria during the The Dosimetry Committee of the EANM has past two years from BTG Biocompatibles for been actively promoting the implementa- lectures, consultancy and one symposium tion of dosimetric optimisation of radionu- during the 2015 EANM Congress . He was clide therapy for more than a decade . It is not supported by BTG Biocompatibles at the last predictable when and to what extent such two EANM Congresses . In 2015 he was also a optimisation will be accomplished . What is consultant for MedPace core lab . beyond doubt is that such an advance on a large scale cannot happen without the em- The other authors have nothing to disclose . ployment of technologists . By law, physicists have the responsibility for dose calculations, Ethical policy but several preliminary operations can and This work has an educational goal . All clini- EANM should be done by technologists . cal images contained herein were acquired for diagnostic or therapeutic purposes for In the Nuclear Medicine Division of the patient care, after procurement of signed National Cancer Institute of Milan, several informed consent, before this chapter was theses on dosimetry have been written by compiled . Images were copied here for edu- technologists, including two that addressed cational purposes . in particular the role of the technologist in clinical dosimetry . In such institutions, not only data acquisition (patient handling and scanning, whole body counting, blood sample counting) but also segmentation is ordinarily performed by technologists . Tech- nologists therefore have an essential role in the implementation of clinical dosimetry in radionuclide treatments .

Guidelines of the EANM Dosimetry Committee The EANM website, under the section “publication” [24], offers a list of published dosimetry guidelines that are freely downloadable .

33 References

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5 . Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, 16 . Lassmann M, Hänscheid H, Chiesa C, Hindorf C, Flux Morosi C, et al . Yttrium90 radioembolization for inter- G, Luster M . EANM Dosimetry Committee Series on mediate-advanced hepatocarcinoma: a phase II study . Standard Operational Procedures for Pre-Therapeutic Hepatology 2013;57:1826–1837 . Dosimetry I . Blood and bone marrow dosimetry in dif- 6 . http://eur-lex .europa eu/legal-content/EN/TXT/PD. - ferentiated thyroid cancer therapy . 2008 . http://www . F/?uri=CELEX:32013L0059&from=EN eanm .org/publications/guidelines/index .php?navId=37

7 . Loevinger R, Budinger TF, Watson EE . MIRD primer for 17 . Hindorf C, Glatting G, Chiesa C, Lindén O, Flux G . EANM absorbed dose calculations . Society of Nuclear Med- Dosimetry Committee guidelines for bone marrow and icine, 1991 . whole-body dosimetry . http://www .eanm org/publica. - tions/guidelines/index .php?navId=37 8 . http://www .snmmi org/ClinicalPractice/content. .aspx- ?ItemNumber=4363 18 . Fielding SL, Flower MA, Ackery D, Kemshead JT, Lashford LS, Lewis I . Dosimetry of iodine 131 metaiodobenzil- 9 . Sgouros G . Dosimetry of internal emitters J Nucl Med guanidine for treatment of resistant neuroblastoma: 2005;46:18s–27s . results of a UK study . Eur J Nucl Med 1991;18:308–316 .

10 . Zanzonico PB . Internal radionuclide radiation dosimetry: 19 . Ferrer L, Kraeber-Bodéré F, Bodet-Milin C, Rousseau C, Le a review of basic concepts and recent developments . J Gouill S, Wegener WA, et al . Three methods assessing Nucl Med 2000;41:297–308 . red marrow dosimetry in lymphoma patients treated with radioimmunotherapy . Cancer 2010;116 (4 Sup- 11 . Stabin M . Demystifying internal dose calculations . www . pl):1093–1100 . doseinfo-radar .com/demystify .doc 20 . Lhommel R, van Elmbt L, Goffette P, Van den Eynde M, 12 . http://www .doseinfo-radar .com; also Health Physics Jamar F, Pauwels S, Walrand S . Feasibility of 90Y TOF PET- 2003;85:294–310 . based dosimetry in liver metastasis therapy using SIR- Spheres . Eur J Nucl Med Mol Imaging 2010;37:1654–1662 .

34 Chapter 2: Dosimetry Fundamentals for Technologists: Dosimetry in Radionuclide Therapy

21 . Wierts R, Brans B, Havekes B, Kemerink G, Halders S, Schaper N, et al . Dose-response relationship in differen- tiated thyroid cancer patients undergoing radioiodine treatment assessed by means of 124I PET/CT . J Nucl Med 2016;57:1027–1032 . Feb 25 .

22 . Brambilla M,_ Matheoud R, Secco C, Loi G, Krengli M, Inglese E . Threshold segmentation for PET target volume delineation in radiation treatment planning: the role of target-to-background ratio and target size . Med Phys 2008;35:1207–1213 .

23 . Willowson KP, Tapner M, The QUEST Investigator Team, Bailey DL . A multicentre comparison of quantitative 90Y PET/CT for dosimetric purposes after radioembolization EANM with resin microspheres – The QUEST Phantom Study . Eur J Nucl Med Mol Imaging 2015;42:1202–1222 .

24 . http://www .eanm .org/publications/guidelines/index . php?navId=37

35 Chapter 3: International Basic Safety Standards Pedro Fragoso Costa

Introduction Since then, the ICRP has created, maintained Shortly after the discovery of X-rays (by Rönt- and developed the international system of gen in 1895), radiation damage was already radiological protection used worldwide as being studied and documented . As early as the common basis for radiological protec- 1896, an American engineer, Wolfram Fuchs, tion standards, legislation, guidelines, pro- published an article [1] in which the three grammes and practice . The ICRP has pub- fundamental principles of radiation protec- lished more than 120 publications on all tion were presented: aspects of radiological protection, including fundamental recommendations taking into 1 . Exposure should be restricted to a mini- consideration not only the current under- mum . standing of the science of radiation exposure 2 . The X-ray tube should be placed at a se- and effects but also societal expectations, cure distance . ethics and experience gained in application 3 .Protective plates should be used for the of the system [6] . non-exposed body parts . The International Commission on Radiation The increasing interest in the use of X-rays Units and Measurement (ICRU) was found- or radionuclides in medical, industrial and ed simultaneously with the ICRP, the former even commercial applications subsequently having a more fundamental focus on radia- paved the way for numerous accidents for tion-related quantities and units, terminolo- which the source was the biological hazard gy and measurement procedures [7] . caused by ionising radiation [2] . However, the idea that this new radiation could be used to Nowadays, the ICRP plays a central role in a destroy malignant tissues laid the founda- rather complex set-up of interdependent or- tions for radiotherapy, and the first treatment ganisations that work together with the pur- of a cancer by this means was reported in pose of achieving the goals set by the system 1899 [3] . In the diagnostic field, ionising radi- of radiological protection, from inception to ation was used for medical purposes as early regional implementation . as 1897 in military field hospitals [4] . Global players It was not until 1928 that the first internation- At the international scale, various institutions al organisation was created for the protec- and personalities have historically played tion of workers, patients and public against a fundamental role in the peaceful use of ionising radiation, namely the organisation atomic energy . The speech by U .S . President known today as the International Commis- Eisenhower in 1953, entitled: “Atoms for sion on Radiological Protection (ICRP) [5] . Peace” [8], was a milestone in stopping the

36 from ICRPPublication 109)[11] Figure protection androles chain,showing bodies(adapted actions ofinternational 1:Radiation purposes, to provide and materials assistance development of nuclear energy for peaceful ated and empowered onthe actions to take In 1957theIAEAwascre- made ornatural[9]. sources, whether peaceful, military, man- fects ofionisingradiationfrom allpossible responsible for controlling thelevels andef- became theoffi cialauthority international diation (UNSCEAR) . The latter, created in1955, tifi c CommitteeEff onthe Ra- ects of Atomic (IAEA)andtheUnited NationsScien- Agency Atomiccreation Energy oftheInternational laid down theideological background for the would notberepeatedsaki . This speechalso nuclear disasters from andNaga- Hiroshima thatthe and indelivering asenseofsecurity “nuclear race” withtheformer SovietUnion Chapter 3:International Standards Safety Basic 37

as shown by Figure 1. specifi cationsandbeintegrated into thelaw, recommendations thatwillsuittheregional bodies usethisinformation inorder to make don exposure), ICRP and other international accident orepidemiological studiesonra- the atomic theChernobyl bombinJapan, ed to anumber ofexposure situations(e .g . While UNSCEARpresents thefi elddata relat- or adoptnuclearsafety standards [10]. and,technical fi knowledge nally, to establish world, to foster theexchange ofscientifi cand the needsofunderdeveloped areas ofthe (e .g . energy, and health) relevant to industry for applications of atomic energy practical

EANM International System of Radiological in radiation protection . There are three cate- Protection gories of exposure: Since its foundation, the International Sys- tem of Radiological Protection has been • Occupational exposures: those exposures subject to many updates and fundamental that occur in a range of industries, medical changes . Over the years, not only have dose institutions, educational and research quantities and their units been redefined, establishments and nuclear fuel cycle but weighting factors and body-related dose facilities [15] quantities have been revised and dose limita- • Public exposures: exposures to natural tions for occupational and public exposures, radiation sources and man-made sources redefined . Despite the continual implemen- [16] tation of this self-optimisation process, the • Medical exposures: exposures of patients fundamental principles of radiation protec- and comforters, carers or volunteers in tion were in fact defined in the first ICRP rec- research and in diagnostic, interventional ommendations in 1958 [12]: “The objectives and therapeutic procedures [17] of radiation protection are to prevent or minimise somatic injuries and to minimise Three exposure situations have been de- the deterioration of the genetic constitution fined, which are considered to encompass of the population” . Nowadays, this principle the entire range of possible situations involv- has been reformulated as the prevention of ing exposure [18]: deterministic effects caused by high doses (mainly of an acute nature and appearing • Planned exposure situations: those after a known dose threshold) and the re- situations in which a radioactive source duction of stochastic effects caused by both is introduced or operated in a set-up high and low doses and that can be detected designed for that purpose a long time after exposure [13] . • Emergency exposure situations: unexpected situations that arise from The concept of dose has been introduced planned exposures and require urgent as the quantity of interest relating physical attention measurements with biological effects of ra- • Existing exposure situations: situations diation . The term “dose” has been medically that exist regardless of any protective act appropriated in analogy to the pharmaco- or decision, mainly regarded as natural logical dose, as used in the prescription of a background radiation medicine [14] . However, there are situations in which exposure to radiation is not related The use of radiation in Nuclear Medicine is to a medical act . Differentiation of exposure a planned exposure situation . All workers situations is, therefore, a fundamental topic and facilities need to be under regulatory

38 Chapter 3: International Basic Safety Standards

control, with appropriate authorisation from established limits (only applies to the occu- the competent authority in order to operate . pational and public exposure categories) . There are situations in which incidents, accidents or errors (e .g . radiopharmaceutical mis- IAEA International Basic Safety Standards administration, spills or contamination) result (IBSS) in a potential exposure [19] . A potential ex- As mentioned previously, the development posure may result from an accident involving and application support of safety standards a source or an event or sequence of events of is a statutory function of the IAEA . To achieve a probabilistic nature, including equipment this mission, IAEA periodically publishes failures and operating errors . Safety Standard Series, which cover nuclear safety, radiation safety, transport safety and The most important part in a system of radio- waste safety . The IBSS are a part of the safe- logical protection is the ruling principles that ty requirements category within the IAEA EANM apply to all situations and persons involved . scheme . The latest IBSS [20] is a joint effort Again, there are three fundamental princi- of the European Commission (EC), the Food ples of radiation protection [13]: and Agriculture Organization of the United Nations (FAO), the IAEA, the International 1 . The principle of justification: Any change Labour Organization (ILO), the OECD Nuclear to an exposure situation (e .g . a decision to Energy Agency (OECD/NEA), the Pan Ameri- perform a PET/CT scan, changing from an can Health Organization (PAHO), the United existing exposure to a planned exposure Nations Environment Programme (UNEP) situation) should result in a net benefit to and the World Health Organization (WHO) the individual . and uses the latest recommendations provided by ICRP [13], in particular with atten- 2 . The principle of optimisation of protection: tion to the possible exposure situations . The likelihood of incurring exposures, the number of people exposed and the mag- In general all safety standards follow the nitude of their individual doses should all fundamental principle of protecting people be kept as low as reasonably achievable from the hazardous effects of ionising radi- (this is commonly known as the ALARA ation . In all possible interactions in which a principle), taking into account economic radioactive source could produce damage and societal factors . to an individual, there is a role for protection . There is, however, a difference between 3 . The principle of limitation of doses: The total these two concepts: while radiation protec- dose to any individual from planned expo- tion is mainly focussed in controlling exposures, with the exception of medical exposure to a source, to attenuate its effects, ra- sures of patients, should not exceed the diation safety is about maintaining control

39 over exposures . Since radioactive sources them . The complementary nature of safety potentially represent a danger to individuals, and security is one of the fundamental prin- there is also a responsibility to secure those ciples of the IBSS [21] (Fig . 2) . sources and prevent unauthorised access to

Control

measures, Safety safety/security Security synergies

Figure 2: In the health context safety/security synergies can refer to the joint efforts of the chief of a nuclear medicine department and the radiation protection officer in the design of the department, categorisation of radioactive sources, management of radioactive waste and establishment of an emergency response plan (diagram’s reproduction with permission by the IAEA) [21]

IBSS provides a series of requirements that three exposure categories and, for each cat- must be fulfilled by the government and reg- egory, the three possible exposure situations ulatory bodies . These requirements are divid- (following ICRP nomenclature) . Figure 3 sche- ed into requirements that are applied gener- matises the possible exposure situations and ally (i .e . in all exposure situations) and those categories to which the IBSS are applicable . that are applied separately for each of the

40 Chapter 3: International Basic Safety Standards

Source

Type of exposure Planned Emergency Existing Situation Exposure Exposure Exposure

Category of Exposure Occupational Public Medical Occupational Public Occupational Public

Figure 3: The possible exposure situations and categories according to the ICRP publication 103 EANM

With respect to medical exposure in particu- cases where a female patient is or might lar, the IBSS [20] presents a series of require- be pregnant or is breast-feeding ments that have various purposes, including: The IBSS represents a fundamental tool for the establishment of a radiation protection • Ensuring that all health professionals office in any country . While the IBSS is of a working with ionising radiation are non-binding nature, it can be applied and specialised in the appropriate area, adapted in countries that wish to do so . meet the educational and training However, if a country asks the IAEA for IBSS requirements in radiological protection co-sponsorship, then compliance with the and are registered in a database for future security standards is a condition that must assessment be met in order to receive assistance . • Ensuring that medical exposures are justified European legislation • Ensuring that protection and safety are The recent directive from the European Com- optimised for each medical exposure mission (EC) [22] from December 2013 is the (design considerations, operational latest legislative act to lay down the IBSS and considerations, calibration, diagnostic ICRP recommendations and requirements reference levels, quality assurance for for EU countries . It is an excellent example medical exposures, dose constraints) of how international standards can be har- • Ensuring that arrangements are in place monised and applied regionally in different for appropriate radiation protection in countries .

41 Type of limit Occupational Apprentices Public Emergency and students occupational (aged 16–18 exposure years)

Effective dose 20 mSva 6 mSv 1 mSv <100 mSvd

Equivalent doses:

Lens of the eye 20 mSvb 15 mSv 15 mSv

Skin 500 mSvc 150 mSvc 150 mSvc

Extremities 500 mSv 150 mSv 150 mSv

Table 1: Exposure limits according to the EU Directive of December 2013 [22] a In special situations up to 50 mSv/year, as long as the averaged dose in any 5 consecutive years is not above 20 mSv/year b In special situations up to 50 mSv/year, as long as the total dose in any 5 consecutive years is under 100 mSv c Averaged over any area of 1 cm2 d In exceptional situations, in order to save life, prevent severe radiation-induced health effects or prevent the development of catastrophic conditions, a reference level for an effective dose from external radiation of emergency workers may be set above 100 mSv, but not exceeding 500 mSv

The European Basic Safety Standards ensure by avoiding accidents in radio-diagnosis [23]: and radiotherapy • Strengthened requirements regarding • Protection of workers exposed to ionising emergency preparedness and response, radiation, such as workers in the nuclear incorporating lessons learnt from the industry and other industrial applications, Fukushima accident medical staff and those working in places with indoor radon or in activities involving Especially relevant to the medical field are naturally occurring radioactive material the requirements in respect of a high level (NORM) of competence and clear definition of com- • Protection of members of the public, for petencies for health professionals in order to example from radon in buildings ensure the proper radiological protection of • Protection of medical patients, for example patients and workers involved in medical ra-

42 Chapter 3: International Basic Safety Standards

diation (as set out in the European Directive define the range of options considered in the 2013/59/Euratom [24]) . The directive is also process of optimisation for a given radiation an excellent reference document, since it source in a planned exposure situation . includes modern technical data (e .g . activity concentration values for exemption or clear- Nuclear medicine ance of materials that can be applied, radia- The practice of nuclear medicine is regulat- tion weighing factors, tissue weighing factors ed by the member states’ authorities, whose and effective dose calculation formulas) re- stance is influenced by the existing recom- lated mainly to the latest ICRP publication . At mendations (Fig . 1) . The IAEA provides, in the same time it provides new dose limits, in addition to the general IBSS, practice-specific particular with regard to the eye lens . Table regulatory guidance, including with respect 1 summarises the yearly dose limits for work- to the safe practice of nuclear medicine [25] . ers (covering all authorised practices) and for EANM apprentices and students (aged between 16 All aspects of nuclear medicine are subject to and 18 years) who, during the course of their safety requirements, including certification, studies, are obliged to work with radioactive application of radiation principles (justification sources and the general public . The emergen- of practices, limitation of doses and optimisa- cy occupational exposure limit is also shown; tion of protection), quality assurance of proce- it must be ensured that emergency workers dures and equipment, facility design and secu- liable to incur an effective dose exceeding rity of sources . In all these areas, health profes- 100 mSv are informed in advance of the risks sionals have the responsibility for protection and the available protection methods . and safety, and the avoidance of accidental exposures resulting from decisions, operation/ All recent publications have placed special handling of sources or equipment . Potential emphasis on the use of optimisation tools accidental exposures may relate to the patient when managing planned exposures . The (e .g . radiopharmaceutical misadministration), annual effective dose limit is a regulatory act the health professional (e .g . loss of radioactive that applies to different groups of profession- shipment, damage to Tc-generator or radioac- als (e .g . health professionals, reactor operators tive spills) or all persons in the department (e .g . and researchers) . Since this is non-specific to fire) . In order to avoid or minimise occurrenc- the nature of each individual occupation, it is es of these kinds, it is essential for the health never to be expected that medical technol- professional both to possess knowledge of the ogists will even approach the effective dose factors that may lead to accidental exposures limit within any given year . In these cases, a and to provide written operational protocols prospective upper bound of individual dos- and materials (i e. . emergency kit) to be used in es, known as dose constraint, can be used to the event that such exposures occur .

43 Fact box

Summary of the typical causes of, and factors contributing to, accidental exposures in nuclear medicine (reproduced with permission of the IAEA) [25]

The following types of error can be made: • Communication errors • Faulty transmission of information • Misunderstanding of prescriptions and protocols or use of obsolete protocols • Errors in identification of the patient • Use of the wrong source, the wrong radiopharmaceutical or the wrong activity • Calibration errors • Maintenance errors

The following factors may influence the frequency and severity of incidents and accidents:

• Insufficient training and expertise of nuclear medicine physicians, medical physicists or nuclear medicine technologists • No reassessment of staffing requirements after purchase of new equipment, hiring of new technologists or increasing workload • Inadequate quality assurance and lack of defence in depth • Lack of a programme for acceptance tests • Lack of a maintenance programme • Poor, misunderstood or violated procedures • Lack of operating documents in a language understandable to users • Misunderstanding of displays or software messages • Inattention • Inconsistent use of different quantities and units

In most accidents there are several contributing factors, which can be summarised as:

• Lack of commitment of the licensee (hospital administrators and department managers) • Insufficient briefing or training of staff • Insufficient quality assurance Acknowledgement: The author would like to thank IAEA publishing section for their support in the reproduction permission process .

44 Chapter 3: International Basic Safety Standards

References

1 . Fuchs WC . Effect of the Röntgen rays on the skin . West- 15 . International Atomic Energy Agency . Occupational ra- ern Electrician 1896;291 . diation protection . Safety Guide No RS-G-11 . Vienna: IAEA; 1999 . 2 . Sansare K, Khanna V, Karjodkar F . Early victims of X-rays: a tribute and current perception . Dentomaxillofacial 16 . United Nations Scientific Committee on the Effects Radiol 2011;40:123–125 . doi:10 .1259/dmfr/73488299 . of Atomic Radiation (UNSCEAR) . Sources and effects of ionizing radiation . Vol 1, Annex B . Exposures of the 3 . Mould RF . A century of X rays and radioactivity in medi- public and workers from various sources of radiation . cine . 2nd ed . London: CRC Press/Taylor & Francis Group; New York; 2008 . 1993 . 17 . United Nations Scientific Committee on the Effects of 4 . Churchill WS . The story of the Malakind field force . Lon- Atomic Radiation (UNSCEAR) . Sources and effects of don: Longman’s Green & Co .; 1898 . ionizing radiation . Vol 1, Annex A . Medical radiation 5 . Kang KW . History and organizations for radiological exposures . New York; 2008 . protection . J Korean Med Sci 2016;31:S4–S5 .

18 . John RC . Radiation protection principles . J Radiol Prot EANM 6 . Clarke RH, Valentin J . The history of ICRP and the evo- 2012;32:N81 . lution of its policies: Invited by the Commission in Oc- 19 . International Atomic Energy Agency . Nuclear medicine tober 2008 . Ann ICRP 2009;39:75–110 . doi:10 .1016/j . physics: A handbook for teachers and students . Vienna: icrp .2009 .07 .009 . IAEA; 2014 . 7 . Tailor LS . History of the international commission on ra- 20 . International Atomic Energy Agency, Radiation Pro- diological units and measurements . Health Phys 1958;1 . tection and Safety of Radiation Sources . International 8 . Eisenhower DD . Address before the General Assem- basic safety standards . Series No GSR Part 3 . Vienna: bly of the United Nations on Peaceful Uses of Atomic IAEA; 2014 . Energy . In: Woolley GPaJT, ed . New York: The American 21 . International Atomic Energy Agency . IAEA safety glos- Presidency Project; 1953 . sary terminology used in nuclear safety and radiation 9 . United Nations Scientific Committee on the Effects of protection, 2007 edition . Vienna: IAEA; 2007 . Atomic Radiation (UNSCEAR) http://www .unscear .org/ 22 . European Council Directive 2013/59/Euratom on basic unscear/about_us/history .html . safety standards for protection against the dangers aris- 10 . International Atomic Energy Agency, History of the In- ing from exposure to ionising radiation and repealing ternational Atomic Energy Agency . The first forty years . Directives 89/618/Euratom, 90/641/Euratom, 96/29/Eur- Vienna: IAEA; 1997 . atom, 97/43/Euratom and 2003/122/ Euratom . Official 11 . ICRP . Application of the Commission’s recommenda- Journal of the European Union 2014;L13:1–17 . tions for the protection of people in emergency expo- 23 . European Commission . https://ec .europa .eu/energy/ sure situations . ICRP Publication 109 . Ann ICRP 2009;39 . en/topics/nuclear-energy/radiation-protections . 12 . ICRP . Recommendations of the International Commis- 24 . Summary of the European Directive 2013/59/Euratom: sion on Radiological Protection . ICRP Publication 1 . Ann Essentials for health professionals in radiology . Insights ICRP 1958 . into Imaging 2015;6:411-417 . doi:10 .1007/s13244-015- 13 . ICRP . The 2007 recommendations of the International 0410-4 . Commission on Radiological Protection . ICRP Publica- 25 . International Atomic Energy Agency . Applying radiation tion 103 . Ann ICRP 2007;37 . safety standards in nuclear medicine . Safety Reports 14 . Carlsson GA . 1 - Theoretical basis for dosimetry A2 . Series No 40 . Vienna: IAEA; 2005 . In: Kase KR, Bjärngard BE, Attix FH, eds . The dosimetry of ionizing radiation, vol I . New York: Academic Press; 1985:1–75 .

45 Chapter 4: Radiobiological Principles Lovisa Lundholm, Beata Brzozowska and Andrzej Wojcik* *Author responsible for the integrity of the work as a whole

Introduction variable called linear energy transfer (LET), A mechanistic understanding of biological which is given in units of keV µm-1 . The LET effects of ionising radiation is essential for is defined as a ratio of the amount of ener- proper evaluation of health risks . Ionising ra- gy, dE, lost by a particle and the length of a diation has the potential to disrupt the struc- track, dl, in a medium where the energy was ture of organic molecules in cells . Thanks imparted . The cut-off value of 10 keV µm-1 to efficient repair mechanisms, damaged is used by the International Commission on molecules can be repaired, but this process Radiological Protection (ICRP) to discriminate is not error free and may cause mutations, between low LET radiations with LET <10 keV cell death or cell transformation, leading to µm-1 (e .g . photons, electrons) and high LET cancer . Quantification of cancer risk, as well radiation >10 keV·µm-1 (e .g . alpha particles, as the risk of other stochastic detriments, is heavy ions) . LET is an average quantity al- possible through epidemiological studies . lowing description of the energy deposition However, after exposure to low radiation along a certain distance . At the microscopic doses, the effects are so limited that epidemi- level, the energy deposition may vary strong- ological analyses often lack statistical power . ly within this distance . The reason for this is It is here that a mechanistic understanding is that the interaction cross-section (which de- of particular importance because it provides scribes the probability of an interaction) of a reassurance that the risk level extrapolated charged particle increases as the particle los- from the high dose region is not underesti- es its energy along a track . This relation is not mated . This chapter gives a very brief review linear and the interaction cross-section of an of the biological radiation effects on cells and incoming particle is highest at the end of the organisms . track, resulting in a large energy deposition in a small volume of matter . This “burst” of en- Physical principles of radiation ergy at the end of a track is called the Bragg interaction, LET and RBE peak . It is applied clinically in hadron thera- The interaction between incoming radiation py using protons and heavy ions to deliver a and the biological material can be described high dose inside the tumour while the tissue in terms of ionisation and excitation events . ahead of and behind the tumour is spared . Different types of radiation induce different ionisation patterns . For example, X-ray pho- The energy deposited in a mass unit of living tons interact sparsely with atoms, while al- matter gives the absorbed dose, expressed in pha particles create well-localised tracks with Gy, with 1 Gy corresponding to 1 J kg-1 . The dense energy deposition . The energy lost absorbed dose is a physical quantity that is during interaction of radiation with atoms used to describe the effect of radiation . Al- can be measured and is characterised by a though the same value of the absorbed dose

46 This is the dominant process after high LET This isthedominantprocess highLET after it iscalledadirecteffect ofradiation(Fig ionises atoms in macromolecules DNA like survival ofgenes isessentialforing thestability cell - acid(DNA).Maintain the deoxyribonucleic exposure ofthecell, isthegenetic material targetation, buttheprincipal ofradiation All cell organelles can be damaged by radi- Radiation-induced DNAdamage Cellular of effects radiation crease inthenumber ofhitcells[1]. and(2)ade sufficient tocauseadetriment damage per hit cell above a level which is related phenomena:(1)an accumulationof effect which results fromtwocalled overkill higher LET, RBEvaluesdecrease dueto aso- mental setupusedfor itsassessment,e effect .RBEstrongly- dependsontheexperi tion, both resulting inthe same biological radiation andthedoseoftested radia- doseofthestandard theabsorbed between cobalt-60 source or gamma radiation from acaesium-137 or standard radiation,whichisX-rays of250keV where atested radiationiscompared with ness (RBE).RBEisderivedfrom experiments derived valueofrelative biological effective difference by anexperimentally isdescribed biological effects perunitdosediffer is usedfor different radiationqualities, their PrinciplesChapter 4:Radiobiological it reaches µm a peak at about 100 keV related tostrictly LET, initiallyincreasing until and theanalysedbiological endpoint.RBEis energies thebiological material ofparticles, . directly When theincomingparticle . RBE is defined as the ratio .g . This -1 .the . At .1) - - 47 formed are >50,000total lesionspercellday frequencies ofthesethreedamage types per cell >1000 BD, about 1000SSBsand20–40DSBs ma radiationhasbeenestimated to induce breaks ofgam- (DSBs).1Gy double-strand breaks (SSBs)and age (BD),single-strand cell:basedam- lesion occurinanirradiated Three ofradiation-inducedDNA majortypes cancertherapy during also mosteasilymodified by radiosensitisers amifostinelike oprotectors (SH)compounds are sulfhydryl enging free radicals donors reduces the level of damage by scav- age cause athreefold lower level ofDNAdam- the highlyreactive free radicalion H sis, awater moleculebecomesionisedand theprocess ofwater radiation.In - radioly LET indirect effects ter, which is targeted when radiationcauses radiation .About75%ofthecellmassiswa- restored to itsreduced form by anH however, theDNAradicalcanbechemically theabsenceofoxygen, intheDNA.In ROOH ther reactionsyieldsthechemicallystable produce H reactive oxygen speciesRO rapidly with an oxygen molecule, it forms a ygen concentration;iftheDNAradicalreacts damage theDNA. This effect relies onthe ox distancesand OH·, whichcandiffuseshort reacts withwater to form hydroxyl radical .Consequently, thepresence ofproton . The indirecteffect occurswhenH In comparison, thespontaneous comparison, .In 2 O, andistherefore assumedto . This isthemainresult oflow . These indirect effects are .Examples of such radi- . 2 ·, whichviafur + ionto 2 O . The + 2 O is + - -

EANM critical lesion is the DSB, because it leads to a disruption of the DNA molecule . Most spontaneous DSBs are products of enzymatic activity and are regarded as “clean” in that they

Figure 1: Chain of events in a cell exposed to ionising radiation . Damage pathways that lead to deterministic and stochastic effects are indicated . The bottom line illustrates the time during which various events take place are repairable in an error-free way . Radiation DSBs since they can be easily repaired using induces “dirty” DNA DSBs in such a way that the opposite strand as a template, except pieces of the broken strands must be ex- when two SSBs are located only a few bases cised before ligation, with potential loss of from each other, resulting in a DSB [1, 2] . genetic material . About half of radiation-induced DSBs are misrejoined, which may lead DNA damage repair, chromosomal to changes in the gene sequence of a DNA aberrations and epigenetic effects of strand . Moreover, 30%–40% of DSBs induced radiation after gamma radiation are complex and this Cells use specialised signalling pathways to type of damage creates serious problems for sense, respond to and repair DNA damage . the DNA repair machinery, with an increased Single-base damage is handled by base probability of misrepair . High LET radiation excision repair, nucleotide excision repair has higher ionisation density, and hence removes bulky DNA adducts induced by ul- higher DSB complexity, than low LET radia- traviolet light (UV radiation) and mismatch tion . This is the reason for the higher RBE of repair corrects mismatches occurring during high versus low LET radiation . SSBs and BD replication . DNA DSBs can be repaired by ei- are far less prone to cause cell death than ther of two processes, non-homologous end

48 Chapter 4: Radiobiological Principles

joining (NHEJ) or homologous recombina- volve a markedly changed chromosomal tion (HR), where NHEJ is suggested to be the morphology and cells carrying them may di- primary repair mechanism for the majority vide a few times but will eventually die . of DSBs . NHEJ occurs in all cell cycle phases and joins DNA ends directly; therefore it is re- Epigenetic changes can also be induced garded as the more error-prone repair path- by radiation exposure . These are heritable way . HR is active during late S/G2 phase only, changes in gene expression that do not al- where it uses the undamaged homologous ter the DNA sequence per se, such as DNA strand as a template, and thus is an error-free methylation or acetylation/methylation of process . The first attempt to repair damage is residues in histone proteins which wrap up made by NHEJ, but if it is unsuccessful there the DNA . There is a global decrease in DNA is a switch to HR . For example, HR repairs a methylation within one day after radiation larger fraction of high LET-induced damage, exposure of normal cells . Mouse data show EANM where NHEJ is impeded by the complexity of that epigenetic alterations could be inherited the damage . Another factor that promotes transgenerationally, but this area of research the preferential use of HR is location of the has not yet been thoroughly investigated [4] . DSB in a region of a more condensed, heter- ochromatic structure [3] . Cell death modes Cells may survive with mutated DNA but still Despite these repair processes, the probabil- experience delayed cell death . Alternatively, ity of damage misrepair increases with dam- due to the accumulation of several muta- age complexity . Short or long sequences of tions or genomic rearrangements, neoplas- DNA may be deleted, inverted or translocat- tic cell transformation and cancer can arise . ed to another chromosome . Chromosomal Following a high dose of radiation, the DNA aberrations are changes large enough to be damage may exceed a cell type-specific visible at the level of chromosomes, which threshold, causing failure to repair damage can be visualised by microscopic staining . and promote cell death instead . Death can Radiation induces chromosome-type aber- occur before or after the first post-radiation rations following irradiation in G1, chroma- mitosis; the latter is commonly called mitot- tid-type aberrations after irradiation in G2 or ic catastrophe and is thought to be a domi- both after exposure in S phase . Stable aber- nant event after radiation, although only as a rations can persist in the progeny of irradi- pre-process . The mechanism of death is the ated cells since the chromosomes have ex- active, programmed death, termed apopto- changed genetic material without changing sis, or, in cases of high radiation doses and their overall structure . Unstable aberrations, especially lack of oxygen or energy, necrosis . exemplified by dicentric chromosomes, in- Cells can also go into permanent cell cycle

49 arrest, senescence . Since radiation-induced fects to late effects . The immune system is cell death can occur at different time points always triggered by deterministic effects, after exposure, the most commonly used so extensive damage of organs and tissues method of measuring cell survival is to assess is associated with a massive inflammatory the ability of cells to form clones, clonogenic response that by itself can be detrimental cell survival [1] . and potentiate the radiation effect . Follow- ing whole-body exposure this can lead to Normal tissue response to radiation multi-organ dysfunction syndrome (MODS) . The effects of ionising radiation at the level of tissues and organisms can be divided into Stochastic effects originate from cells that deterministic and stochastic events . Deter- survive a dose of radiation with mutated ministic effects originate from cell death DNA, which, in turn, can lead to neoplastic events . If a high number of irradiated cells die, transformation . They are probabilistic in na- this will lead to necrosis of the tissue . Hence, ture in that it is impossible to predict wheth- deterministic effects show a dose threshold er a particular cell will carry a mutation or that corresponds to the dose which kills a not . Consequently, stochastic effects have no sufficiently high number of cells for the tissue dose threshold . In contrast to deterministic to break down . The threshold dose depends effects, the severity of a radiation-induced on the tissue type, but also on the irradiated neoplasm is independent of the dose . The volume . Moreover, lowering the dose rate, or only relationship between the dose and the splitting the dose into fractions, has a sparing effect is the probability of cancer induction . effect on deterministic effects . Importantly, It is important to bear in mind that radia- deterministic effects show a direct correlation-induced cancers carry no “fingerprint tion between the dose and severity . of exposure” . In other words, they cannot be distinguished from cancers induced by other Deterministic effects occur in two phases: agents . This is the reason why it is generally a prodromal phase and a late, acute phase . difficult to estimate the risk of cancer induc- Examples of the prodromal phase are skin tion by low doses of radiation (below ca . 200 reddening, vomiting or dizziness . The nature mGy whole-body exposure), where the inci- of these reactions is not understood . Follow- dence of spontaneous cancers is much high- ing moderate doses of radiation, prodromal er than that of radiation-induced cancers [2] . effects disappear after a few days and late effects occur after a time delay which may be Tumour tissue response to radiation months or years . Very high doses of radiation Radiotherapy and the four Rs induce consequential late effects, meaning Tumour cells have acquired a number of char- an immediate transfer from prodromal ef- acteristics that distinguish them from normal

50 Chapter 4: Radiobiological Principles

cells . Several of these hallmarks of cancer are tumours can have variable levels of oxygen relevant for their response to radiation: ability supply . Within a tumour hypoxic cells form to sustain proliferative signalling, evasion of populations in areas distant from blood ves- growth suppressors, resistance of cell death, sels . Hypoxic tumours are generally more genome instability and mutations, and tu- difficult to cure . The difference in radiosen- mour-promoting inflammation [5] . Different sitivity between hypoxic and normoxic cells tumour types also display differences in their is particularly strong for low-LET radiation inherent radiosensitivity, which provide a like photons, where the indirect effect of ra- basis for the choice of radiotherapy among diation dominates . This is one of the reasons other treatment modalities such as surgery, why hadron therapy is believed to be most chemotherapy, targeted therapy and immu- efficient in curing hypoxic tumours . The ratio notherapy . of doses required to give the same killing effect in normoxic and hypoxic cells is called EANM The aim of radiotherapy is to eradicate cancer the oxygen enhancement ratio (OER) [1] . cells by delivering the prescribed dose of ionising radiation to the tumour with minimal The time schedule of irradiation has a big damage to surrounding healthy tissues . This impact on the final consequence of patient is achieved with the help of various physical treatment during radiotherapy . In curative techniques . At the same time, efficient tu- external beam radiotherapy the total dose mour control must take into consideration prescribed to the tumour (usually 50–80 Gy) the radiosensitivity of cancer cells, which may is divided into multiple smaller fractions of 2 vary even within a single tumour . Hence, clin- Gy per day . That this form of therapy yields ical radiobiology deals with the relationship the best curative results with minimal side between a given physical absorbed dose, the effects has been established empirically . Bi- resulting biological response and the factors ologically, the fractionation method is based that influence this relationship . on four elementary principles called the 4 Rs of radiotherapy: (1) repair, (2) redistribution, One of these factors is the partial pressure of (3) reoxygenation and (4) repopulation . 1: molecular oxygen inside a cell . Well-oxygen- Tumour cells generally proliferate faster than ated cells are more sensitive to radiation than normal cells and thus have less time to repair hypoxic cells because oxygen participates in the DNA damage before they enter mitosis the indirect effect of radiation (Fig . 1) . Conse- and suffer from mitotic catastrophe . Hence, quently, inactivation of hypoxic cells requires they are more sensitive to fractionated irradi- a higher dose than inactivation of normoxic ation than normal cells . 2: Radiation induces cells . Depending on the localisation inside a cell cycle arrest in the relatively radiosensi- the body and the density of blood vessels, tive G2 phase of the cell cycle . This leads to

51 a redistribution of the cells in the cell cycle Low and high dose rate in brachytherapy so that each next fraction of radiation hits Brachytherapy can be performed at a low cells that are blocked in G2, leading to a high dose rate, for example as done in treatment level of cell death . 3: As cells become nor- of thyroid cancer with iodine-131 . Here, the moxic they begin to proliferate and become high affinity of the thyroid gland for iodine radiosensitive . 4: In the first line, radiation is exploited . Another form of low dose rate kills normoxic, proliferating tumour cells . As brachytherapy is applied in prostate can- these die, hypoxic cells move towards blood cer patients treated with iodine-125 seeds vessels and become normoxic . This process (called permanent brachytherapy) . Seeds are of reoxygenation needs some time; hence left permanently in the body and irradiation irradiations should not be carried out during ends when iodine-125 has decayed . As an weekends [1] . alternative to seeds, high-activity radioactive sources (iridium-192) can be used in an af- Radioresistance and cancer stem cells terloading setup that yields a high dose rate . Another level of complexity is added when In prostate cancer treatment, the choice be- consideration is given to tumour hetero- tween low and high dose rate brachytherapy geneity, which is not directly related to the is based on tumour stage but also on eco- oxygen status . Not all tumour cells respond nomic and practical factors [5] . equally to radiation, and accumulating evidence supports the concept of cancer stem Irradiation in utero – developmental and cells (or tumour-initiating cells), which are teratogenic effects and cancer resistant to radio- and chemotherapy . This The embryo and foetus represent the most subpopulation of cells is believed to be re- radiosensitive stages during the lifetime of a sponsible for tumour regrowth as well as human . Various stages of pregnancy demon- metastasis . Suggested mechanisms of can- strate different specificities with respect to cer stem cell radioresistance include both radiation effects . Gametes and the embryo intrinsic factors, such as altered DNA damage during the preimplantation stage are char- repair capacity, enhanced reactive oxygen acterised by extreme sensitivity to the lethal species defence and activated cell survival effects of radiation . This is described as an pathways, and extrinsic factors, e .g . mainte- “all or nothing effect”: gametes and embryos nance of a hypoxic niche . Radiation could either die or survive as normal, with a negli- also induce microenvironmental changes gible level of detrimental effects . The lack of through release of growth factors and cyto- genetic transgenerational effects among the kines from cancer-associated fibroblasts and children of Hiroshima and Nagasaki survivors macrophages, which might confer cellular can be explained by this mechanism . plasticity [6] .

52 Chapter 4: Radiobiological Principles

Radiation exposure of the embryo after it context, it is of interest that two large epide- has implanted in the uterus can lead to three miological studies, published recently, have types of effects: growth and mental retarda- shown that natural background radiation is tion, malformations and cancer . There is little a risk factor in childhood leukaemia, with the indication for a threshold of dose . Among lowest effect detectable after an accumulat- Hiroshima and Nagasaki survivors, growth re- ed dose to the bone marrow of 5 mGy [9, 10] . tardation was evident only when the embryo Thus, there is ample evidence that exposure was exposed before week 16 of pregnancy . to low doses of radiation, both acutely (as in Mental retardation occurred predominantly CT scanning) and chronically (as in areas of following exposure during weeks 8–15, with high natural background radiation), increases a four times lower level of effect between the risk of childhood leukaemia . It is import- weeks 15 and 25 . Congenital malformations ant to note that the level of risk estimated in are uncommon among the atomic bomb these studies is consistent with predictions EANM survivors, but based on animal studies and of models based upon data from studies of women exposed to radiation for medical pur- moderate to high doses received after birth poses it is understood that they are induced at a high dose rate [8] . only when the embryo is exposed during organogenesis (weeks 3–8 of pregnancy) [1] . Practical application of radiobiology principles In their famous “Oxford study” from 1954, Al- The principles of radiological protection are ice Stewart and co-workers showed for the based on biological and medical evidence first time that diagnostic irradiation in utero of radiation effects . The principles are devel- leads to an increased risk of leukaemia during oped by the ICRP based on scientific data early childhood [7] . The result expanded data that are regularly summarised by the United from atomic bomb survivors, among whom Nations Scientific Committee on the Effects a large relative risk of childhood leukaemia of Atomic Radiation (UNSCEAR) and the Bi- (10 cases instead of the expected 1 .6) was ological Effects of Ionizing Radiation (BEIR) observed among teenagers exposed at the group of the National Research Council age of 0–9 years [8] . The interest in estimating (NRC) of the USA . ICRP publishes recommen- the risk of childhood cancers has increased in dations which are generally implemented recent years because of modern methods of into legal systems of all countries . The latest medical radiography such as paediatric com- recommendation was published in 2007 [11] . puted tomography (CT) . Also, questions have been posed as to whether there is a thresh- The ICRP assumes that no deterministic ef- old of dose and whether chronic irradiation is fects occur in any tissue in the absorbed dose equally as effective as acute irradiation . In this range up to around 100 mGy (low LET or high

53 LET) . In the case of stochastic effects, notably based on cancer incidence, providing more cancer, epidemiological and experimental reliable estimates of risk principally because studies provide evidence of radiation risk at cancer incidence can allow for more accurate doses below 100 mSv (effective dose, see be- diagnosis . low) . At the same time, results of biological experiments on cells and animals support The atomic bomb survivors were exposed the hypothesis that cancer can arise from a to an acute dose of radiation and statistical- DNA mutation in a single cell . Consequently, ly significant results on cancer induction are no dose threshold exists for stochastic effects seen only after doses in excess of 200 mSv . and the ICRP assumes that even at doses However, the nominal risk coefficients for below about 100 mSv a given increment in stochastic effects derived from the LSS study dose will produce a directly proportionate are used to predict cancer incidence follow- increment in the probability of incurring can- ing occupational or environmental exposure, cer . This dose-response model is generally which is generally low and chronic . For de- known as “linear non-threshold” or LNT . The terministic effects it is known that reducing ICRP emphasises that whilst the LNT model the dose rate of radiation is associated with remains a scientifically plausible element in a sparing effect . The question arises as to its practical system of radiological protection, whether the risk coefficients derived from its adoption is to a large extent guided by the LSS study should be lowered when they the requirement to follow the precautionary are being applied to low, chronic exposure principle which is generally applied in health scenarios . Based on the results of biological protection . experiments, the ICRP decided to introduce a dose and dose rate effectiveness factor An important dose concept in radiological (DDREF) of 2, which reduces by half the protection is the effective dose, which is used nominal risk coefficients when applied to for optimising planned radiation exposures . low and chronic exposure scenarios . Due to It is calculated based on radiation and tissue lack of statistical power, current results from weighing factors . The latter are derived from epidemiological studies on cohorts environ- epidemiological results describing the risk of mentally or occupationally exposed to low organ-specific cancers following exposure to dose rate radiation do not permit a precise radiation . The major source of information is estimate of DDREF . Currently, the value of 2 the Life Span Study (LSS) on atomic bomb for DDREF is being debated and a task group survivors in Hiroshima and Nagasaki . The ear- of the ICRP is critically evaluating all available ly evidence was based on cancer mortality evidence in an attempt to come up with a data . Thanks to an improved cancer registry more reliable value [12] . system in Japan, current risk estimate can be

54 Chapter 4: Radiobiological Principles

References

1 . Hall EJ, Giaccia AJ . Radiobiology for the radiologist . 7th 7 . Stewart A, Webb J, Giles D, Hewitt D . Malignant disease ed . Philadelphia, Baltimore, New York: Lippincott Wil- in childhood and diagnostic irradiation in utero . Lancet liams & Wilkins Publishers; 2012 . 1956;271:447 .

2 . Wojcik A, Martin CJ . Biological effects of ionizing radi- 8 . Wakeford R . The risk of childhood leukaemia following ation . In: Martin CJ, Sutton DG, eds . Practical radiation exposure to ionising radiation – a review . J Radiol Pro- protection . Oxford: Oxford University Press; 2015:21–38 . tect 2013;33:1–25 .

3 . Kakarougkas A, Jeggo PA . DNA DSB repair pathway 9 . Kendall GM, Little MP, Wakeford R, Bunch KJ, Miles JC, choice: an orchestrated handover mechanism . Br J Ra- Vincent TJ, et al . A record-based case-control study of diol 2014;87:20130685 . natural background radiation and the incidence of childhood leukaemia and other cancers in Great Britain 4 . Zielske SP . Epigenetic DNA methylation in radiation bi- during 1980-2006 . Leukemia 2013;27:3–9 . ology: on the field or on the sidelines? J Cell Biochem

2015;116:212–217 . 10 . Spycher BD, Lupatsch JE, Zwahlen M, Roosli M, Niggli F, EANM Grotzer MA, et al . Background ionizing radiation and the 5 . Skowronek J . Low-dose-rate or high-dose-rate risk of childhood cancer: a census-based nationwide co- brachytherapy in treatment of prostate cancer – be- hort study . Environ Health Perspect 2015;123:622–628 . tween options . J Contemp Brachytherapy 2013;5:33–41 . 11 . ICRP 103 . 2007 recommendations of the Internation- 6 . Lundholm L, Haag P, Zong D, Juntti T, Mork B, Lewen- al Commission on Radiological Protection . Ann ICRP sohn R, Viktorsson K . Resistance to DNA-damaging 2007;21 . treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and 12 . Ruhm W, Woloschak GE, Shore RE, Azizova TV, Grosche diminished cell cycle arrest . Cell Death Dis 2013;4:e478 . B, Niwa O, et al . Dose and dose-rate effects of ionizing radiation: a discussion in the light of radiological protection . Radiat Environ Biophys 2015;54:379–401 .

55 Chapter 5: Dose Optimisation for Diagnostic Procedures Frederic H . Fahey, Alison B . Goodkind and David Gilmore

Introduction According to the National Council on Radi- The fields of nuclear medicine and molecular ation Protection and Measurements (NCRP) imaging continue to grow due to the abili- Report 160, nuclear medicine procedures ty of the employed procedures to provide have increased from 6 .3 million in 1984 to 18 physicians with unique information . Specifi- million in 2006 [2] . This increase has led to a cally, these procedures provide insights into rise in per capita annual radiation dose to the patients’ physiology and metabolic process- US population from nuclear medicine pro- es rather than information on anatomy and cedures . In 2006, the per capita annual dose structure, as delivered by other imaging mo- to the US population from nuclear medicine dalities . Because disease functional chang- was estimated to be 0 .8 mSv compared to es typically are visible before anatomical 0 .14 mSv in 1982, with a large fraction of this changes, nuclear medicine can allow for ear- dose attributed to nuclear cardiology . ly detection and evaluation of the extent of disease; it can also establish whether or not This increase in the utilisation of nuclear med- disease is progressing and assist in evaluat- icine procedures has led to an increase in ion- ing the effectiveness of a given treatment . ising radiation exposure and thus the possible Nuclear medicine methodologies reveal in- risk of adverse health effects . Bearing in mind formation about nearly all human systems, that concerns regarding these risks have been including the heart and the brain as well as expressed by the media and the general pub- the musculoskeletal, gastrointestinal and lic, the nuclear medicine professional needs urological systems . Nuclear medicine can to have a solid understanding of their nature also be essential for imaging various types of and magnitude, as well as of the factors that cancer . In addition, these modalities are min- can affect the radiation dose to our patients imally invasive and safe as they utilise only and ourselves . Having this understanding will trace amounts of radiopharmaceuticals and, allow us to better communicate with patients thus, are non-toxic and non-allergenic [1] . regarding the potential benefits and risks as- Not only is nuclear medicine often essential sociated with nuclear medicine procedures . for diagnosis, but it can also play an import- This can be essential for the patient’s health . ant role in the treatment of many diseases, If a procedure providing important clinical in- an example being the administration of 131I formation is not performed due to fear of radi- for the treatment of thyroid disease . More ation, it can be detrimental to the patient . This recently, targeted radionuclide therapy has chapter will discuss dose optimisation, which been shown to be useful in the treatment of considers the potential risk from undergoing bone metastases from prostate cancer and a nuclear medicine procedure, as well as the neuroendocrine tumours . many benefits that these imaging modalities have to offer patients . Ultimately, performing

56 organ andself-dose Figure 1:MIRDequation: source organ, target asself-dose gan; thisisalsoknown organ can be bothasource and a target or maceutical haslocalised(Fig ation dosefor emitters internal has developed anequationto calculate radi (SNMMI) Imaging andMolecular ar Medicine ofNucle Committee (MIRD)oftheSociety try Dosime Radiation International The Medical fornuclear medicine Internal dosimetry dosimetry Radiation optimisation [3]. to dose timeisthekey patient andattheright doseontheright test withtheright the right Chapter 5:DoseOptimisation for Procedures Diagnostic target organ (r theradiationdoseto aparticular describes from asource organ (r T ) dueto radiation emanating S ) where theradiophar .1)Note that an . The equation . - - - - - 57 may beconsidered source organs liver, bladder and remaining body kidneys, S(r gan [4].Σ present inthesourcegan perunitactivity or representing themeandoseto thetarget or often beestimatedoften withthesimpleequation port 21isgiven by port The MIRD formula in MIRD Re as described and thebiological half-life where where lar target organ (r clearance, it stayed there fective meanlife how long thatdescribes went to thesource organ andT activity, orodeoxyglucose ( tributes organs where dis- theradiopharmaceutical ed activity in a selected source inaselected organ (r ed activity T

← D(r r D(r S .For flu- example, withfluorine-18 A ) is the radionuclide-specific quantity quantity ) istheradionuclide-specific is the fraction of that activity that ofthatactivity F isthefraction 0 S T istheamountofadministered T indicates summingover allsource - ) istheradiationdoseto aparticu T ) =Σ T eff eff Ã(r dependsonboththephysical =1.44 If one assumes exponential .If S S T ) =A ), Ã(r Ã(r 18 F-FDG), the brain, heart, F-FDG), thebrain,heart, S S ) isthetime-integrat

0 ) S(r FT (T (T P P +T T eff T B ←r B ) ) eff .Ã(r istheef- S ) S S ) and ) can - - - -

EANM where TP and TB are the physical and biolog- been developed and adopted by a number ical half-lives for the particular radiopharma- of organisations such as the European As- ceutical and source organ . S(rT ← rS) is given sociation of Nuclear Medicine (EANM), the by SNMMI and the International Commission on Radiation Protection (ICRP) . Thus, if one knows the amount of administered activity, S(r r ) = Δ φ /M T ← S Σi i i T the size of the patient and the biokinetics and physical properties of the radiopharmaceutical in question, one can make a reason- where Δi is the mean energy per nuclear able estimate of the radiation dose to all of transformation for the ith radiation emitted by the potential target organs . However, it has the radiopharmaceutical, φi is the fraction of been estimated that the uncertainty in these energy emitted by the ith radiation from the estimates could be as much as a factor of 2 source organ that is absorbed by the target [5] . organ and MT is the mass of the target organ .

Σi indicates summing over all radiations, i, The concept of effective dose (ED) was pro- emitted from the radiopharmaceutical . posed by the ICRP to provide a risk-based parameter to allow different radiological As one can see from the above formulas, practices to be compared . Effective dose was the estimated dose depends on many fac- developed to be equivalent to the absorbed tors . Most notably, it depends directly on dose given to the whole body of the patient the amount of administered activity . With re- that would result in the same biological ef- spect to internal dosimetry, this is the prima- fect . It is the weighted sum of the absorbed ry dose index . Radiation dose also depends dose delivered to each target organ with on the type and energy of the radiation each organ weighted by its radiation sensi- [penetrating (gamma rays) versus non-pen- tivity . The formula is etrating (alphas/betas/positrons)] emitted by the associated radionuclide, the size, shape and composition of the source and target ED = Σ HT × WT organ(s), the spacing between the source and target organ(s) and the type of material where HT is dose to organ, T, and WT is the separating them, as well as on the energy ab- radiosensitivity weight assigned to that sorbed from ionising radiation per unit time organ . Effective dose is based on a popu- within the source and target organ(s) . Models lation-based estimate of radiation risk and of patients of different sizes, from newborns does not apply to a specific patient (Table 1) . to adults as well as pregnant women, have It should be noted that the risk-based organ

58 Chapter 5: Dose Optimisation for Diagnostic Procedures

weights are based on population averages kinetics of the compounds [6] . Although the across all ages and both genders and thus tabulated calculations from the ICRP calcula- are not directly applicable to any individual tions include absorbed and effective doses to patient . In particular, they do not reflect the children, the biokinetic models used in these higher risks associated with young children, calculations are typically derived from adult as discussed in the next section . data . Thus, the applicability of these models to children has not yet been ascertained . Tissue or Organ ICRP 103 The UF phantom sets from the University of Florida provide anthropomorphic models of Gonads 0 .08 patients of a variety of sizes and shapes [7] . Red bone marrow 0 .12 Another resource for dose estimation is the Lung 0 .12 RADAR website, which also has data on stan- Colon 0 .12 dardised dose methods, models and results . EANM Stomach 0 .12 It is important to note that the effective dose Breast 0 .12 is based on a population-based estimate of radiation risk and does not apply to a specific Bladder 0 .04 patient . Liver 0 .04 Oesophagus 0 .04 The primary factor affecting the radiation Thyroid 0 .04 dose to the nuclear medicine patient is Skin 0 .01 administered activity, as discussed above . However, there are many issues that can be Bone surface 0 .01 considered when determining the optimal Brain 0 .01 level of administered activity, including the Salivary glands 0 .01 patient size, the imaging time and the type Remainder 0 .12 of instrumentation used . The standardisa- Total 1 .00 tion of administered activities in children will be described in a subsequent section . For Table 1: List of weights for effective dose planar nuclear medicine and SPECT, factors (adapted from ICRP Report 103) regarding instrumentation may include the thickness and composition of the detector material, as well as the number of detectors . The ICRP has published standardised dose es- Another factor that contributes to dose is timates for many radiopharmaceuticals . This the choice of collimator (i .e . whether to use extensive set of dose estimates represents pinhole, ultra-high-resolution, high-reso- the best available understanding of the bio- lution, general purpose or high-sensitivity

59 collimation) . With respect to PET, the design, activity was 930±118 (range 710–1315) MBq composition and configuration of the detec- for 99mTc-MDP and 508±117 (range 108–875) tor material comes into play . The diameter MBq for 18F-FDG . There was no difference and axial extent of the detectors also affect in administered activity according to the the scanner sensitivity . One may also consid- type of site (hospital, private, free-standing er the effect that new approaches to image and multispecialty, mobile); although mo- processing and tomographic reconstruction bile units appeared to be associated with a may have on image quality and their po- higher activity, information was available for tential impact on dose reduction . Recent only a limited number of sites in both cases reports have indicated that the application (n=1 and n=3 for 99mTc-MDP and 18F-FDG, re- of adaptive filtering or iterative reconstruc- spectively) . These data show that although a tion with resolution recovery may allow for a large percentage of the sites are reasonably dose reduction of a factor of 2 or more while consistent with regard to their administered maintaining or perhaps even improving im- activities, a wide variation still remains (Fig . 2) age quality [8–11] . [12] .

There is limited information regarding the ac- Hybrid imaging tual practice of nuclear medicine procedures . PET/CT imaging using a single, hybrid device Based on surveys of practice, diagnostic ref- was introduced commercially around the erence levels may be developed to serve turn of the century and its clinical impact was as guidelines to the clinical practitioner . In recognised immediately . Within 5 years of its some instances, these levels may be regulat- introduction, PET-only devices were no lon- ed to represent acceptable practice . At this ger being marketed . The combination of the point, very little survey data regarding nucle- functional/molecular information provided ar medicine practice is available in the liter- by PET and with the anatomical information ature . The SNMMI Dose Opt Task Force and provide by CT were deemed invaluable by the Intersociety Accreditation Commission the clinician . A few years later, SPECT/CT was (IAC) partnered to look at nuclear medicine introduced . Although SPECT/CT has been practice data within the United States . The shown to be valuable for a number of spe- IAC provided data that had been submitted cific clinical applications, its application has to them as part of the accreditation process . not been as widespread as that of PET/CT . For technetium-99m methylene diphospho- The CT component of both PET and SPECT nate (MDP) bone scans, data from 225 sites involves the use of X-rays that also expose and 522 total patient studies were analysed . the patient to ionising radiation, which is dis- For 18F-FDG PET, 95 sites and 424 total pa- cussed in this book . However, the total radi- tients were analysed . The mean administered ation dose to the patient is the sum of that

60 Chapter 5: Dose Optimisation for Diagnostic Procedures

received from both the administration of the perfusion . In addition, PET/MRI may provide radiopharmaceutical and the CT . methods to correct for patient motion occurring during the exam . Nevertheless, there PET/MRI, a new form of hybrid imaging, has are several issues with PET/MRI that need to recently emerged . This technology has many be resolved in order for it to become the pre- similarities to PET/CT in that it is able to pro- ferred hybrid imaging technique . Most no- vide important information regarding patient tably, the PET and MRI systems can interfere physiology and anatomy/structure; however, with one another and technologies need to it does not involve CT, and MRI does not ex- be developed in order to ameliorate this is- pose the patient to radiation . Additionally, sue . Moreover, the accuracy of attenuation MRI may provide unique anatomical infor- correction may be limited in some cases as mation with better soft tissue contrast res- compared to that for PET/CT [13] . olution as compared to CT, as well as other EANM functional information . For example, MRI can PET/MRI has the potential to offer a substan- provide images related to flow, diffusion and tial reduction in the patient dose as compared

Figure 2: Reference levels in nuclear medicine for 18F-FDG [12] (used with permission of the Journal of Nuclear Medicine)

61 to PET/CT beyond the elimination of the CT to clinical nuclear medicine, and one there- component . Utilising the SIGNA PET/MR, a fore needs to extrapolate to the condition of time-of-flight (TOF) PET/MRI scanner, Queiroz interest . This may involve the extrapolation of et al . examined both phantom and clinical high-dose data in humans or low-dose data data . By increasing the PET axial FOV (25 vs in animals to low-dose (below 100 mSv) ef- 15 cm) and decreasing the PET ring diameter fects in humans . Our basic understanding of (622 vs 810 cm), the authors determined that the effects of exposure to ionising radiation PET/MRI could be performed with half of the on human health derives from the Life Span administered activity [14] . It has also been Study of the survivors of the bombings of Hi- shown that adopting the longer acquisition roshima and Nagasaki, as reported by the Ra- time associated with MRI for the PET scan can diation Effects Research Foundation . In 2011, improve dose optimisation . Oehmigen et al . Ozasa et al published a review of these data . imaged a standardised phantom to compare In this study, 86,600 subjects had been fol- the dose from PET/MRI under various time lowed from 1950 to 2003, and it was estimat- constraints (2, 4, 8 and 16 min) [15] . Ultimate- ed that there had been 527 excess deaths ly, they discovered that they could reduce ra- from solid tumours in that population [16] . diotracer activity by compensating for longer Other epidemiological studies have evalu- imaging times . These findings could lead to ated the risk of ionising radiation in humans, a large decrease in dose amongst patients, and, in general, their results corroborate the while maintaining imaging quality . Specifical- findings of the Life Span Study . Data from the ly, the effective dose for an FDG PET/CT scan Life Span Study clearly indicate a relationship is approximately 12–22 mSv; however, using between induction of solid cancer and ra- PET/MRI, the effective dose could be as low as diation dose at levels >0 .5 Gy . However, un- 1 .8 mSv . These quantities illustrate a potential certainties in the data make it difficult to es- for dose reduction of administered activity by timate the risk at the dose range associated a factor of 4–8 . with clinical nuclear medicine (i .e . 0 .05–0 .1 Gy) . Differences in dose rate or the fraction- Radiation risk ation of dose between the epidemiological Estimation of the risk of adverse health ef- subjects and nuclear medicine patients can fects from exposure to ionising radiation in also affect the accuracy of the estimation . the dose range commonly encountered in For these reasons, the evaluation of findings clinical nuclear medicine involves the appli- from investigations in radiobiology can often cation of models based on the most current provide valuable insights . knowledge of pertinent epidemiological and biological data . However, these scientific data The National Academy of Sciences Com- were acquired in a situation quite dissimilar mittee on the Biological Effects of Ionizing

62 Chapter 5: Dose Optimisation for Diagnostic Procedures

Radiation (BEIR) issued a report in 2006 that of between 10 and 13 mSv, depending on reviewed the state of knowledge in radia- the actual administered activities . Therefore, tion epidemiology and biology at that time nuclear cardiology accounts for about 85% and developed models of radiation risk as of the total collective radiation dose from nu- a function of dose, sex and age at the time clear medicine in the United States . On the of exposure . This review was published in other hand, more than half of the patients what is referred to as the BEIR VII Phase 2 re- receiving radionuclide myocardial perfusion port [17] . This report recommended a linear studies are over the age of 65 years and at no-threshold model for cancer induction lower risk of adverse effects from radiation by ionising radiation in solid tumours and than younger individuals . a linear quadratic model for leukaemia . Al- though some controversies exist regarding Since nuclear cardiology is the most common the scientific validity of the linear no-thresh- nuclear medicine procedure and accounts EANM old model for estimating radiation risk at low for the largest contribution to the nuclear doses, it may be considered a conservative medicine collective dose, there have been a and thereby prudent model for radiation number of discussions regarding dose opti- safety purposes . According to the mod- misation in this arena [20–22] . In 2011, the els provided by the BEIR VII Phase 2 report, Cardiovascular Council of the SNMMI issued those exposed at an earlier age are in gen- a position paper [23] stating that “…radionu- eral at higher risk for cancer induction from clide MPI can provide scientifically validated, ionising radiation than adults . accurate, and in certain cases unique information for management of patients with Cardiovascular nuclear medicine known or suspected coronary artery disease The utilisation of myocardial perfusion im- at risk for major cardiovascular events . The aging (MPI) using radiopharmaceuticals radiation exposure risk associated with radio- has increased substantially over the past 30 nuclide MPI, albeit small and long term as op- years, such that it has become an essential posed to the higher and more immediate risk component of the armamentarium available for major cardiovascular events, mandates to assess patients for the risk of a significant careful adherence to appropriateness criteria myocardial event [18, 19] . In 2006, it was es- and guidelines developed or endorsed by timated that nuclear cardiology accounted the Society of Nuclear Medicine, the Ameri- for 57% of the nuclear medicine procedures can Society of Nuclear Cardiology, the Amer- performed in the United States [2] . These ican College of Cardiology and the American studies are typically performed as a rest Heart Association . With recent developments study followed by a stress study, resulting in in technology, there are many opportunities an effective dose when using99m Tc-sestamibi to further reduce radiation exposure and fur-

63 ther enhance the benefit-to-risk ratio of this stress-only protocol (high dose or low dose) well-established, safe imaging modality ”. as compared to a standard rest-stress protocol [24] . They showed that similar image One approach to dose optimisation in MPI quality could be obtained with a low-dose is to perform the stress portion of the study stress-only protocol using this device when first, with a low administered activity . The compared to the standard technique and rest study is then performed only if the stress instrumentation, but at a fraction of the ra- study is positive . This approach can yield a diation dose (estimated effective doses of 4 .2 substantial reduction in the patient’s radia- and 11 .8 mSv, respectively) . tion dose in a number of cases, but requires a 2-day rather than a one-day protocol, which The combination of proper patient selection, can be inconvenient for the patient . MPI can consideration of a stress-only protocol, new also be performed with PET using 82Rb or 13N high-sensitivity instrumentation and ad- ammonia (NH3) . The radiation dose from ei- vanced reconstruction techniques can lead 82 13 ther Rb or NH3 can be quite low due to the to substantial reductions in the amount of short half-lives of these two radionuclides activity administered to the patient, and sub- (1 .3 and 10 min, respectively) . However, sequently in the radiation dose . It is expect- availability of the PET scanner as compared ed that many of these advances will soon be- to a SPECT scanner for MPI may be an issue . come standard practice in nuclear cardiology and that these reductions in radiation dose MPI SPECT is most commonly performed on will thus be routinely realised in the clinic . a dual-detector gamma camera configured in a 90° orientation and typically takes about Communication of risk 15–20 min to complete . Over the past de- As nuclear medicine professionals, it is im- cade, SPECT devices dedicated to myocardial portant to be able to properly communicate SPECT have been developed that not only the risk of a given scan to patients and/or have a smaller footprint than conventional their family members . It is also important to SPECT systems, but also have higher sensi- be able to discuss these issues with the refer- tivity by perhaps a factor of 5–8 relative to ring physicians, who clearly understand the a conventional dual-detector SPECT system . clinical reasoning behind the study, but may This increased sensitivity can be used to re- have little understanding of radiation risk or duce either the imaging time or the amount perceive nuclear medicine procedures as of administered activity (and thereby the “high dose” . Reports have shown that inform- patient radiation dose) or a combination of ing patients regarding radiation risk does not the two . Duvall et al . evaluated the use of adversely affect their willingness to have an the GE 530c camera in conjunction with a appropriately ordered scan [25] . First, the

64 Chapter 5: Dose Optimisation for Diagnostic Procedures

technologist should explain to the patient While providing cost-benefit analyses to the that nuclear medicine procedures involve patient, it may also be helpful to compare the the use of a small administration of ionising risk to the lifetime risk of death from every- radiation . They may also discuss that this day activities . For example, the likelihood of may lead to a slight increase in the likelihood developing a fatal cancer as a result of un- of cancer developing within the patient’s dergoing an FDG PET scan is similar to the lifetime . It is important to emphasise the chance of falling down the stairs and dying benefits of the scan and that any potential (Fig . 4) . Another approach to explaining risk risk is very small . For example, a person who is to highlight that individuals receive a sim- receives an FDG PET scan has approximately ilar dose from this procedure as they would a 1 in 2500 probability of developing a fatal receive from background radiation in 1–3 cancer as a result of the scan . It has been years . A parent who chooses to stay with found that pictorial approaches to commu- his or her child while the child undergoes a EANM nicating risk are more beneficial than verbal nuclear medicine procedure would receive a explanation of the risk (Fig . 3) . dose on the order of radiation received from a transcontinental flight . Ultimately, it is important to address the patient’s concerns in a caring and knowledgeable manner and to clearly elucidate that the benefits of the procedure far outweigh the potential risk .

Programmes for dose optimisation Paediatric nuclear medicine In 1990 the European Association of Nuclear Medicine (EANM) published a weight-based guide for calculating the amount of radiopharmaceutical to be administered in children [26] . In 2007, this was replaced by the first version of the EANM Paediatric Dosage Figure 3: Communicating the risk of FDG PET card, with guidance for 39 radiopharmaceu- scan . This pictorial approach may help pa- ticals [27] . The dosage card was amended to tients understand the small risk of develop- include 18F-FDG in 2008 [28] . Most of the ra- ing a fatal cancer as a result of this procedure . diopharmaceuticals commonly used in pae- The red star indicates the risk of developing a diatric nuclear medicine were represented fatal cancer (1/2500) [25] . (Used with permis- on this dosage card . sion of the Journal of Nuclear Medicine)

65 Figure 4: Putting risk into context . The lifetime risk associated with various every day activities as compared to nuclear medicine procedures .

In North America, a survey was performed America, including the SNMMI, the American that demonstrated wide variation in the ad- College of Radiology, the Society of Pediatric ministered activities of radiopharmaceuticals Radiology and Image Gently, convened as an in children [29] . This survey showed that ad- expert working group to evaluate the pos- ministered activities per body weight (MBq/ sibility of developing consensus guidelines kg) and maximum total doses for larger pa- aimed at reducing the wide variability in pae- tients varied on average by a factor of 3, and diatric radiopharmaceutical administered by as much as a factor of 10 . For the smallest activities . In addition, it was hoped that this patients, the minimum dose range factor var- would lead to an overall reduction in radia- ied on average by a factor of 10 and by as tion exposures from nuclear medicine pro- much as a factor of 20 . The Alliance for Radi- cedures performed in children . The initiative ation Safety in Pediatric Imaging, which had led to the development, publication and dis- launched the Image Gently program at the semination of the North American consen- time, engaged several practitioners in paedi- sus guidelines for administered activities in atric nuclear medicine to address this issue . children [30] . A follow-up survey of the initial A number of professional societies in North paediatric hospitals surveyed revealed that

66 Chapter 5: Dose Optimisation for Diagnostic Procedures

there has been a reduction in administered in Medicine (AAPM), the American Society of activities as well as a reduction in the vari- Radiologic Technologists (ASRT) and the Ra- ability [31] . In a recently reported survey of diological Society of North America (RSNA) general hospitals in the United States, 82 .4% collaborated to form the Image Wisely cam- of general hospitals indicated that they were paign . To date, over 19,000 health profession- familiar with Image Gently, 57 .1% were famil- als, 30 medical organisations and 300 med- iar with the 2010 North American Guidelines ical facilities have taken the Image Wisely for children and 54 .9% altered their protocols pledge to optimise the use of radiation in im- because of the Guidelines [32] . aging patients . The Image Wisely campaign launched a website (www .imagewisely .org), In 2012, members of both the EANM and the which contains a wealth of information on SNMMI met to discuss the possibility of har- dose optimisation for referring physicians monising the guidelines of the two societies . and patients . The initial emphasis of the EANM Most of the radiopharmaceuticals covered groups was on CT, but the effort soon grew by the North American consensus guidelines to encompass other radiological modalities . noted that the EANM dosage card could also be used . This discussion identified areas of Image Wisely collaborated with organisa- agreement and discrepancy between the tions such as the American Society of Nucle- two guidelines . A working group consisting ar Cardiology (ASNC), the SNMMI and SNMMI of members of both organisations met over Technologist Section (SNMMI-TS) to address the next few years to study the possibility of dose optimisation in the fields of general harmonising the two sets of guidelines . This nuclear medicine, nuclear cardiology, PET/ resulted in the “Paediatric radiopharmaceu- CT and nuclear physics . In 2012, a nuclear tical administration: harmonization of the medicine page on the Image Wisely site was 2007 EANM paediatric dosage card” (ver- developed to inform patients and referring sion 1 .5 .2008) and the 2010 North American physicians (http://imagewisely .org/Imag- consensus guidelines document published ing-Modalities/Nuclear-Medicine) . in 2014 [33] . Twelve radiopharmaceuticals were included in the new guidelines, with Conclusion the promise that others will soon be incor- Nuclear medicine plays an important role in porated . the diagnosis and treatment of many diseases . Considering that they provide such valu- Adult nuclear medicine able information, the amount of nuclear med- In order to address concerns about ionising icine procedures has soared tremendously in radiation in medical imaging in adults, in the past several years . This increased utilisa- 2010 the American Association of Physicists tion corresponds to an increase in effective

67 dose amongst the world population . As a nuclear medicine technologist it is important to understand the risk of such procedures and how to communicate the benefits as well as the potential harm from these procedures to patients, family members and attending physicians . Having an understanding of internal dosimetry for PET, SPECT, PET/CT, SPECT/CT and PET/MRI, as well as a comprehension of how the appropriate dose is determined, will help to minimise risk and maximise the many benefits of nuclear medicine .

68 Chapter 5: Dose Optimisation for Diagnostic Procedures

References

1 . Fahey F, Treves ST, Lassmann M . Dose optimization in 10 . Stansfield EC, Sheehy N, Zurakowski D, Vija AH, Fahey pediatric nuclear medicine . Clinical and Translational FH, Treves ST . Pediatric 99mTc-MDP bone SPECT with Imaging 2016;4:5–11 . ordered subset expectation maximization iterative reconstruction with isotropic 3D resolution recovery . 2 . Schauer DA, Linton OW . NCRP report No . 160 . Ioniz- Radiology 2010;257:793–801 . ing radiation exposure of the population of the Unit- ed States, medical exposure—are we doing less with 11 . Sheehy N, Tetrault TA, Zurakowski D, Vija AH, Fahey FH, more, and is there a role for health physicists? Health Treves ST . Pediatric 99mTc-DMSA SPECT performed by Phys 2009;97:1–5 . using iterative reconstruction with isotropic resolution recovery: improved image quality and reduced radio- 3 . Treves ST, Falone AE, Fahey FH . Pediatric nuclear medi- pharmaceutical activity . Radiology 2009;251:511–516 . cine and radiation dose . Semin Nucl Med 2014;44:202– 209 . 12 . Alessio AM, Farrell MB, Fahey FH . Role of reference levels in nuclear medicine: a report of the SNMMI Dose Op- 4 . Bolch WE, Eckerman KF, Sgouros G, Thomas SR . MIRD timization Task Force . J Nucl Med 2015;56:1960–1964 . pamphlet no . 21: a generalized schema for radiophar- EANM maceutical dosimetry—standardization of nomencla- 13 . Bolus NE, George R, Newcomer BR . PET/MRI: the blend- ture . J Nucl Med 2009;50:477–484 . ed-modality choice of the future? J Nucl Med Technol 2009;37:63–71 . 5 . Stabin MG . Uncertainties in internal dose calculations for radiopharmaceuticals . J Nucl Med 2008;49:853–860 . 14 . Queiroz MA, Delso G, Wollenweber S, Deller T, Zeimpekis K, Huellner M, et al . Dose optimization in TOF-PET/MR 6 . Mattsson S, Johansson L, Svegborn SL, Liniecki J, Noßke compared to TOF-PET/CT . PloS One 2015;10:e0128842 . D, Riklund K, et al . ICRP Publication 128: Radiation dose to patients from radiopharmaceuticals: a compendium 15 . Oehmigen M, Ziegler S, Jakoby BW, Georgi J-C, Paulus of current information related to frequently used sub- DH, Quick HH . Radiotracer dose reduction in integrated stances . Ann ICRP 2015;44(2 suppl):7–321 . PET/MR: implications from National Electrical Manu- facturers Association phantom studies . J Nucl Med 7 . O’Reilly SE, Plyku D, Sgouros G, Fahey FH, Ted TS, Frey 2014;55:1361–1367 . EC, et al . A risk index for pediatric patients undergoing diagnostic imaging with (99m) Tc-dimercaptosuccin- 16 . Ozasa K, Shimizu Y, Suyama A, Kasagi F, Soda M, Grant EJ, ic acid that accounts for body habitus . Phys Med Biol et al . Studies of the mortality of atomic bomb survivors, 2016;61:2319–2332 . Report 14, 1950-2003: an overview of cancer and non- cancer diseases . Radiat Res 2011;177:229–243 . 8 . Fahey F, Zukotynski K, Zurakowski D, Markelewicz R, Falone A, Vitello M, et al . Beyond current guidelines: 17 . National Research Council (US) Board on Radiation Ef- reduction in minimum administered radiopharmaceu- fects Research . Health risks from exposure to low levels tical activity with preserved diagnostic image quality in of ionizing radiation: Beir VII phase II . Washington (DC): pediatric hepatobiliary scintigraphy . Eur J Nucl Med Mol National Academic Press; 2006 . Imaging 2014;41:2346–2353 . 18 . Berman DS, Shaw LJ, Min JK, Hachamovitch R, Abidov 9 . Hsiao EM, Cao X, Zurakowski D, Zukotynski KA, Drubach A, Germano G, et al . SPECT/PET myocardial perfusion LA, Grant FD, et al . Reduction in radiation dose in mer- imaging versus coronary CT angiography in patients captoacetyltriglycerine renography with enhanced with known or suspected CAD . Q J Nucl Med Mol Im- planar processing . Radiology 2011;261:907–915 . aging 2010;54:177–200 .

69 19 . Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, 27 . Lassmann M, Biassoni L, Monsieurs M, Franzius C, Jacobs Cabico JA, et al . Incremental prognostic value of myo- F, Dosimetry E, et al . The new EANM paediatric dosage cardial perfusion single photon emission computed card . Eur J Nucl Med Mol Imaging 2008;35:1748 . tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocar- 28 . Lassmann M, Biassoni L, Monsieurs M, Franzius C, Dosim- dial infarction . Circulation 1998;97:535–543 . etry E, Paediatrics C . The new EANM paediatric dosage card: additional notes with respect to F-18 . Eur J Nucl 20 . Kaul P, Medvedev S, Hohmann SF, Douglas PS, Peterson Med Mol Imaging 2008;35:1666–1668 . ED, Patel MR . Ionizing radiation exposure to patients admitted with acute myocardial infarction in the United 29 . Treves ST, Davis RT, Fahey FH . Administered radiophar- States . Circulation 2010;122:2160–2169 . maceutical doses in children: a survey of 13 pediatric hospitals in North America . J Nucl Med 2008;49:1024– 21 . Small GR, Chow BJ, Ruddy TD . Low-dose cardiac imag- 1027 . ing: reducing exposure but not accuracy . Expert Rev Cardiovasc Ther 2012;10:89–104 . 30 . Gelfand MJ, Parisi MT, Treves ST . Pediatric radiopharmaceutical administered doses: 2010 North American 22 . Small GR, Wells RG, Schindler T, Chow BJ, Ruddy TD . Ad- consensus guidelines . J Nucl Med 2011;52:318–322 . vances in cardiac SPECT and PET imaging: overcoming the challenges to reduce radiation exposure and im- 31 . Fahey FH, Ziniel SI, Manion D, Treves ST . Effects of Image prove accuracy . Can J Cardiol 2013;29:275–284 . Gently and the North American guidelines: administered activities in children at 13 North American pedi- 23 . Sadeghi MM, Schwartz RG, Beanlands RS, Al-Mallah MH, atric hospitals . J Nucl Med 2015;56:962–967 . Bengel FM, Borges-Neto S, et al . Cardiovascular nuclear imaging . J Nucl Med 2011;52:1162–1164 . 32 . Fahey FH, Ziniel SI, Manion D, Baker A, Treves ST . Ad- ministered activities for pediatric nuclear medicine pro- 24 . Duvall WL, Croft LB, Godiwala T, Ginsberg E, George T, cedures and the impact of the 2010 North American Henzlova MJ . Reduced isotope dose with rapid SPECT guidelines on general hospitals in the United States . J MPI imaging: initial experience with a CZT SPECT cam- Nucl Med 2016 57:1478–1485 . era . J Nucl Cardiol 2010;17:1009–1014 . 33 . Lassmann M, Treves ST, Group ESPDHW . Paediatric ra- 25 . Fahey FH, Treves ST, Adelstein SJ . Minimizing and com- diopharmaceutical administration: harmonization of the municating radiation risk in pediatric nuclear medicine . 2007 EANM paediatric dosage card (version 1 .5 . 2008) J Nucl Med 2011;52:1240–1251 . and the 2010 North American consensus guidelines . Eur J Nucl Med Mol Imaging 2014;41:1036–1041 . 26 . Piepsz A, Hahn K, Roca I, Ciofetta G, Toth G, Gordon I, et al . A radiopharmaceuticals schedule for imaging in paediatrics . Paediatric Task Group European Association Nuclear Medicine . Eur J Nucl Med 1990;17:127–129 .

70 components for conventional designs andSPECT/CT Figure 1:PET/CT inherentpharmaceutical to nuclearmedicine to that from the administration of the radio es the patient to ionising radiation in addition tions (Fig medicalindica for certain lished, particularly has been clinically estab recently, SPECT/CT scan by closeto 50% . More PET whole-body scan reduced thetimerequired a to perform tion inlieuofthemuchslower transmission forrelatively attenuation correc low-noise CT to utilisetherapidlyacquiredthe ability and inthefieldofoncology ticularly was deemed invaluable by clinicians, par CT anatomical correlationwith thesuperior of and molecularimaging capabilitiesofPET (Fig by anymarketed ofthemajormanufacturers later, PET-only scannerswere no longer being andby 2005,only5years ofthecentury turn became commercially available around the medicine imaging ofnuclear hasbeenanessentialaspect CT For thepast15years, hybrid imaging using Introduction Frederic H.Fahey, Elizabeth Romero andAdam Alessio Imaging inHybrid OptimisationofCT Dose Chapter 6: A . 1A) . The combination of the functional .1B)However, expos theuseofCT Hybrid PET/CT scanners PET/CT . Hybrid Illustration of the major PET/CT (A) and SPECT/CT (B)scanner (A) and SPECT/CT ofthemajorPET/CT .Illustration In addition, .In ------. 71 correction, the CT acquisitionparameters can theCT correction, pose for thispur mission information necessary sinceitprovides thephoton trans- SPECT) oftheemissionscan(i.e correction canbeusedfor attenuation portion the CT es oracombinationthereof subsequently usedfor- three purpos distinct canbe acquired and the CT or SPECT/CT, CT ofhybrid imaging, thepractice eitherPET/ In inhybridUses imaging ofCT the lowest possibleradiationdose the clinicalquestionathandwhiledelivering to address the imageinformation necessary to optimise theacquisitioninorder to obtain of associated radiation doses and approaches hybrid imaging, how itisacquired, therange of usedinthecontext istypically the way CT thischapter,by thepatient.In we willreview dose receivedtion of theradiationabsorbed can comprise a small or a considerable frac can comprise used and thereby how it is acquired, the CT As will be discussed, depending on how itis B If the CT isonlyusedfor attenuation theCT .If In thefirstcase, .In . PET or .PET - - EANM be substantially reduced without impairing attenuation coefficient, µ, can be assumed the ability of the CT to provide adequate at- and the correction can be substantially sim- tenuation correction [1] . Secondly, it can be plified . For example, in SPECT of the abdo- used for anatomical correlation of the PET or men, all of the soft tissue can be assumed to SPECT data . In this instance, the CT need not have a µ value similar to water (i .e . 0 .15 cm-1 be of diagnostic image quality, but it must be for the 140-keV gamma ray emitted by 99mTc) of a sufficient standard to permit correlation and a first-order Chang correction can be ap- with the emission scan based on adequate plied . However, this single tissue approach depiction of the anatomical features of inter- cannot be applied in the thorax, where the est . Lastly, the CT may be acquired in a man- lungs have considerably different attenuat- ner appropriate for a diagnostic CT study of ing properties compared to soft tissue . Thus, the region of interest . If the patient requires to adequately perform attenuation correc- a CT and an emission scan for diagnosis, the tion for emission tomography in the thorax, ability to acquire both in a single imaging one must incorporate transmission data into session is not only convenient and efficient the reconstruction process, and CT has been for the patient, but also allows dose reduc- shown to be very useful in this regard . In tion by potentially eliminating the need for fact, this was one of the early motivations for an additional CT scan . In many instances, the the development of hybrid imaging . For CT- CT portion of hybrid imaging may be used based attenuation correction to be applied, for more than one of the above-mentioned certain adjustments need to be made since purposes . For example, a CT of diagnostic the nature of CT does vary from that of emis- quality may also be used for anatomical cor- sion tomography . relation and attenuation correction or a CT for anatomical correlation may also be used The first adjustment is that the energy at for attenuation correction . These three uses which these studies are acquired is different . of CT have considerably different require- In CT, the tube voltage is typically between ments with respect to both the complexity 80 and 140 kVp, and, thereby, the effective of the image data acquisition and the radia- photon energy is probably between 40 and tion dose delivered to the patient . 80 keV whereas the photon energy associated with SPECT (assuming 99mTc) and PET The probability of detecting a photon emit- is routinely 140 or 511 keV, respectively [2] . ted from the centre of the patient is lower In general, this necessitates a reasonably than that of detecting a photon emitted simple adjustment through application of a from the patient’s periphery . In regions of multilinear transformation between the re- the body where the tissue has similar attenu- constructed CT (or Hounsfield) unit and the ating properties, a single value for the linear corresponding linear attenuation coefficient

72 Chapter 6: Dose Optimisation of CT in Hybrid Imaging

(or µ), as shown in Fig . 2 . For example, a CT modalities . The spatial resolution associated value of 0 corresponds to water and thus can with CT is on the order of a millimetre where- be assigned the µ-value of 0 .15 cm-1 or 0 .093 as it is typically 5–10 mm for PET and 10–15 cm-1 for 99mTc SPECT and PET, respectively . mm for SPECT . This difference in spatial res- For CT values below 0, the material can be olution between transmission and emission considered a mixture of soft tissue and air, tomography would lead to an edge artefact . and for CT values greater than 0, a mixture of Thus, the CT data are typically blurred to the soft tissue and bone . A third region may be resolution of SPECT or PET prior to applying applied to compensate for CT contrast mate- the correction . As a result the typical meth- rial . Due to the change in materials in these od for CT-based attenuation correction is as three regions, the slope also changes (Fig . follows: acquire the CT scan and reconstruct 2) . In general, this transformation has been it, apply the energy transformation from CT shown to work quite well [2] . energies to that for SPECT or PET, re-project EANM the transformed data to generate a correction matrix, smooth the correction matrix to the resolution of PET/SPECT and, lastly, apply these modifications during reconstruction .

If the CT scan is truly only to be used for attenuation correction, the acquisition parameters, both kVp and mAs, can be reduced almost as far as the device will allow (e .g . 80 kVp and around 10 mAs) and an acceptable attenuation correction can still be applied [1, 3] . For example, this may be reasonable for brain PET, where MRI is the anatomical modality of choice and CT is not used clinically . Figure 2: Bi-linear scaling method used to However, in many cases, the low-dose CT is convert CT pixel values to linear attenuation used for anatomical correlation of the PET coefficients for PET at 511 keV . Similar data . This can be particularly useful when conversions are used to convert for different the pertinent PET or SPECT scan finding is SPECT energies (figure used with permission merely an amorphous feature in space with [1]) few anatomical landmarks for localisation . In these cases, the CT image quality may only The second required adjustment is due to the need to be sufficient for localisation and less variation in spatial resolution between the than that necessary for diagnosis . Thus, the

73 mAs can often be drastically reduced by a CT acquisition and dosimetry factor of possibly 3–5, depending on the task CT measures the differential absorption of at hand and the size of the patient, leading to X-rays passing through the patient and thus a considerable reduction in radiation dose to provides a 3D map of tissue density . The CT the patient compared to that for a diagnos- signal is more specifically related to electron tic CT scan . The scan may also be easier to density, which in many cases is well correlat- acquire, not requiring a breath hold or posi- ed with mass density . X-rays are generated tioning of the patient’s arms above the head when electrons from the cathode of the x-ray for the entire scan . tube are liberated via thermionic emission and accelerated towards the anode through Lastly, there may be instances where acquir- an applied voltage . When the electrons strike ing a diagnostic CT scan in conjunction with the anode, they de-accelerate, leading to the the PET scan makes the most sense . For ex- production of bremsstrahlung and character- ample, it may be reasonable to acquire an istic X-rays . The number of electrons striking abdominal/pelvic CT in conjunction with the the anode per second is characterised by the PET scan, leading to a more efficient imaging tube current in milliamperes (mA) . Thus the approach as well as being more convenient total number of electrons striking the anode for the patient . This approach may be partic- is directly related to the product of the tube ularly helpful in children or other challenging current and the duration of the exposure (in patients, when the ability to perform both seconds) reported in mAs . Therefore, the total scans simultaneously may reduce the need number of X-rays generated and subsequent- for sedation or other approaches to immo- ly the X-ray dose to the patient is directly pro- bilisation . On the other hand, diagnostic portional to mAs . The voltage across the tube, CT requires the highest radiation dose to be reported as the kilovoltage peak (kVp), deter- delivered to the patient . One should keep mines the energy of the electrons striking the in mind that diagnostic CT is often applied anode (in keV) by definition and thereby the to specific regions of the body such as the maximum energy of the resultant X-rays . In head/neck, the chest, the abdomen or the addition, higher energy electrons are more ef- pelvis whereas the typical 18F-fluorodeoxy- ficient at generating X-rays and higher energy glucose PET field of view encompasses all of X-rays are more likely to exit the tube and its these . Therefore, approaches that limit the filtration prior to reaching the patient . As a re- diagnostic quality CT to the area of interest sult, the X-ray exposure or air kerma rate varies (e .g . to the abdomen and pelvis in the above roughly as the square of the kVp . example) while delivering a low dose to the rest of the field of view may be most appro- The emitted X-rays, after passing through the priate . patient, are detected by a two-dimensional

74 Chapter 6: Dose Optimisation of CT in Hybrid Imaging

array of detectors . The X-ray tube and the where μV represents the measured mean lin- detector array are fixed relative to each other ear attenuation coefficient within the voxel and rotate constantly about the patient, typ- of interest and μwater is the linear attenuation ically at a speed of about one to three revo- coefficient for water at the effective keV for lutions per second . This provides full sets of the X-ray spectrum of the CT acquisition . transmission projection data for subsequent reconstruction . In addition, the image bed Modern CT scanners, including those in- moves during the acquisition, allowing a vol- corporated into hybrid systems, typically ume of the patient to be imaged in a helical provide some level of automatic exposure fashion . The table speed is generally report- control (AEC) . In many cases, the low-dose ed relative to the beam width as a parameter topogram or “scout” acquisition used to de- known as the pitch, given by termine the CT field of view also serves to provide information for the AEC . For exam- EANM Pitch = ple, less radiation may be necessary for imag- Table distance travelled in a single gantry rotation ing the lungs as compared to the abdomen Width of the beam collimation since there is less attenuation, and less is needed when acquiring data in the anteri- A pitch of unity (1:1) indicates that the table or–posterior direction rather than the lateral travels a distance equivalent to the width of direction as the body is thinner in this direc- the beam collimation during a single gantry tion . Subsequently, the mA can be modified rotation . Faster table speeds lead to pitch accordingly during the acquisition . Typically, values greater than 1:1 (e .g . 1 .5:1), yielding the user can define some criteria such as a slightly under-sampled data . However, in maximum mA level or a noise index that sets most cases, interpolation between the ac- the acquisition at a given exposure level that quired axial data can yield an adequate re- is then modified . AEC can lead to a 25–40% construction . reduction in radiation dose depending on the nature of the acquisition and the size of The CT signal is quantified in CT or Hounsfield the patient . units, which estimate the mean linear attenuation coefficient within a voxel relative to The radiation dose delivered by CT is typically that for water: characterised by the CT dose index (CTDI), defined as the dose delivered to a standard acrylic, cylindrical phantom (16- or 32-cm diameter CT number (or Hounsfield units) = for the head or whole-body acquisition, re- μV - μwater 1000 x μwater spectively) . When CTDI is averaged over several locations within the phantom (central and

75 peripheral) and normalised by the pitch, it is ning is important as it will affect the image referred to as CTDIvol . The dose–length prod- quality as well as the dose of radiation that is uct (DLP in units of mGy-cm) is the product delivered to the patient . The patient should of CTDIvol and the axial length of the CT acqui- be positioned so that the radiation from the sition in cm . DLP may be more closely linked X-ray beam is not applied to sensitive areas to radiation risk as it also takes into account that do not need to be imaged . Using laser the extent of the scan . CTDIvol and DLP are lights for positioning is helpful to ensure that routinely displayed on the CT operator’s con- the patient is in the isocentre of the gantry . sole during an acquisition and recorded in the If the patient is not in the isocentre then the structured dose report or in the DICOM head- dose delivered from the CT could be too low er . It should be noted that these dose indices or too high . If the dose is too low, the image do not represent the radiation dose to a par- quality suffers and the scan may need to be ticular patient, but that measured in standard repeated; too high and the patient receives phantoms . If the size of the patient is known, unnecessary radiation dose . This, along with the CTDIvol can be modified and reported as the use of a scout or topogram scan, can help the size-specific dose estimate (SSDE) [4] . in ensuring that the field of view is consistent Therefore, CT acquisition parameters should with the exam that was ordered . For exam- be reduced for smaller patients . ple, if a chest CT is ordered, the scout scan will show whether the entire chest cavity is In order to investigate the range of expo- in the field of view . sures associated with the CT component of PET/CT, data for whole-body PET/CT from If motion is detected in a scan, it may need the American College of Radiology CT dose to be repeated; therefore it is essential that index registry were reviewed for over 28,000 the patient is instructed to remain as still as PET/CT acquisitions from 35 facilities in the possible during scanning and is positioned United States . The median values (and in- comfortably . If needed, soft positioning deter-quartile scores) for the CTDIvol and DLP re- vices can be used to help the patient to hold ported for these scans were 6 .3 (4 .0, 9 .0) mGy still . In some paediatric patients or patients and 541 (364, 831) mGy-cm, respectively . who are experiencing high amounts of anx- From these values, the estimates of the medi- iety, a sedative can be administered to help an (and inter-quartile scores) of the effective with compliance during the scan . dose are 8 .9 (6 .0, 13 .4) mSv [5] . Guidelines and national regulations for Best practice in patient positioning in CT acquiring CT within hybrid imaging acquisition for hybrid imaging CT scans are routinely performed in the Unit- Positioning of the patient during CT scan- ed States and account for a large proportion

76 Chapter 6: Dose Optimisation of CT in Hybrid Imaging

of diagnostic radiology exams . The clinical in- technology . Accordingly, all professionals formation that is gained from CT exams is in- working in the field need to ensure that they credibly beneficial to patient outcomes and are fully acquainted with the latest develop- outweighs the risk that comes with the radi- ments . Technologists need to be aware of ation exposure . However, in 2009 and 2010 published practice standards and the chang- reports were released regarding 400 patients es in regulations in order to perform scans who received radiation overdoses from a CT that provide the best image quality and en- exam [6] . Similar reports regarding the risk sure optimal patient care . of radiation have led to a growing concern regarding the safety of CT . Conclusion The addition of CT to both PET and SPECT In the United States, the American College of has had a substantial impact on clinical prac- Radiology (ACR) has published a practice pa- tice . However, CT exposes the patient to ion- EANM rameter for performing diagnostic CT scans [7] . ising radiation in addition to that associated This is not a set of rules but rather an educa- with the administration of the radiopharma- tional tool designed to advise on how to pro- ceutical . Therefore, basic knowledge of the vide care for patients undergoing CT scans . The physical aspects of CT and the factors that audience for the ACR document is physicians . affect dose is essential for the nuclear med- For technologists, the American Society of icine professional involved in hybrid imaging . Radiologic Technologists (ASRT) has also pub- Care must also be taken to optimise the dose lished Computed Tomography Practice Stan- associated with CT . For example, the CT ac- dards in their Practice Standards for Medical quisition parameters should be adjusted de- Imaging and Radiation Therapy [8] . Again, this pending on how the CT is to be used (i .e . for is not a rule book, but a guide to appropriate attenuation correction, anatomical correla- practice in the performance of diagnostic CT . tion or diagnosis) and the size of the patient . Since PET/CT scans typically extend over a National and local authorities may regulate substantial portion of the patient’s body, it what training and credentialling is required may be prudent to restrict the diagnostic to perform CT in the context of hybrid im- study, when necessary, to the body region of aging . This varies greatly depending on the clinical concern . jurisdiction and may depend on whether the CT portion of the study is being used for diagnostic purposes .

The field of radiology and CT continues to grow and evolve, with ongoing changes in

77 Chapter 6: Dose Optimisation of CT in Hybrid Imaging

References

1 . Fahey FH, Palmer MR, Strauss KJ, Zimmerman RE, Badawi RD, Treves ST . Dosimetry and adequacy of CT-based attenuation correction for pediatric PET: phantom study 1 . Radiology 2007;243:96–104 .

2 . Lonn A . Evaluation of method to minimize the effect of x-ray contrast in PET-CT attenuation correction . IEEE Medical Imaging Conference 2003;M6:146 .

3 . Rui X, Cheng L, Long Y, Fu L, Alessio AM, Asma E, et al . Ultra-low dose CT attenuation correction for PET/ CT: analysis of sparse view data acquisition and reconstruction algorithms . Phys Med Biol 2015;60:7437–7460 .

4 . Boone J, Strauss K, Cody D, McCollough CH, McNitt- Gray MF, Toth TL . AAPM report No . 204: size-specific dose estimates (SSDE) in pediatric and adult body CT examinations . College Park, MD: American Association of Physicists in Medicine, 2013 .

5 . Alessio A, Sengupta D, Bhargavan-Chatfield M, Butler P, Kanal K, Fahey F . Survey of CT radiation dose levels during PET/CT from ACR CT Dose Index Registry . J Nucl Med 2015;56(Suppl 3):1696 .

6 . Harvey HB, Pandharipande PV . The federal government’s oversight of CT safety: regulatory possibilities . Radiology 2012;262:391–8 .

7 . ACR Practice Parameter for Performing and Interpret- ing Diagnostic Computed tomography (CT) . Reston, VA: 2014 .

8 . The Practice Standards for Medical Imaging and Radi- ation Therapy: Computed Tomography Practice Stan- dards . Albuquerque, NM: American Society of Radio- logic Technologists, 2015 .

78 effectiveness oftreatment [1–3]. 131 131 clide therapy iswithradioiodine(iodine-131, ways therapy canbeusedinvarious Radionuclide Marga Ouwens Optimisationfor Dose Radionuclide Therapy Chapter 7: estimation ofthesize ofthethyroid andthe es isusuallybasedonacalculationinvolving optimisationforDose benign thyroid diseas- disease therapy for benignIodine-131 thyroid will bethesame therapy, thatthe endresult intheknowledge care ofthepatientby avoiding excessive possible result withtherapy whilsttaking optimisation . The aimisto achieve thebest issueintherapy isdose The mostimportant readily available different radionuclidesuseful for therapy are the thyroid gland for the treatment of benign conditionsof to beusedinhumans radiopharmaceutical effective half-life of maybecause they lower and the the uptake iouracil) before radioiodine administration carbimazole) oratleast2–3weeks (propylth- stopped for atleast2days (methimazole and tissue ofhealthy for thyroid preservation important level is thyroid (TSH) stimulatinghormone favourable conditions acquisitions, and also therapy, occur under thatthediagnostic isofutmostimportance It During the1940s,I) .During I uptake after 24h[1]. after I uptake . The mostcommonform ofradionu- In addition,anti-thyroid .In drugsmustbe . . .Nowadays, anumberof 131 I, thereby reducing the .Asuppressed (<0 .1) 131 I becamethefirst 79 the approximate weight ofthethyroid thenumberofpixelsto into convert intheROI around thethyroid (Fig or manuallydrawn regions ofinterest (ROIs) whereby thetechnologist creates automatic programar acquisition,asoftware isused To thethyroid determine size withanucle and a zoom of a 2 .29 256×256 matrix factor may use, for example, atimeframeof10min, collimator acquisition (size ingrams) withahigh-energy ultrasound (size inmillilitres) [2]orby static The size ofthethyroid canbeevaluated by 1 .45canbeused and azoom of of a256×256matrix factor nign diseasepresent (Figs thebe collimator canbeusefulindescribing A staticacquisitionobtainedwith apinhole approximation ofthethyroid weight Figure around 1:AnROI thethyroid gives an .For acquisition,one high-energy . .1) isable The software .2–4)Parameters . - -

EANM Figure 2: An example of Graves’ disease (au- Figure 4: An example of solitary hyperfunc- toimmune hyperthyroidism) [1, 2] tioning thyroid nodule [1 ,2]

There is a possibility that a ‘cold spot’ on the static acquisition is seen, and further examinations such as a biopsy will then be required .

Some patients suffer from tracheal deviation, e .g . patients with toxic multinodular goitre or non-toxic goitre [2] . In these cases, a SPECT/ CT is usually performed to check whether the thyroid is causing the deviation . SPECT complements the morphological information provided by CT by demonstrating radioiodine uptake in the thyroid . If a ‘cold’ part of the thyroid is found to be the cause of the deviation (Fig . 5), therapy with 131I will not Figure 3: An example of Plummer’s disease solve the problem, and the patient must be (toxic multinodular goitre) [1, 2] referred to the surgical department [3] .

80 Chapter 7: Dose Optimisation for Radionuclide Therapy

MBq = (V×25×Gy) ÷ [RAIU (24 h) × Teff]

where MBq = the calculated activity in MBq, V = the gland volume in ml or g, Gy = the estimated dose at the thyroid level, RAIU (24 h)

= % of thyroid uptake at 24 h, Teff = effective half-time and 25 is a constant .

Figure 5: The arrow shows the ‘cold’ part of In either toxic or non-toxic multinodular goi- the thyroid, causing the tracheal deviation. tre, radioiodine doses have been empirically In this case, treatment with 131I is excluded established . Currently, an absorbed radiation EANM dose of 100–150 Gy is recommended . In patients with autonomous nodules, the recommended dose is 300–400 Gy . In patients with Calculation of dose Graves’ disease, the dose applied with the The aim is to restore euthyroidism, with the aim of restoring a euthyroid status is approx- exception of ‘definitive’ treatment of Graves’ imately 150 Gy, whereas the dose to achieve disease [2] or when a patient is allergic to an- complete ablation is in the range of 200–300 tithyroid drugs . Gy [2] .

There is ongoing discussion regarding the Hypothyroidism is a possibility in the longer optimal method for determination of the term, certainly when a complete ablation activity that can be recommended for clin- has been planned . Some of the reasons for ical practice: estimation (the so-called fixed choosing a higher dose (ablation) are the dose) versus calculation (based on radioio- presence of Graves’ disease and allergies to dine uptake measurements) . antithyroid drugs [3] .

The calculated dose method may be used Patient preparation in the selection of a more accurate dose of At the initial consultation, patients should be radioiodine for treatment . There are multiple advised of what the treatment will entail . methods for dose calculation, but the simplest formula is as follows [1]: In addition to the likely effectiveness of the treatment, the patient’s attention should especially be drawn to:

81 • the slow onset of action of radioiodine • A hypersensitivity reaction following the • the effect of radiation on the thyroid and administration is very unlikely [2, 3] . the body • the possibility of persistent or recurrent Absolute contra-indications [1–3] to therapy hyperthyroidism and what may be done are pregnancy and breastfeeding: about it • the possibility of hypothyroidism and its • In female patients of childbearing symptoms, implications and treatment potential, a routine pregnancy test should be performed within 72 h before the • the need for regular follow-up to detect administration of 131I [1–3] . hypothyroidism [3] . • Breastfeeding should be stopped before administration of 131I . The nuclear medicine physician should inform the patient of the common side effects Special recommendations and radiation pro- of treatment: tection information, applicable with or without hospitalisation, must be orally discussed • Nausea and vomiting are acute side and, in addition, presented on paper [1, 2] effects . At lower doses there is a lower prior to commencement of therapy: incidental risk . • Patients with a large goitre may • Depending upon national regulations, notice transient swelling of the goitre recommendations relating to conception and dyspnoea . The swelling lasts for may have to be provided . Generally, approximately 1 week following therapy it is suggested that after 131I therapy, and some discomfort or dyspnoea may be contraception should be used for 4–6 associated with it [1, 2] . months by both men and women [1–3] . • Slight discomfort of the salivary glands may • Breastfeeding may not be started after be present, but injury is uncommon [2] . therapy . • Hypothyroidism is the main late side effect • The patient should be encouraged to drink of radioiodine treatment . Its rate varies and a large volume of fluid for a 24-h period its incidence continues to increase over time, following radioiodine therapy to lower the so that life-long follow-up is essential [1, 2] . radiation dose to the bladder [2] . • Administration of prednisone helps to • Contamination may occur at home . prevent exacerbation of ophthalmopathy . The most common cause of such The status of thyroid eye disease activity contamination is radioactive urine . Sitting can be established by an experienced while urinating and washing of hands are ophthalmologist [1–3] . important to prevent contamination .

82 Chapter 7: Dose Optimisation for Radionuclide Therapy

Another possibility is contamination with • Lymph node metastases may be treated radioactive saliva . Tableware must not be with 3 7–6. .5 GBq . Cancers that extend shared before being cleaned (extra care through the thyroid capsule and have must be taken when feeding children) and been incompletely resected are treated no kissing is permissible for a few days . with 3 .7–7 .4 GBq [4, 5] . • The patient may need to take time off • Patients with distant metastases are work/school for a period in accordance usually treated with 7 .4 GBq [4, 5] with the activity of radioiodine received and the nature of his or her work [2, 3] . The main goal is to ablate the thyroid tissue • The patient should avoid prolonged close with one therapeutic dose . The thyroid tissue contact with (small) children and pregnant can be ablated successfully when it is small women for a period in accordance with enough and there are no metastases . Metas- EANM the activity of radioiodine received [2, 3] . tases can also be treated, but with a palliative • Usually the patient is advised to keep a response . Therefore a patient with metasta- distance between themselves and (other) ses could return for further treatments [4] . adults, and to keep contact times as short as possible for a limited amount of time, When the thyroid tissue is too large for abla- depending on the activity of radioiodine tion with only one therapeutic dose, or there received . [2] . are metastases in lymph nodes, an experienced surgeon is consulted to clarify wheth- • There may be restrictions on travel er a second or third surgical intervention is depending on the activity of radioiodine possible before giving 131I therapy . received [3] .

It is of utmost importance that the TSH val- Iodine-131 therapy for thyroid carcinoma ue exceeds 30 mIU/L [4] . This value may be There are multiple choices for establishing obtained: the necessary dose for radioiodine therapy, but administration of a ‘fixed dose’ of 131I is • At least 3–6 weeks after surgery in the absence the simplest and most widely used method . of thyroid hormone replacement therapy [4, 5] .

• After 4–5 weeks of levothyroxine (LT4) The indications for radioiodine are as follows: withdrawal [4] or after 2–3 weeks of

triiodothyronine withdrawal (LT3) [5] . • Remnant ablation: The dose may be 1 11,. • After administration of recombinant TSH 1 .85, 2 .59 or 3 .7 GBq, according to the in two intramuscular injections on two volume of the tissue, the uptake and the consecutive days, if the patient is under level of thyroglobulin (Tg) [4, 5] (Fig . 6) . hormonal treatment [4, 5] .

83 Patient preparation Special recommendations and radiation pro- The nuclear medicine physician should in- tection information must be orally discussed form the patient of the most common side and, in addition, presented on paper prior to effects of treatment: commencement of therapy [5]:

• An acute side effect is nausea and vomiting . • Depending upon national regulations, • Salivary dysfunction is the most common recommendations relating to conception side effect associated with high-dose may have to be provided . Generally, radioiodine . Prevention of salivary damage it is suggested that after 131I therapy, is an important issue . contraception should be used for 4–6 • Salivation-inducing snacks, such as lemon months by both men and women [4] . candy, have proved helpful in preventing • Breastfeeding may not be started after salivary side effects of131 I therapy . The sour therapy . ingredient stimulates the salivary glands to • Patients should be encouraged to drink produce saliva, and the increase in salivary a large volume of fluid for a 24-h period flow reduces radiation exposure . Lemon following radioiodine therapy to lower the candy should not be used until at least 24 radiation dose to the bladder [2] . h following 131I therapy, because before • Contamination may occur at home . that time it will just increase damage The most common cause of such owing to a higher blood flow [4, 6] . contamination is radioactive urine . Sitting • Hypothyroidism will already be present while urinating and washing of hands owing to the thyroidectomy . The are important to prevent contamination . radioiodine therapy may exacerbate the Another possibility is contamination with hypothyroidism a little . Levothyroxine radioactive saliva . Tableware must not be should be initiated a few days after shared before being cleaned (extra care radioiodine administration . must be taken when feeding children) and no kissing is permissible for a few days . Absolute contra-indications [4] to therapy • The patient may need to take time off are pregnancy and breastfeeding . work/school for a period of a duration in accordance with the activity of radioiodine • In female patients of childbearing received and the nature of his or her work potential, a routine pregnancy test should [2, 3] . be performed within 72 h before each • The patient should avoid prolonged close administration of 131I [4, 5] . contact with (small) children and pregnant • Breastfeeding should be stopped 6–8 women for a period in accordance with weeks before administration of 131I [4] . the activity of radioiodine received [2, 3] .

84 Chapter 7: Dose Optimisation for Radionuclide Therapy

• Usually the patient is advised to keep a 153Sm-EDTMP will have pain that limits nor- distance between themselves and (other) mal activities and/or is not easily controlled adults, and to keep contact times as short by regular analgesics . [7] . as possible for a limited amount of time, depending on the activity of radioiodine Samarium-153 EDTMP concentrates in osteo- received [2] . blastic lesions, with high tumour-to-normal • There may be restrictions on travel in bone tissue and tumour-to-soft tissue uptake accordance with the activity of radioiodine ratios . While the benefits of153 Sm-EDTMP are received [3] . evident after a single injection, treatment over a longer duration (weeks to months) is Post-therapy whole-body scintigraphy is possible . The treatment can be repeated at usually performed because of its high sen- an interval of at least 8 weeks, depending sitivity in localising and characterising the on the recovery of adequate bone marrow EANM extent of thyroid remnant and tumour and in function . detecting previously occult lesions . Scintig- raphy should not be performed sooner than The skeleton-seeking nature of this radio- 72 h or later than 7 days after radioiodine ad- pharmaceutical results in immediate delivery ministration . Whenever available, SPECT or, of beta radiation to disease localisations . Be- preferably, SPECT/CT should be performed cause of the relatively long range of the beta at the same time [4] . By providing a three-di- particles emitted by 153Sm, the main dose-lim- mensional image of involved lymph nodes, iting factor in this treatment method is the the SPECT study is an excellent way of vi- toxicity to bone marrow cells . This toxicity sualising lymph node lesions, whilst the CT restricts the maximum dose that can be used component adds morphological information for the palliative treatment of painful skeletal to the functional data furnished by SPECT metastases and precludes more extensive alone [4, 5] . use of 153Sm-EDTMP in clinical settings .

Samarium-153 therapy Calculation of dose Samarium-153 (153Sm) EDTMP is a radiophar- Patients are given a standard “fixed” dose: 37 maceutical that is effective in the treatment MBq/kilogram body weight [7, 8] . of painful metastatic disease of the skeletal system . The highest prevalence of such bone Patient preparation metastases occurs in prostate and breast Before the therapy is administered, some pre- carcinoma patients, in whom pain relief is cautions need to be taken . It must be ensured the most important criterion for improve- that kidney function is normal (owing to the ment in quality of life . Patients considered for excretion in urine) . Adequacy of bone mar-

85 Figure 6: Dose of 3700 MBq Figure 7: Dose of 7400 MBq

86 Chapter 7: Dose Optimisation for Radionuclide Therapy

row reserve must be checked within 7 days • Patients should be informed of the prior to the proposed treatment, and positive duration of the analgesic effect, generally bone scintigraphy must be obtained no more 2–6 months, and that retreatment is than 4 weeks before initiation of treatment [7] . possible [7] . There are conflicting data as to whether bis- • It should be checked that the patient phosphonates inhibit the uptake of radiola- understands that 153Sm-EDTMP is a belled phosphonates in bone metastases [7] . palliative treatment especially designed for treating bone pain and that it is unlikely to Patients to be treated with 153Sm are in- cure metastatic cancer [7] . formed of the radioactivity to be administered, the type of radiation involved and the The contra-indications are bone marrow effect of the radiation (beta-radiation) on the suppression (low blood cell count) (relative), bone marrow . Retreatment is possible [7] . pregnancy and breastfeeding (both abso- EANM lute) [7] . The nuclear medicine physician must speak to the patient about the common side ef- Special recommendations and radiation pro- fects of treatment and provide other relevant tection information must be discussed orally information . and, in addition, presented on paper prior to commencement of therapy [7] . • Bone marrow suppression can be caused by this therapy . It is important that the Keeping the principles of beta and gamma patient’s blood count is monitored for 6 radiation in mind, the following measures are weeks following the injection . necessary: • Between 60% and 80% of patients benefit from 153Sm-EDTNP therapy [7] . • Patients must be advised to reduce unnec- • Patients should be warned of the risk of essary radiation exposure to family mem- a temporary increase in bone pain (pain bers and the public [7] . They must be told: flair), usually within 72 h [7] . • To avoid prolonged close contact with • Pain reduction is unlikely within the first (small) children and pregnant women for week; it is more probable in the second a period in accordance with the activity week and may occur as late as 4 weeks received . after injection . Patients should continue • To keep a distance between themselves to take prescribed analgesics until bone and (other) adults for a period in pain decreases and should receive advice accordance with the activity received . regarding subsequent analgesic dose reduction where appropriate [7] .

87 • Patients must be informed that radioactive The difference is that223 Ra is an alpha-emit- urine is the most common source of ting nuclide [9], while 153Sm is a beta-emit- contamination and that rigorous hygiene ting nuclide . The radiation characteristics of must be observed in order to avoid alpha particle-emitting radionuclides seems contaminating groups at risk using the more favourable than those of beta-particle same toilet facility . Sitting while urinating emitters . The former are able to irradiate in a and washing of hands are urgent matters . smaller target volume (such as skeletal me- Patients should be warned to avoid tastases) (Fig . 8) and there is less exposure soiling underclothing or areas around of surrounding normal tissues, i .e . less bone toilet bowls for 1 week post-injection marrow toxicity is to be expected [9] . and that significantly soiled clothing should be washed separately . A double flush is recommended after urination . If their hands are contaminated with urine, patients should wash them abundantly with cold water, without scrubbing . Special precautions (catheterisation before and until 24 h after treatment [7]) have to be taken when a patient has unmanageable urinary incontinence . • Patients must be advised, when necessary, that pregnancy should be avoided for at least 6 months after therapy [7] . 223 • Patients should be appropriately hydrated Figure 8: Mechanism of action of Ra [9] before and after therapy [7] . • Patients must be told that there may be In a phase 3 trial of Alpharadin in symptom- restrictions on travel, depending on the atic prostate cancer patients (ALSYMPCA), activity of radioiodine received . there was a 30% reduction in the risk of death among patients receiving 223Ra treatment Radium-223 compared with those receiving placebo . Me- Radium-223 (223Ra) is used for radionuclide dian overall survival was 14 .9 months with therapy primarily in patients with prostate or 223Ra and 11 .3 months with placebo [9] . In breast cancer and painful bone metastases [9] . that study a treatment cycle comprised one injection every 4 weeks, and a completed The skeleton-seeking property of 223Ra is sim- course consisted of six cycles [9] . Control of ilar to that of other radionuclides, like 153Sm . blood samples is always necessary before the

88 Chapter 7: Dose Optimisation for Radionuclide Therapy

• Bone marrow suppression can be caused next treatment to confirm absence of bone by this therapy . It is important that the marrow toxicity . patient’s blood count is monitored following the injection . The skeleton-seeking nature of this pharmaceutical results in immediate delivery of Bone marrow suppression is an absolute alpha radiation to the disease localisations . contra-indication . Because of the relatively short gestation of the alpha particles of these radionuclides, Special recommendations and radiation pro- bone marrow toxicity is less likely . tection information, applicable with or without hospitalisation, must be orally discussed In the aforementioned study, 223Ra had a ben- and, in addition, presented on paper prior to eficial effect in delaying pain and preserving commencement of therapy . health-related quality of life [9] . EANM Keeping the principles of alpha and gamma Calculation of dose radiation treatment in mind, the patient is The dose is calculated in a standard way: 50 advised: kBq/kilogram body weight . • Because alpha radiation travels only a Patient preparation short distance, there are no restrictions on Before the therapy is administered some contact with children, pregnant women or precautions are taken . It is checked that hae- other adults . matological, liver and kidney functions are • The most common route of contamination normal/adequate and a positive bone scin- is via radioactive faeces or urine . Sitting tigraphy is obtained, revealing at least two while urinating and washing of hands are visible metastases . urgent matters .

When a patient is treated with 223Ra, the pa- Special precautions must be taken when a tient is informed of the radioactivity to be patient has unmanageable urinary inconti- administered, the type of radiation involved nence . and the effect of the radiation (alpha radiation) on the bone marrow . The facility and personnel The facility requirements will depend on na- The nuclear medicine physician must speak tional legislation on the therapeutic use of to the patient about the common side ef- radioactive agents [2, 7] . They may vary by fects of treatment: country and by radionuclide, also depending on the dose .

89 When inpatient therapy is required, this in unsealed source therapy must also be should take place in an approved environ- knowledgeable about and comply with all ment with appropriately shielded rooms . The applicable national and local legislation and rooms must have separate washing and toi- regulations . let facilities and the patient must be under continuous surveillance by the staff [5, 7] . External and, more importantly, internal con- taminations need to be prevented; avoid- The administration of 131I for the treatment of ance of internal contamination is especially thyroid carcinoma is typically performed un- important with 131I . Internal contamination, der hospitalisation (inpatient) and patients usually caused by accidental ingestion of a are discharged in accordance with national radionuclide, results in a higher dose to the radioprotection regulations [5] . personnel involved and is more difficult to eliminate than external contamination . The The administration of all radionuclide thera- use of gloves when handling radioactivity is pies should be undertaken by appropriately very important . trained medical staff with supporting nursing staff, when inpatient therapy is required, and It is recommended to check personnel who an available medical physics expert . All of the have contact with patients treated with 131I clinical staff must know and respect the ra- (physicians, technologists, nursing staff), for diation protection measures relating to staff the possibility of internal contamination . protection, handling of radiopharmaceuticals The check can be performed periodically or and patient safety . Lead shielding, lead dis- at random . A check 24 hours after assisting posal bins and lead transport holders are pro- therapy may result in a bigger chance of de- vided to weaken the strength of the radiation . tection of an internal contamination . It is the Staff must be aware of procedures for responsibility of the health care professional waste handling and disposal, handling of to perform the appropriate checks, but na- incidental contamination, and monitoring tional regulations regularly demand checks of personnel for accidental contamina- twice a year, with supporting documenta- tion and control or limitation of its spread . tion . Physicians responsible for treating patients should have a general knowledge of the In many countries, therapies with 223Ra, 153Sm pathophysiology and natural history of rele- and low-dose radioiodine are performed in vant diseases, should be familiar with alterna- an outpatient setting . tive forms of therapy and should be able to liaise closely with other physicians involved In patients presenting with unmanageable in patient management . Clinicians involved urinary incontinence, inpatient treatment (if

90 Chapter 7: Dose Optimisation for Radionuclide Therapy

not regular standard of care) may be con- icine technologist plays a major role in the sidered, in accordance with the national diagnostic imaging and treatment of a pa- legislations . This should be discussed before tient with thyroid disease; in particular, the commencement of treatment . An indwelling technologist is responsible for performance catheter is recommended before therapy is of scintigraphy and dose calculations, there- given . by enabling the nuclear medicine physician to make optimal treatment decisions . Radioiodine is preferentially administered With 153Sm and 223Ra therapies, a “fixed dose” orally (capsule), but can be administered in is used, and the patient also needs to be in- liquid form or intravenously in patients in formed of the need for prevention of con- whom vomiting is a problem . The liquid form tamination . Certainly in the case of 223Ra has the advantages that it is less expensive therapy, the technologist plays an important and can be stored and easily dispensed as role in patient care given that patients attend EANM needed, but the risk of spoiling and contam- regularly for their treatment . ination is higher [2] .

Samarium-153 and 223Ra are administered intravenously [7, 8] . Approval for the clinical use of radiopharmaceuticals may vary between countries . The choice of the radiopharmaceutical is based on the physical characteristics of the radionuclide in relation to the extent of metastatic disease, the bone marrow reserve and the availability of the radiopharmaceutical in individual countries [7] .

Conclusion It is very important to administer the recommended dose for both diagnostic and therapeutic purposes . Thyroid disease is highly treatable with 131I, provided that precautions are maintained and radiation protection of the personnel involved is clearly understood . The patient needs to be informed of the need for prevention of contamination to other family members . The nuclear med-

91 Chapter 7: Dose Optimisation for Radionuclide Therapy

References

1 .Piciu D . Section II . 2 . Radionuclide therapy in benign thyroid disease . In: Peștean C, Veloso Jéronimo V, Hogg P . Radionuclide metabolic therapy . Clinical aspects, dosimetry and imaging . A technologist’s guide . European Association of Nuclear Medicine; 2013:77–80 .

2 . Stokkel M, Handkiewicz Juank D, Lassmann M, Dietlein M, Luster M . EANM procedure guidelines for therapy of benign thyroid disease . Eur J Nucl Med Mol Imaging 2010;37:2218–2228 .

3 . Royal College of Physicians London . Radioiodine in the management of benign thyroid disease; clinical guidelines . 2007 .

4 . Luster M, Clarke SE, Dietlein M, Lassman M, Lind P, Oyen WJG, et al . Guidelines for radioiodine therapy of differ- entiated thyroid cancer . Eur J Nucl Med Mol Imaging 2008;35:1941–1959 .

5 . Piciu D . Section II, 1 . Radionuclide therapy in thyroid carcinoma . In: Peștean C, Veloso Jéronimo V, Hogg P . Radionu- clide metabolic therapy . Clinical aspects, dosimetry and imaging . A technologist’s guide . European Association of Nuclear Medicine; 2013:61–76 .

6 . Nakada K, Ishibashi T, Takei T, Hirata K, Shinohara K, Katoh S, et al . Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer . J Nucl Med 2005;46:261–266 .

7 . Bodei L, Lam M, Chiesa C, Flux G, Brans B, Chiti A . EANM procedure guideline for treatment of refractory metastatic bone pain . Eur J Nucl Med Mol Imaging 2008;35:1934– 1940 .

8 . Mantel ES, Williams J . Section I, 1 . Principles in radionuclide therapy . In: Peștean C, Veloso Jéronimo V, Hogg P . Radionuclide metabolic therapy . Clinical aspects, dosimetry and imaging . A technologist’s guide . European Association of Nuclear Medicine; 2013:9–17 .

9 . Shore ND . Radium-223 dichloride for metastatic castra- tion-resistant prostate cancer: The urologist’s perspective . Urology 2015;85:717–724 .

92 timate is a statistical entity derivedfromtimate isastatisticalentity the es- inmindthatarisk isalsoto beborne It ofchildrenity istheirlongerlife expectancy in tributes explaining the higher radiosensitiv - thatcon- cancer [ICRP103].Anadditionalfact tissue andtheassociated incidenceofbreast owing of breast to the higher radiosensitivity 50%increase inrelative posed to afurther risk compared withmales,the risk: females are ex also influences with an adult [1, 2] . Gender times higherfor a10-year-old childcompared 3 timeshigherfor a1-year-old childand1.8 radiationexposure id tumourafter isabout ofdeveloping a sol- assessment,therisk of risk sensitive than adults than adolescentsandthatthelatter are more much more sensitive to radiation damage growing cells;thisimpliesthatchildren are younger thechild, thelarger thenumberof and thegastrointestinal epithelium). tract The to radiation damageare thebonemarrow is why inadults thetissuesmore susceptible mutagenic effect ofionisingradiation(which renewing tissuesare more sensitive to the until roughly theageof 18 years that thehumanbodygrows andmatures up thisgrouptween andadultsisjustified, given per agelimit. inmedicinebe The distinction with legaldifferences with to theup respect inaccordance countries between varying those aged0–18years, theprecise definition neous patientgroup broadly encompassing inhomoge populationisavery The paediatric ofdoseoptimisation importance Paediatric population andthe Ana IsabelSantos Palma andDiegoDe Chapter 8:Paediatric Optimisation Dose .Usingthecurrent system . Growing or . - - - - 93 ing atoilet-trained generously childto drink organcritical for calculatingtheED excretion; thismeansthatthebladderis undergo renal primarily pharmaceuticals renal . Radio function) normal/abnormal or roughly dividedinto (e categories two renal are function, considered asconstant of voiding, bowel status, hydration, and inthebody,pharmaceutical e fluencing the residence timeoftheradio administered activity theamountofadmits astheonlyvariable fixed reference ages),butthecalculation the child(for reasons, practical rounded at value is modified according to the age of oftheradiopharmaceutical tivity pressed asmSv/MBq ofadministered ac- as theeffective dose(ED),isgenerallyex associated withaprocedure, measured nuclearmedicine, theradiationburdenIn it burdenRadiation andways to minimise benefit . a diagnostic procedure againsttheexpected ofexposurepotential impact associated with are required in children when balancing the cancer [5,6],theutmostattention andcare and increased ofthyroid risk of iodine-131 nite thediagnostic association between use miological studyhasto date found adefi- fallout [4] .Although, for example, no epide atthetimeofChernobyl and Ukraine [1,3]orpeoplelivinginBelarus survivors atomiculations suchastheJapanese bomb data available for muchlarger exposedpop All other factors in- . All other factors .g .frequency . The given . Teach- .g - - - - - .

EANM Chapter 8: Paediatric Dose Optimisation

and to void the bladder at fixed intervals is a in order to avoid an excessively long scan safe and simple way to reduce the radiation time . Another problem encountered at that burden . Similarly, administration of small time was the variability in adult reference amounts of furosemide in a toddler helps, activities, which was later partially overcome as does frequent changing of diapers . by the publication as law in many EC countries of the Diagnostic Reference Levels . In With the increased use of hybrid cameras, 2005 an important paper [12] was published, concern over the additive radiation burden aimed at defining a scaling system based on and risks of CT [7, 8] is increasing . When keeping the ED stable across the different performing hybrid procedures involving ages . The authors found that radiopharma- CT, such as SPECT/CT and PET/CT, the im- ceuticals can be grouped into three classes, portance of dose optimisation must not be each with a different set of scaling factors . neglected, and it has to be obtained mainly This led to the publication of a new version of with the use of standardisation of low-dose the EANM dosage card [13], and for the first protocols [2, 9, 10] . time an online dosage calculator was made available via the EANM website . The EANM dosage card Considering that in nuclear medicine, the This version of the EANM dosage card re- ED received after the administration of a ra- ceived some criticism, mainly focussed on diopharmaceutical depends on the admin- the “minimum activity to be administered” istered activity, there is a definite need to concept [14–17] . A footnote was then added standardise and minimise the latter . The first admitting that experienced teams can use version of the EANM dosage card was pre- activities lower than those recommended, pared and published in 1990 by members of but asserting that the overall value of the the EANM Paediatric Committee [11] . At that card as a general reference remained intact time, the main purpose was to help in har- [18] . After this publication, a joint EANM–SN- monising administered activities across Eu- MMI group started a process aimed at har- rope; this card, substantially an “expert con- monising recommendations between the sensus paper”, used the child’s weight as the two societies [19, 20] . The last update in this reference for scaling down activities . It has to respect was published in 2014 [21, 22] and a be noted that the value was calculated us- further new version of the EANM paediatric ing body surface; the authors thereafter gave dosage card is now available, both as an on- weight as the reference because it is easier line calculator and as an App for Android/IOS to obtain and, in children, displays a direct devices [http://www .eanm .org/publications/ relationship with body surface . A minimum dosage_calculator .php?navId=285] . was also set for each radiopharmaceutical,

94 Chapter 8: Paediatric Dose Optimisation

Image quality and dose optimisation tectors [24, 25], may also impact positively on The desire to keep administered activities paediatric nuclear medicine, allowing better as low as possible (the ALARA principle) will image quality with lower administered ac- probably find new allies in improvements in tivities . Among software improvements, the hardware and software, since a better sensi- most important include enhanced planar tivity and an improved signal-to-noise ratio processing [26, 27] and iterative reconstruc- have to be pursued . The availability of PET tion with resolution recovery [28, 29] . Simple scanners with a larger axial field of view and measures such as acquisition of renal studies a smaller ring diameter will be of benefit, with technetium-99m dimercaptosuccinic and simultaneous acquisition PET/MR hybrid acid (99mTc-DMSA) in dynamic mode, for fur- systems will allow longer PET acquisition ther movement correction and reframing times [23] . Considering conventional nuclear into a single image, can also help in obtain- medicine, the advances in instrumentation ing diagnostic quality images with low ad- EANM for cardiac imaging, such as cameras with ministered activities [30] . cadmium-zinc-telluride (CZT) solid-state de-

Figure 1A–C: A set of three 99mTc-DMSA images, obtained from a dynamic scan of 40 images, 15 s each . A) Image obtained from the sum of the first 20 images, for a total acquisition time of 300 s . B) Image obtained from the sum of the first 30 images (450 s) . C) Image obtained from the sum of all 40 images (600 s) . The images show no difference in quality after both qualitative and semi-quantitative (cortex/medullary ratio and noise index, i .e . the ratio between the standard deviation and the mean counts per pixel in the kidney region of interest) assessment

95 Best practice principles While the need to estimate risk related to • Compliance with the justification process: the radiation burden must always be kept in only studies capable of yielding results that mind, this risk must not be allowed to over- may change the clinical management of shadow those risks associated with ionising the child should be performed, especially radiation-free procedures when, like MRI, when dealing with benign diseases; they require sedation, general anaesthesia or • Use of (basically) the activities calculated the use of contrast media . according the EANM paediatric dosage card; • Use of rational systems to expedite Another clinical risk that must be weighed elimination of the radiopharmaceutical via against the risk associated with radiation urine or stools; exposure is the danger of missing some • Careful evaluation of the impact of modern clinically relevant information because of or new hardware/software technologies . either (a) poor quality radionuclide imaging For example, compared with PET/CT, PET/ on account of a low count density or move- MRI requires a longer acquisition time per ment artefacts due to an excessively long ac- bed position, due to the MRI sequences . quisition time or (b) failure to perform what As PET image quality represents a product would have been a useful scan . of acquisition time and radiotracer activity, the implication is that radiation exposure Take-home messages may be reduced by lowering the injected The process of dose optimisation and re- radiotracer activity . duction in paediatric nuclear medicine is a comprehensive one, with different and con- current approaches [10, 23] .

A practical approach to dose reduction entails:

96 Chapter 8: Paediatric Dose Optimisation

References

1 . Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi 12 . Jacobs F, Thierens H, Piepsz A, Bacher K, Wiele CV de, K . Studies of the mortality of atomic bomb survi- Ham H, et al . Optimised tracer-dependent dosage cards vors . Report 12, Part I . Cancer: 1950-1990 . Radiat Res to obtain weight-independent effective doses . Eur J 1996;146:1–27 . Nucl Med Mol Imaging 2005;32:581–588 .

2 . Gelfand MJ . Dose reduction in pediatric hybrid and pla- 13 . Lassmann M, Biassoni L, Monsieurs M, Franzius C, Jacobs nar imaging . Q J Nucl Med Mol Imaging 2010;54:379– F, for the EANM Dosimetry and Paediatrics Committees . 388 . The new EANM paediatric dosage card . Eur J Nucl Med Mol Imaging 2007;34:796–798 . 3 . Ozasa K, Shimizu Y, Suyama A, Kasagi F, Soda M, Grant EJ, et al . Studies of the mortality of atomic bomb survivors, 14 . Warbey VS, Schleyer PJ, Barrington SF, O’Doherty MJ . Report 14, 1950-2003: an overview of cancer and non- The new EANM paediatric dosage card — does it con- cancer diseases . Radiat Res 2012;177:229–243 . form to ALARA for PET/CT? Eur J Nucl Med Mol Imaging 2007;34:1881–1882 .

4 . Fushiki S . Radiation hazards in children – lessons from EANM Chernobyl, Three Mile Island and Fukushima . Brain Dev 15 . Holm S, Borgwardt L, Loft A, Graff J, Law I, Højgaard 2013;35:220–227 . L . Paediatric doses — a critical appraisal of the EANM paediatric dosage card . Eur J Nucl Med Mol Imaging 5 . Dickman PW, Holm L-E, Lundell G, Boice JD, Hall P . Thy- 2007;34:1713–1718 . roid cancer risk after thyroid examination with 131I: a population-based cohort study in Sweden . Int J Cancer 16 . Lassmann M, Biassoni L, Monsieurs M, Franzius C, EANM 2003;106:580–587 . Dosimetry and Paediatrics Committees . The new EANM paediatric dosage card: additional notes with respect to 6 . Hahn K, Schnell-Inderst P, Grosche B, Holm LE . Thyroid F-18 . Eur J Nucl Med Mol Imaging 2008;35:1666–1668 . cancer after diagnostic administration of iodine-131 in childhood . Radiat Res 2001;156:61–70 . 17 . Lassmann M, Biassoni L, Monsieurs M, Franzius C . The new EANM paediatric dosage card: additional notes 7 . Sodickson A . CT radiation risks coming into clearer fo- with respect to F-18 . Eur J Nucl Med Mol Imaging cus . BMJ 2013;346:f3102 . 2008;35:2141 .

8 . Mathews JD, Forsythe AV, Brady Z, Butler MW, Goergen 18 . Lassmann M, Biassoni L, Monsieurs M, Franzius C, Jacobs SK, Byrnes GB, et al . Cancer risk in 680,000 people ex- F . The new EANM paediatric dosage card . Eur J Nucl Med posed to computed tomography scans in childhood Mol Imaging 2009;36:1–2 . or adolescence: data linkage study of 11 million Aus- tralians . BMJ 2013;346:f2360 . 19 . Gelfand MJ, Parisi MT, Treves ST, Pediatric Nuclear Med- icine Dose Reduction Workgroup . Pediatric radiophar- 9 . Treves ST, Falone AE, Fahey FH . Pediatric nuclear medi- maceutical administered doses: 2010 North American cine and radiation dose . Semin Nucl Med 2014;44:202– consensus guidelines . J Nucl Med 2011;52:318–322 . 209 . 20 . Treves ST, Parisi MT, Gelfand MJ . Pediatric radio- 10 . Fahey FH, Treves ST, Adelstein SJ . Minimizing and com- pharmaceutical doses: new guidelines . Radiology municating radiation risk in pediatric nuclear medicine . 2011;261:347–349 . J Nucl Med 2011;52:1240–1251 . 21 . Treves ST, Lassmann M, for the EANM/SNMMI Pediatric 11 . Piepsz A, Hahn K, Roca I, Ciofetta G, Toth G, Gordon I, Dosage Harmonization Working Group . International et al . A radiopharmaceuticals schedule for imaging in Guidelines for Pediatric Radiopharmaceutical Admin- paediatrics . Eur J Nucl Med 1990;17:1–3 . istered Activities . J Nucl Med 2014;55:869–870 .

97 22 . Lassmann M, Treves ST, EANM/SNMMI Paediatric Dosage 27 . Fahey FH, Zukotynski K, Zurakowski D, Markelewicz R, Harmonization Working Group . Paediatric radiophar- Falone A, Vitello M, et al . Beyond current guidelines: maceutical administration: harmonization of the 2007 reduction in minimum administered radiopharmaceu- EANM paediatric dosage card (version 1 .5 .2008) and the tical activity with preserved diagnostic image quality in 2010 North American consensus guidelines . Eur J Nucl pediatric hepatobiliary scintigraphy . Eur J Nucl Med Mol Med Mol Imaging 2014;41:1036–1041 . Imaging 2014;41:2346–2353 .

23 . Fahey FH, Treves ST, Lassmann M . Dose optimization in 28 . Sheehy N, Tetrault TA, Zurakowski D, Vija AH, Fahey FH, pediatric nuclear medicine . Clin Transl Imaging [Online] Treves ST . Pediatric 99mTc-DMSA SPECT performed by 2016 . Available from: doi:10 .1007/s40336-015-0153-8 using iterative reconstruction with isotropic resolution recovery: improved image quality and reduced radio- 24 . Imbert L, Poussier S, Franken PR, Songy B, Verger A, Mo- pharmaceutical activity . Radiology 2009;251:511–516 . rel O, et al . Compared performance of high-sensitivity cameras dedicated to myocardial perfusion SPECT: a 29 . Stansfield EC, Sheehy N, Zurakowski D, Vija AH, Fahey comprehensive analysis of phantom and human im- FH, Treves ST . Pediatric 99mTc-MDP bone SPECT with ages . J Nucl Med 2012;53: 1897–1903 . ordered subset expectation maximization iterative reconstruction with isotropic 3D resolution recovery . 25 . Gunalp B . Role of cardiac ultrafast cameras with CZT Radiology 2010;257:793–801 . solid-state detectors and software developments on radiation absorbed dose reduction to the patients . Ra- 30 . Piepsz A, Colarinha P, Gordon I, Hahn K, Olivier P, Roca I, diat Prot Dosimetry 2015;165:461–463 . et al . Guidelines on 99mTc-DMSA scintigraphy in children . [Online] EANM . pp . 1–7 . Available from: http://www . 26 . Hsiao EM, Cao X, Zurakowski D, Zukotynski KA, Drubach eanm .org/publications/guidelines/gl_paed_dmsa_ LA, Grant FD, et al . Reduction in radiation dose in mer- scin .pdf [Accessed: 31 January 2016] captoacetyltriglycerine renography with enhanced planar processing . Radiology 2011;261:907–915 .

98 The lesstimeonespends standinginthefield Time radiation exposure Protection ofworkers against external the bestavailable protection method[1,2]. (sources), which is required for of selection ofradiationemitted fromtype theisotopes protection ofthe process isknowledge intheradiation aspect Another important personnel substancesin the depositionofradioactive withpreventingis concerned orminimising nuclide body iscontaminated witharadio internally radiationexposure occurswhenthe Internal optimisation ofthesefundamentaltechniques require radiationprotection4] .Good practices distance from thesource and(c) shielding [1– the timeofexposure, (b)maximisationofthe radiation hazard areexternal of (a) restriction The three basicmethodsusedto reduce the contamination. vent andexternal internal exposure aswellminimise external asto pre sources ods that can be usedto limitexposure to these standing ofradiationsources andofthemeth andunder ofthisprocessaspect isknowledge .Animportant inthedepartment everybody torestricted aminimum,thereby protecting sure thatthereceived radiationexposure is The maintaskofradiationprotection isto en Introduction Rep Sebastijan ProtectionChapter Radiation 9:Occupational . can be deployedThis to knowledge . Thus, radiationprotection internal . - - - - - . 99 in nuclearmedicine canbeassumedto be the source is within three times the largest dimension of can be regarded as a point source when one the square ofthedistance from apointradiationsource decreases by dose rate dose rate with distance is not linear: distance from the source doserate decreasesRadiation withincreasing Distance [5] . fashion asthedurationofexposure increases time) . The radiation dose increases in linear radiation doseandtime(dose =doserate × There isadirectlinearrelationship between • • • • • exposure timeare: the thatshorten Examples ofgoodpractice ofthesametasks repeated performance oferror thatwouldlikelihood necessitate the the taskswhilesimultaneouslyrestricting deed theminimumtimeneededto perform ensure exposure that the actual time is in- outside the range of radiation and practice athighspeed,Working proper preparation of radiation,thelower isthedosereceived environment Preparation ofequipmentinaclean amongmore ofwork Distribution staff durationofwork the actual remain withintheradiationfieldonly for to ensure thatpersonnel Restrictions rate Work Precise planningandorganisation ofwork . For this reason, almost all sources . The decrease in the .Aradiationsource . . EANM point sources . It is also important to note that It is important to know how to derive the for point sources in air the radiation spreads dose rate at a certain distance from a known uniformly to all sides [6] . dose rate at a different distance . In this case, a slightly modified equation is used for the When extrapolating from measurements at dependence of dose rate on distance [1–4]: longer distances, assuming a point-source ₂ ₂ distribution can lead to significant overesti- I₁ * D₁ = I₂ * D₂ mation of dose rates closer to the patient . A linear-source model with attenuation correction can be used to more accurately reflect where I1 is the intensity at the original dis- the activity distribution for some procedures . tance (D1) and I2 is the intensity at a new dis-

In a line-source model, the fall-off of the dose tance (D2) [5] . with distance depends on both the distance and the length of the source [1, 7] . In prac- Shielding tice, this implies that doubling the distance Although maximisation of distance from the in any direction will reduce to one-quarter source and limitation of the time of expo- the value of the exposure . sure are important measures for protection against external radiation, the shielding fac- Bearing in mind the above, maximisation of tor is also very important for reduction of distance from the radiation source is a sim- the dose rate in a nuclear medicine depart- ple and very effective method for reducing ment . In practice the shielding depends on radiation exposure to workers . The distance the type of work, the type of radiation, the between workers and the radioactive source total activity and the practice and workload can be maximised by using long-handled of each area in the department . In fact, all tools to keep radioactive materials well away departments are designed and built to in- from the body and by storing radioactive corporate barriers that take these factors into materials as far from workers as possible [8] . account .

The distance from the source of radiation is All sources used in nuclear medicine arrive increased if: in their own container (shield) and best practice warrants that all prepared activities • Pliers, tweezers and other adapted tools and sources are manipulated or transported are used . within this container, with additional protec- • Remotely operated tools are used . tion . The shielding normally varies between • Television surveillance is used . 3 and 6 mm of lead equivalent, according to • One communicates at distance . the energy and type of radiation . However,

100 Chapter 9: Occupational Radiation Protection

protection can in fact be provided by any of stray radiation from the thick shielding is material with a sufficient thickness . substantially higher than the attenuated radiation that comes directly from the source . Due to the scattering of gamma rays and the Therefore, the equations shown are only es- bremsstrahlung, the radiation shield is diffi- timates [10] . cult to calculate . For this reason, it is advis- able to consult a radiation protection officer A 0 .25-mm lead apron will provide a dose re- 99m [1–4] . The method of shielding depends on duction of 59% for TcO4 (140 keV) while a the type of radiation . Gamma radiation de- 0 .5-mm lead apron, weighing about 8 .5 kg, creases exponentially with the thickness of will provide a dose reduction of about 76% the shield and can be written as: [11, 12] . A lead apron is of little use at higher energies, examples being 131I (360 keV) and 1 18F (511 keV) . Thus a 0 .25-mm lead apron will EANM D = D x * 2n provide a calculated dose reduction of about 3% for 18F and 6% for 131I while a 0 .5-mm lead where n is the number of half-value layers apron will provide a calculated dose reduc- 18 131 (HVL): n = d/d1/2 . DX indicates the dose rate tion of about 6% for F and 11% for I [13] . without a shield and D, the dose rate with a shield (at the same distance from the source) Beta radiation contributes to external ex- [5] . posure in two ways: via the beta rays themselves, i .e . fast electrons (or positrons), and Values of HVL for photons with different en- via scattered radiation (bremsstrahlung) that ergies (keV) are shown in Table 1 . is the result of interaction of the electrons or positrons with matter . Beta particles are The same equation can be written using the relatively easy to stop, and therefore brems- tenth-value layer (TVL): strahlung is the major contributor to external exposure . The proportion of bremsstrahlung 1 radiation can be reduced by using a material D = D x * 10n with a low atomic number Z (polyethylene, acrylic glass) instead of a high Z material . where n is the number of tenth-value layers: Therefore, the internal shield is intended only n = d/d1/10 [5] . to stop beta particles and is enclosed by an outer sheath made of material with a high Z These formulas include only photons that (lead), which reduces the bremsstrahlung [1, pass through the shield and do not entail any 14] . interaction . It turns out that the contribution

101 Specific gamma-ray dose constant (Γ) of new entry, because of natural radioactive For every isotope it is possible to use the decay and because of biological elimination specific gamma-ray dose constant (Γ) to esti- from the body via the digestive tract, urinary mate an absorbed dose . The constants of the tract and exhalation . Options for artificially isotopes more commonly used in nuclear accelerated washout of radionuclides in the medicine are published in the literature . The body are very limited, so the main protective absorbed dose is directly proportional to the measure against internal exposure is preven- time of exposure and the activity at the point tion of entry of these materials into the body . of origin and inversely proportional to the Accordingly, protection begins with the square of the distance from the same point . prevention of contamination of the environ- It can be seen from Table 2 that for 1 MBq of ment in which people live and work . 18F at 1 m and for an exposure of 1 h, an absorbed dose of 0 .143 mSv is obtained . Unlike in external exposure, in an internal exposure the doses received cannot be directly Protection of workers against internal measured, but only calculated or estimated radiation exposure [15] . Internal contamination is the presence of radioactive material inside the human body Protection against internal exposure is based and results from the ingestion or inhalation on the following principles: of radioactive material (radionuclides) . The more common ways for radionuclides to en- • Limitation of open sources: radiation ter the body are: sources and processes that can cause radioactive contamination of surface or • With food and drink (ingestion) air should be limited to a reasonably small • By breathing (inhalation) number of specific areas . • Through the skin (absorption) • Through open wounds (absorption) • Monitoring of areas with radiation sources: Premises on which there is The received dose can depend on the mode radiation activity should be appropriately of entry into the body . In contrast to exter- designed architecturally . Surfaces should nal exposure, alpha and beta emitters are the be made of materials that allow efficient most dangerous sources of internal exposure decontamination, and special care must [1, 10] . be taken to ensure controlled drainage and good ventilation with air filtration . The concentration of radionuclides in the Work with open sources involving a body decreases over time, in the absence possibility of contamination is carried

102 Chapter 9: Occupational Radiation Protection

out within a controlled area to which throughout the body . No substance, radioac- access is physically restricted . Only tive or not, remains in the body indefinitely . workers who meet certain conditions Normal biological processes remove all sub- (regarding personal protective equipment, stances from the organism; their concentra- training, etc .) are allowed to work in tion decreases approximately exponentially . this area, and at the exit there must be On the basis of the biological and radioactive suitable equipment for measurement of half-time, the effective half-time can be cal- personal contamination and, if needed, culated . The equation for calculating the ef- decontamination . fective half-life is: • Protection of workers: Eating, drinking T T and smoking must be strictly forbidden in F * B TEF = areas where open sources are present . T + T F B EANM • Protection of workers: Workers must

always wear personal protective where TEF is the effective half-life;T F is the

equipment when manipulating sources . half-time of the isotope and TB is the biologi- This is intended to prevent contamination cal half-life [1, 5] . of the skin (through the wearing of protective clothing) and to limit the intake Personnel monitoring for external and of radioactive substances by inhalation internal radiation exposure (through use of respiratory equipment) [10, 15] . The best way to estimate the total dose to which a person has been exposed is by means of personal dosimetry . In the case of Effective half-life nuclear medicine both whole-body dosim- Different tissues and organs in the human etry and extremity dosimetry are advised . body display differing susceptibility to a va- External radiation exposure is measured by riety of radioactive isotopes . It is known that personnel monitoring devices . iodine accumulates in the thyroid, calcium in the bones, etc . Some other elements are Three main types of monitoring device are in evenly distributed throughout the body . use today: film badges, thermoluminescent dosimeters (TLD) and optically stimulated Also, radioactive isotopes of each element luminescent (OSL) dosimeters . If the body is accumulate in specific target organs after exposed more or less equally, the dosimeter entering the body . Thus, 90Sr and 223Ra ac- should be worn on the trunk of the body . cumulate in the bones and 131I in the thy- This will allow the dose to internal organs to roid while 60Co and 137Cs are distributed be estimated .

103 When wearing a protective lead apron, the be controlled by using a whole-body count- dosimeter should be worn inside the lead er [1] . apron . Ring badges or wrist badges must be worn when amounts of radioactive material Acknowledgements . The editor would like to on the hands may be high . Ring badges must thank the medical physicist Rui Parafita for his be worn on the inside of gloves to avoid con- valuable support in reviewing this chapter . tamination . Internal contamination may also

HVL d½ cm

Photon energy (keV) Lead H2O 25 0 .002 1 .5 50 0 .008 3 .2 100 0 .01 4 .1 250 0 .08 5 .5 500 0 .40 7 .1

Table 1: Values of HVL for photons of different energies (keV) and two materials (as examples) [9]

104 Chapter 9: Occupational Radiation Protection

Radionuclide Physical half-life mSv m2/MBq h

64Cu 0 .529 days 0 .0324 67Cu 2 .578 days 0 .0157 18F 109 .8 min 0 .143 67Ga 3 .261 days 0 .0204 68Ga 68 .3 min 0 .134 123I 0 .55 days 0 .0435 124I 4 .2 days 0 .185 EANM 125I 14 days 0 .0384 131I 8 .04 days 0 .0595 111In 2 .83 days 0 .0868 13N 9 .96 min 0 .148 15O 2 .04 min 0 .148 82Rb 76 s 0 .159 99mTc 0 .251 days 0 .0204 201Tl 3 .044 days 0 .0121

Table 2: Physical half-lives and gamma constants for various radionuclides [5, 6]

105 References

1 . Mattsson S, Hoeschen C, eds . Radiation protection in 9 . Markovic S, Spajic R . Radiacija i zdravje . Drustvo za bio- nuclear medicine . Berlin Heidelberg New York: Springer; medicinsko inzenirstvo i medicinsko fiziko . Beograd 2013:109–128 . 2001 .

2 . Le Heron J, Padovani R, Smith I, Czarwinski R . Radiation 10 . Khalil MM, ed . Basic sciences of nuclear medicine . Berlin protection of medical staff . Eur J Radiol 2010;76:20–23 . Heidelberg New York: Springer; 2011:15–17 .

3 . Woodings S . Radiation protection recommendation 11 . Warren-Forward H, Cardew P, Clack L, McWhirter K, for I-131 thyrotoxicis, thyroid cancer and phaeo- Johnson S, Wessel K . A comparison of dose savings of chromocytoma patients . Australas Phys Eng Sci Med lead and lightweight aprons for shielding of 99m-tech- 2004;27:118–128 . netium radiation . Radiat Prot Dosim 2007;124:89–96 .

4 . Markelewicz RJ Jr, Lorenzen WA, Shusterman S, Grant FD, 12 . Ahmed S, Zimmer A, McDonald N, Spies S . The effec- Fahey FH, Treves ST . Radiation exposure to family care- tiveness of lead aprons in reducing radiation exposures givers and nurses of pediatric neuroblastoma patients from specific radionuclides . J Nucl Med 2007;48:470 . receiving 131I-metaiodobenzylguanidine (131I-MIBG) therapy . Clin Nucl Med 2013;38:604–607 . 13 . Saha GB . Physics and radiobiology of nuclear medicine . 3rd ed . Berlin Heidelberg New York: Springer; 5 . Wells P, ed . Practical mathematics in nuclear medicine 2006:56–70 . technology . Society of Nuclear Medicine; 1999:93–113 . 14 . Office of Federal and State Materials and Environmen- 6 . Syeda NA . Physics and engineering of radiation detec- tal Management Programs, US Nuclear Regulatory tion . Amsterdam: Elsevier; 2007:65–7 . Commission . Consolidated guidance about materials licenses: program-specific guidance about medical use 7 . Siegel JA, Marcus CS, Sparks RB . Calculating the ab- licenses . NUREG-1556 . 2008; vol 9, Rev . 2 sorbed dose from radioactive patients: the line-source versus point-source model . J Nucl Med 2002;43:1241– 15 . Turpin BK, Morris VR, Lemen L, Weiss BD, Gelfand MJ . 1244 . Minimizing nuclear medicine technologist radiation exposure during 131I-MIBG therapy . Health Phys 2013;104 8 . Radiation Safety Manual Radioisotopes . Available at: (2 Suppl 1):S43–S46 . http://www2 bakersfieldcollege. .edu/erp/Radiation/ chp6 .htm (5 6. .2016) .

106 The requirements of a new department will The requirements department ofanew department Requirements ofanuclearmedicine gist inthedesign process design andoutlinestherole ofthetechnolo provides astep-by-step guideto department dressed when designing department, a new theissuesthatneedto bead- summarises rates shielding andoccupancy focus onradiation withaparticular services, on minimum room size, shielding and other medical physicist andradiationsafety expert is mandatory, withadviceneededfrom the are required assist withcomplianceifchangesinprocess ing thecurrent workflows andprotocols will development . Engaging the staff in - review remembering to allow for future growth and numberofpatientsandbookings, expected thiswillenableyou to estimate the or PET); vice to be offered (nuclearmedicineand/ consulted totypes ofser better definethe stakeholders, includingreferrers, shouldbe holders, and external bothinternal engagement withalltherelevant stake project . The design process mustensure plan, whichcanbemodifiedthroughout the offered isthefirst developingstep in adesign ofservice andthetypes of thedepartment staff andpatients vironment thatissafe andefficient forboth design andlayout willcreate correct anen- suming andcomplex;however, gettingthe istimecon- department Designing anew Introduction Elizabeth Bailey Design Department Chapter 10:NuclearMedicine .Compliance withregulations .Outliningtheoperations . . This chapter External .External - - - 107 covering allspecialtiesand a24-houremer extensive outpatientclinics cer care services, surgical procedures, andinterventional can- hospitalproviding university acute services, be considered adequate diology andotherstandard features would six people, area ashared withra- reporting with awaitingroom to house upto five or a smallhotlab, oneoffice, asmall reception a .mto 5p operate to Monday Friday businesshours(8 occasional urgent acute procedure andto to provide routine non-urgent studiesandan thatyou willberequiredment, thenitislikely hospital adjacentto asmallradiologydepart in a small rural (non-metropolitan)practice are settingupasmall singlegammacamera the equipment needs to be provided and thereforethe services whichshouldhelpto identify department, orto definethegoalsofnew partment) (ifupdatinganexistingde current practice to your review offers anidealopportunity tients whowillusetheservice clinical areas withinthehospitalandpa- executive, referrers, and otherdepartments holders, includingtheinstitution(hospital) the process isto engageyour invested stake therapy cilities andwhetheritwilloffer radionuclide it willhave cardiac exercise stress testing fa- whether oraPET/MRI, aPET/CT a SPECT/CT, willhave asinglegammacamera, partment significantly according to whetherthede ing offered be andservices depend onthefunctionality . Therefore oneofthefirststeps in .m) Therefore, asingleSPECT/CT, . The design willvary andfloorplan .For example, ifyou .However, alarge . This process ------EANM Chapter 10: Nuclear Medicine Department Design

gency department will likely have three or Issues to consider when designing a more SPECT/CT systems, at least one or two nuclear medicine department PET/CT scanners, cardiac stress testing facil- When designing a nuclear medicine depart- ities, lead-lined inpatient rooms for radionu- ment, there are several factors and issues that clide therapies and all the standard features should be considered . The project plan and needed to provide a comprehensive service . development working group should include Knowing this information prior to designing representation from each of the profession- the layout and workflow of the department al groups within the department, including will ensure that the new nuclear medicine nuclear medicine physicians, radiologists, department will meet the expectations and nuclear medicine technologists, medical needs of patients and referrers . physicists, radiopharmacists and nursing and administrative staff . This will ensure that the Regulations and minimum standards at a lo- department meets the needs of the patients, cal, state and national level can vary between referrers and other important stakeholders countries . During the design process, consid- while creating an efficient and safe work en- eration must also be given to international vironment for the employees . standards regulating radiation protection, shielding and waste storage, hot laborato- Be aware of the other departments and clin- ry minimum specifications, gamma camera/ ical areas surrounding the new floorplan, SPECT/PET room layout and size and man- especially paediatrics, ultrasound waiting datory facility services based on department rooms and maternity clinics, as this will im- size and occupancy rate [1–5] . It is important pact on shielding requirements . Areas to be to consult infection control and occupational considered include not only those that are safety guidelines as these will provide informa- immediately adjacent to the department but tion on the number and location of patient/ also those above and below it . All attempts staff toilets and hand-wash basins, dirty utility should be made to ensure that hot areas are rooms, waiting rooms, medical services includ- not adjacent to high-risk areas; for example, ing oxygen, suction, nurse call buttons, cardiac the PET hot lab should not share a common arrest/emergency alarm and closed circuit tele- wall with the maternity clinic . vision (CCTV) monitoring . These must be taken into consideration when defining the layout It is common practice in most nuclear med- and will impact on the space available for hot icine departments to install lead-lined glass laboratories, uptake rooms for PET, changing in gamma camera control rooms so as to be rooms, cardiac stress testing facilities and con- able to observe the patient during the nu- sultation rooms, possibly affecting the number clear medicine test . This is still recommend- of services that can be performed . ed for the nuclear medicine gamma camera

108 Chapter 10: Nuclear Medicine Department Design

area; however, CCTV monitoring is preferred Consideration should also be given to the for the PET unit as the thickness of lead glass location of radiation-sensitive equipment needed to provide adequate shielding has such as gamma counters, dose calibrators a high refractory index, making it very diffi- and area monitors . If the background radi- cult to clearly and safely observe the patient . ation level is too high, the measurements It is also very costly to install . Consideration will be erroneous and therefore impact on should also be given to the use of CCTV clinical results . If this is unavoidable, then monitoring in the hot patient waiting ar- the rooms containing this type of equip- eas, uptake rooms and radionuclide thera- ment will need to be appropriately shielded . py rooms throughout the nuclear medicine Given the higher risk of surface contami- department . This will reduce staff radiation nation and radiation spills in areas such as dose and allow the nursing and technologist the hot laboratories, radiopharmacies and staff to safely monitor the patients in a ‘cold’ gamma and PET camera rooms, it is pref- EANM non-radiation area . erable that the flooring is continuous with no joins, non-absorbent and easy to clean . In PET departments, the thickness of lead The bench surfaces ideally should be stain- required to provide adequate shielding for less steel with a lip at the front to prevent staff can make doors very heavy and can spillage from bench to floor and continuous represent a manual handling risk for staff . to the back surface or wall . The IAEA provide Therefore the designs should be reviewed in guidelines on radiation safety standards that consultation with a medical physicist expert incorporate radiopharmacy and hot labora- in order to ensure compliance with radia- tory design [6] . tion safety regulations while minimising the occupational manual handling risks . A maze The relevant clinical staff, including the tech- design may be an option that minimises the nologist, will need to develop a concise list number of heavy doors required yet still pro- of the types of study and the radionuclides vides adequate radiation shielding . to be used in the department . If the department is to offer a full suite of diagnostic The design should include clearly defined ‘hot’ procedures, PET tracers (with short and long and ‘cold’ areas throughout the department half-lives), radioiodine therapies and other plan with restricted access to patients . The radionuclide therapies, then this will signifi- nuclear medicine department staff should cantly affect the equipment needs, shielding, have areas within the department such as the waste storage in the hot laboratories and control room, staff recreation room and toilet quality control minimum standards . These that are non-radiation areas . These should be must be defined before designing the layout clearly identified in the design and workflow . and workflow of the new department .

109 Many PET departments commonly use au- phase . Departments are now being designed to-dispensing and injectors for fl uorine-18 with a small area or corridor between the up- fl uorodeoxyglucose 18([ F]FDG) and the take rooms to locate the injector, with the equipment is large and diffi cult to manoeu- walls having a small hole where the exten- vre between patients, especially between sion tubing from the auto-dispenser to the uptake rooms when they are not located ad- IV site can be connected to reduce the radia- jacent to each other . It is important to take tion and manual handling needs for the staff , this into consideration as part of the design as illustrated in Fig . 1 .

Uptake 1 Uptake 3

Auto-Injector

Uptake 2 Uptake 4

Figure 1: An example of the layout and functionality of the PET uptake rooms if an auto-dispenser and injector are to be used to administer [18F]FDG

The equipment list, both medical and ture control, medical/emergency services non-medical, must be fi nalised early in the and the location and number of CCTV moni- design process as it impacts on many other tors . This is particularly important for the PET items within the department, including the area uptake rooms, which need to be kept at location and number of power and data out- a constant temperature and to have dimma- lets, lighting (including dimmable), tempera- ble lighting to desensitise the patient during

110 Chapter 10: Nuclear Medicine Department Design

the uptake period . The ambient temperature tion shielding calculations, room layout and in the gamma camera rooms will be critical method for determining occupancy rates to avoid damage to the sensitive NaI detec- [1, 4, 7] . Local and national health regulators tor crystals, especially if equipment is to be often provide health facility guidelines that installed and not used for a significant time cover minimum room sizes, infection control prior to department operation . standards, safe workplace recommendations and non-medical equipment needs [7, 8] . As part of the planning and development process, new workflows for patients and staff The design plan and layout will vary depend- must be identified, especially with respect to ing on whether you are renovating or build- the transit of patients into and out of the de- ing within an existing floorspace as com- partment . It is preferable to avoid transiting pared to being given a ‘blank canvas’ with the through or past ‘cold’ staff areas when enter- ability to design the space as required, which EANM ing and exiting the department, specifically is often easier . Current design guidelines the control rooms, reporting rooms and staff and regulations specific to the country and recreation rooms . the area that you are building must be taken into consideration, as must the radiation Layout and design considerations safety regulations . There are many examples Defining the types of study to be performed of effective department designs, especially in the new department will determine the for new PET departments, that have been equipment needs and therefore the design successfully implemented [9] . The design lay- and layout of the facility . There are, however, out examples given below list the potential many common features that will be manda- medical and non-medical equipment nec- tory in order to comply with local and nation- essary for a nuclear medicine department al regulations irrespective of the equipment ranging in size from a small single gamma to be installed . These include emergency camera department to a larger department services, radiation shielding, room sizes, in- with multiple gamma cameras and PET/CT . fection control for location and number of hand-washing facilities, size of reception Example 1 – a single gamma camera, either areas and office space and the minimum SPECT or SPECT/CT (Fig. 2) standards for patient holding bays . Organ- • Waiting room to house up to six patients; isations such as the American Association • Reception and administrative staff area of Physicists in Medicine (AAPM), the Inter- with enough space for a single receptionist national Council on Radiological Protection and an office for a practice manager; (ICRP) and the International Atomic Energy • SPECT or SPECT/CT camera room with the Agency (IAEA) provide guidelines on radia- radiation shielding determined as per the

111 regulations, dependent on the isotopes to considered a ‘cold’ or non-radiation area for be used . It is important to remember that a the staff ; larger fl oorspace will be needed for SPECT/ • Patient toilet and a separate staff toilet, not CT, usually up to 46–48 m2 (495–517 ft2), necessarily in the department but within compared with 40–42 m2 (430–455 ft2) for close proximity for the staff ; SPECT only; • Hot laboratory that includes a small radioactive waste storage area, with the • Gamma camera control room with size and radiation shielding determined space for up to two nuclear medicine by the radionuclides to be used and the technologists and located in a low patient procedures to be undertaken; occupancy section of the department, • Cardiac stress laboratory with a treadmill or

Entry

CONSULTATION ROOM Waiting Room Patient Trolley Bay

Hot Toilet Waiting Reception Room Exercise Stress Room Change Room O ffi c e Staff Control Room Store Hot Lab/ Room Radiopharmacy

O ffi c e SPECT/CT

O ffi c e Reporting Room

Exit

Figure 2: A sample fl oorplan for a small single gamma camera (either SPECT or SPECT/CT) that accommodates trolley bed patients and cardiac exercise stress testing

112 Chapter 10: Nuclear Medicine Department Design

bicycle to be used for myocardial perfusion • Gamma camera control room with studies . The room will need to be fitted space for up to three nuclear medicine with a full emergency services panel technologists and located in a low patient and cardiac arrest response trolley with occupancy section of the department, a defibrillator . A separate changing room considered a ‘cold’ or non-radiation area for may be needed, depending on the number the staff; of studies to be performed per day; • Patient toilet and a separate staff toilet; • Consultation/injection room equipped • Hot laboratory and/or radiopharmacy for with the materials needed for injection of manufacture that includes a radioactive the radiopharmaceuticals; waste storage area . The size and • Reporting room with one reporting equipment needs of the hot laboratory workstation; and waste storage will vary depending on • A small storage room for general stock the radionuclides used and the diagnostic EANM items and non-medical stores; or therapeutic services performed; • A small staff room with a beverage bay • Cardiac stress laboratory with a treadmill or and sitting area that is located in a ‘cold’ or bicycle to be used for myocardial perfusion non-radiation area of the department . studies . The room will need to be fitted with a full emergency services panel and cardiac arrest response trolley with a Example 2 – two gamma cameras, with 1 × defibrillator; SPECT and 1 × SPECT/CT (Fig. 3) • A pass-through hatch may be useful in • Waiting room to house up to ten patients; certain areas within the department, for • Reception and administrative staff area example between the hot laboratory and with enough space for two receptionist the cardiac exercise laboratory or the staff and an office for an office/data radionuclide therapy room . This will avoid manager; staff transporting patient doses in heavy • SPECT camera room with the radiation shielded canisters between rooms; shielding determined as per the • A separate change room for the cardiac regulations dependent on the isotopes to patients located either adjacent to or be used, size 40–42 m2 (430–455 ft2); opposite the cardiac exercise stress room; • SPECT/CT camera room with the • A consultation or interview room with a radiation shielding determined as per the patient trolley bed that can be used for regulations dependent on the isotopes to brain perfusion and activation studies; be used . It is important to remember that a • An injection room equipped with the larger floorspace will be needed for SPECT/ materials needed for administration of the CT, usually up to 46–48 m2 (495–517 ft2); radiopharmaceuticals to patients;

113 • Reporting room with two reporting • Patient holding bays to accommodate workstations . The room will need to be a patient transferred on a trolley or adequately temperature controlled as wheelchair . This is optional and may there will be several high-end computers not be needed for departments that that generate heat, increasing the ambient only accommodate outpatient room temperature; procedures; • A small storage room for general stock • A nursing staff station adjacent to the items and non-medical stores; patient holding bays (optional, as above); • A separate staff room with a beverage bay • Offi ce area with up to two separate rooms and sitting area that is in a ‘cold’ or non- to be used by the nuclear medicine physi- radiation area of the department; cian/radiologist and a medical physicist,

Entry

O ffi c e O ffi c e O ffi c e Reporting Room Waiting Room Reception

Store O ffi c e Consultation Room Room Patient Staff Toilet Trolley Bay Hot Lab/

Hot SPECT Waiting Nurses Station Room

Exercise Stress Change Toilet Treatment SPECT/CT Staff Control Room Room oom Room

Figure 3: A sample fl oorplan for a two-gamma camera department with both a SPECT and a SPECT/CT that includes a separate change room, multiple holding bays for patient trolleys, a nursing staff station and a ‘hot’ radioactive patient waiting room

114 Chapter 10: Nuclear Medicine Department Design

radiopharmacist or chief nuclear medicine • A PET hot laboratory, which may include a technologist; small waste storage area if the facility will • A separate shielded waiting room to be be using longer half-life tracers such as used by patients following administration iodine-124 or copper-64; of the radiopharmaceutical, especially for • A consultation or interview room to be tests that require patients to wait between used for non-radioactive patients prior to imaging time points or to be monitored, injection; e .g . cardiac patients . It is important to • A common report room for both nuclear remember that there is a requirement that medicine and PET is preferable, with at least all attempts be made to keep the exposure two reporting workstations, and it may to members of the general public, especially be desirable to have a concertina door to pregnant women and small children, as low separate the two reporting zones if needed; EANM as reasonably achievable (ALARA) [10, 11] . • A separate change room located in the PET area close to the department exit so that patients can easily find the exit when Example 3 – 1 × SPECT, 1 × SPECT/CT and 1 × finished, thereby minimising the PET staff PET/CT (Fig. 4) radiation dose; • The nuclear medicine department should • Uptake rooms, with the number needed include the areas outlined in example 2; dependent on the type of PET system however, the waiting area will need space installed, the number and type of studies for up to 12 patients . The items listed to be performed per day and the space below are specific to the PET/CT area . available; • PET/CT camera room with a minimum • If the facility will be performing studies size of 48–50 m2 (516–538 ft2) and the on patients who require a higher level option to include radiation therapy lasers of care during the uptake period or and treatment planning imaging palettes plans to do complex procedures such as (‘flatbed’ palettes); brain activation studies, catheterisation • A PET/CT equipment room that is or anaesthetics, a larger uptake room temperature controlled, either in the (12–13 m2 or 125-139 ft2) will be required, camera room itself or located in a separate fitted with full medical services including area in close proximity to the machine; anaesthetics; • A PET control room for up to three nuclear • A separate radiopharmacy specifically medicine technologists and a nurse; for manufacture, dispensing and tracer • A separate PET patient toilet, which should development . If a hot cell is required, be able to accommodate a patient in a remember to check the floor weighting wheelchair; and access to compressed air and

115 nitrogen . A hot cell can weigh up to 8 When defi ning the layout, functionality and tonnes and require a large amount of workfl ow of the department, it is important space; to include clearly designated ‘cold’ or non-ra- • A meeting room or combined meeting diation areas for the staff at a reasonable dis- room/library is a good addition to larger tance from any radioactive sources, includ- departments to allow for internal as well ing the patients, X-ray sources such as CT and as external meetings and to provide the hot laboratories . A separate ‘hot’ waiting continuing education opportunities for area located within the department with ap- the staff . propriate shielding is suggested to minimise

Staff Entry O ffi c e O ffi c e Toilet Room Uptake 1 Uptake 2 Uptake 3 Uptake 4

Consultation PET/CT Area Open Offi ce Offi Open O ffi c e Meeting Room

Store Change PET Control Room Room Room Waiting Room Hot Lab Room Reporting Exercise SPECT Patient Stress

Room Room Entry Change

SPECT Control Reception Room

Consultation Room Patient Trolley Toilet SPECT/CT Store Bay Room Nurses Station Entry/Exit Figure 4: A sample fl oorplan for a larger department that includes two gamma cameras, both a SPECT and SPECT/CT, and a PET/CT . The addition of a meeting room/library can be used for continuing education of the staff and allows additional space for both internal and external clinical and non-clinical meetings

116 Chapter 10: Nuclear Medicine Department Design

the radiation exposure to reception and ad- cupancy rate of the room for staff, patients ministrative staff as well as members of the and visitors . The radiation shielding require- general public . The use of mobile lead shields ments with respect to infrastructure such as may be helpful, especially in the radionu- walls, flooring and ceiling, internal protection clide therapy areas, where nursing and other devices including mobile or fixed personal non-medical imaging staff may be monitor- protective equipment, the minimum room ing the patient for medical complications . size to safely accommodate six patients and the need for a separate toilet impact Radionuclide therapy facilities significantly on the room layout; it must be The equipment, floorspace, shielding, room ensured that a ‘cold’ zone is provided for the layout and waste storage requirements will staff involved in administering the therapy vary depending on the radionuclide thera- and monitoring the patient [12] . pies being provided and the radiation pro- EANM tection legislation specific to each country . The use of radioactive iodine, specifically io- The radiation exposure rate for a patient at dine-131, for treatment of thyroid cancer or the time of discharge following radionuclide for labelling of mIBG or Lipiodol in the treat- therapy and the waste storage and disposal ment of metastatic phaeochromocytoma, guidelines, e .g . with regard to the need for neuroblastoma or liver cancer, will require a sewerage holding tanks, vary significantly fully equipped isolation room or ward . The between countries [3, 4, 11] . The mandatory room size, radiation shielding, waste storage shielding based on the radionuclides to be facilities (including holding tanks for biolog- used, the minimum room size and the sewer- ical radioactive waste) and discharge expo- age and waste requirements must be incor- sure rates should be determined on the basis porated during the design phase . of the radiation regulations and guidelines for the individual country . Patients treated Newer radionuclide therapies using lute- with iodine-131 must be admitted and iso- tium-177 are commonly performed as a lated from the general public for a period day procedure in most countries due to the of time that will vary between countries . low gamma emission (<15%) and the me- The determination of the isolation period is dium-energy beta emission . It is common based on a number of factors including the practice to treat four to six patients in a single administered activity, the allowable exposure room, with each patient being administered rate at the time of discharge and personal 7–8 GBq and the treatment taking 4–6 h to factors specific to the patient including living perform . As part of the design process, con- arrangements, cognitive ability and indepen- sideration must be given to the total activity dence status as measured using, for example, in the room at a given time as well as the oc- ECOG performance status scoring [13] .

117 Radiation safety and regulatory the products manufactured and the activi- considerations ties . This is less of an issue in PET due to the The radionuclides to be used in the depart- short half-life of most PET tracers; however, if ment and the number of X-ray imaging iodine-124 or copper-64 are to be used, then equipment items, such as CT, to be installed a heavily shielded long-life waste storage will impact dramatically on the level of should be located near the PET laboratory shielding required . The AAPM, ICRP and IAEA [15] . These guidelines often include informa- provide detailed guidelines on shielding re- tion on security of sources and each country quirements that are recognised internation- will have specific regulations with which you ally [10, 14] . These guidelines should be used will need to comply . It is therefore important under the guidance of a medical physics to identify during the design phase a secure expert and consideration must be given to delivery access point for the daily radiophar- the routine doses administered for each pro- maceutical deliveries that uses a path with a cedure and the number of studies to be per- low general public occupancy rate . formed per day as these factors will impact on the amount of any particular radioisotope Nuclear medicine department design: that will be stored and used in the hot lab, A step-by-step guide and the radiation level of the unsealed (‘hot’ The process for designing a new department patient) sources moving throughout the de- or remodelling an existing layout will vary partment . between departments and even countries due to differences in the role of the various The IAEA and local authorities from many oth- stakeholders and staff members and the er countries provide comprehensive state- mandated regulations . This is a step-by-step based, national and international guidelines guide to designing a nuclear medicine de- on radiation protection and waste storage . partment from the perspective of a nuclear Area monitoring of the background radia- medicine technologist that can be used as a tion and contamination in staff areas may be guide . a regulatory requirement . This may include the checking and recording of contamina- I . Identify the size, shape and location of tion on the skin or clothing for staff working the proposed floorspace . in the hot laboratories, mandating the need II . List the equipment needs and the types for wall or bench mounted surveillance me- of equipment that will be installed in the ters at the exit of the laboratory . Waste stor- new department . age needs will be determined by the tracers III . Review the guidelines and regulations and isotopes used, if they are gamma, beta specifically relating to minimum room or alpha emitters, the energy and half-life of size, room fit-out specifications such

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as medical services, power, and air that the layout will meet the needs of conditioning as well as the fire safety the department and other invested and radiation safety regulations for stakeholders such as patients and shielding and occupancy . This should referrers . be done in consultation with a medical physicist or a radiation safety expert . Technologist’s role in the design process IV . Determine the department workflow for The technologist is an integral part of the de- patients, staff and visitors . This will assist sign team and is the best person to advise on in defining the restricted and limited workflows, clinical procedures and patient access areas, the ‘hot and ‘cold’ areas needs . There are certainly particular tasks for within the department and the location which the technologist should have owner- of staff amenities such as staff recreation ship and these have been identified as: EANM room, lockers and toilet . V . Draft a layout for the department to a . Determine the patient, staff and include all equipment and services . general public workflow . This will include identifying how patients will VI . In consultation with the other relevant move through the department when stakeholders, create a room data undergoing procedures . This may differ sheet for each area or room within the between outpatients and inpatients, department that concisely defines the between walking patients and patients room specifications, both medical and who are in a wheelchair or bed bound, non-medical . and between PET and other nuclear VII . Review the room data sheets with a medicine procedures . focus on lighting, temperature control b . Provide details on the number of staff (especially in the PET area), medical employed and their role within the service needs for each space, power department . This will help to identify (including high voltage for rooms in staff who will require a separate which CT equipment is to be installed) office and to assess the need for any and the type of flooring and bench shared office space, separate physics surfaces in the radiation area, including laboratories, radiopharmacy facilities camera rooms and hot laboratories . for manufacture and dispensing and Review the number and location of data meeting rooms or library facilities for outlets for computing equipment and ongoing education and professional the location of CCTV monitors . development . It can also identify training VIII .Modify the draft plan after reviewing the needs and discrepancies in the skills of room data sheets and confirm the existing staff .

119 c . Review the current types and number xiv . The optimal location of of studies performed daily, weekly and handwashing facilities to comply monthly and evaluate whether this with infection control legislation will change in the new or updated xv . What you will need in each of facility . This information will be used to the rooms if you will be doing determine the equipment needs and the paediatric studies: perhaps a TV and/ expected occupancy rates of the rooms or DVD player in the camera room, and to identify any future staff education a separate children’s area in the or training needs . The medical physics waiting room or extra storage for expert can then use this information to immobilisation devices determine the shielding requirements for each space . a . Review the manual handling policies and d . Accurately determine future storage ensure compliance with these, especially needs . Storage of both clinical and in areas such as the hot laboratory and non-clinical equipment can often be radiopharmacy where staff may be problematic in new facilities, so this required to lift heavy equipment, e .g . assessment is important . It is common molybdenum-99 generators . Similarly, for a new department to increase its review infection control standards to workload in the first 12 months of ensure that the design will comply with operation so the design must take into these and consider the number and consideration future development and location of hand-washing facilities, the growth to include room for expansion . need for a dirty utility or pan room, the e . Carefully review the room data sheets, types of flooring used in clinical areas which will list all services, equipment, and the benchtop surface materials for furnishings and flooring for each area . the hot laboratory . Specifically look at: b . If new equipment is to be installed, ix . Lighting assess the staff education and x . Air conditioning or temperature training needs and develop a training control, especially in a PET facility programme in consultation with the manufacture . This will also include xi . Data and power outlets identifying changes in workflow and xii . The height and depth of the writing or updating any new protocols benches, desks and workstations and procedures . xiii . The location of any CCTV monitoring to comply with the The technologist can also play an important safety regulations for patient part in reviewing the future direction of the monitoring during a procedure

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department and consult with the other nuclear medicine professionals to outline a plan for implementing any potential new services . This could be the testing of new tracers, the addition of new technologies such as PET/ MRI and increasing staff participation in research .

Conclusion As a technologist, being involved in the development and design of a new department or modifications to an existing department can be very rewarding and challenging . It EANM will assist in developing your understanding of the importance of a well-designed department that has good workflow for patients and staff, creating a safe environment for everyone . The most important step is to pre-plan the functionality and services to be offered and to understand the needs of the patients, referrers and institution that will be using your services . Allowing for future development and the introduction of new procedures in the design plan will ensure that your department can be progressive, provide a high level of service and be a rewarding place to work .

121 References

1 . Madsen MT, Anderson JA, Halama JR, Kleck J, Simpkin 9 . Peng BJ, Wu Y, Cherry SR, Walton JH . New shielding con- DJ, Votaw JR, et al . AAPM Task Group 108: PET and PET/ figurations for a simultaneous PET/MRI scanner at 7T . J CT shielding requirements . Med Phys 2006;33:4–15 . Magn Reson 2014;239:50–56 .

2 . Dondi M, Kashyap R, Pascual T, Paez D, Nunez-Miller 10 . The 2007 Recommendations of the International Com- R . Quality management in nuclear medicine for bet- mission on Radiological Protection . ICRP publication ter patient care: the IAEA program . Semin Nucl Med 103 . Ann ICRP 2007;37:1–332 . 2013;43:167–171 . 11 .Bevelacqua JJ . Practical and effective ALARA . Health 3 . Kai M . Update of ICRP publications 109 and 111 . Health Phys 2010;98 Suppl 2:S39–S47 . Phys 2016;110:213–216 . 12 . Bakker WH, Breeman WA, Kwekkeboom DJ, De Jong LC, 4 . Paquet F, Etherington G, Bailey MR, Leggett RW, Lipsztein Krenning EP . Practical aspects of peptide receptor radio- J, Bolch W, et al . ICRP publication 130: Occupational nuclide therapy with [177Lu][DOTA0, Tyr3]octreotate . Q intakes of radionuclides: Part 1 . Ann ICRP 2015;44:5–188 . J Nucl Med Mol Imaging 2006;50:265–271 .

5 . Lochard J . Application of the Commission’s recommen- 13 .Sisson JC, Freitas J, McDougall IR, Dauer LT, Hurley JR, dations: the 2013–2017 Committee 4 programme of Brierley JD, et al . Radiation safety in the treatment of pa- work . Ann ICRP 2015;44(1 Suppl):33–46 . tients with thyroid diseases by radioiodine 131I : practice recommendations of the American Thyroid Association . 6 . International Atomic Energy Agency . Applying radiation Thyroid 2011;21:335–346 . safety standards in nuclear medicine . Safety Report Se- ries No . 40 . Vienna: IAEA; 2005 . 14 .Rehani MM . Radiological protection in computed tomography and cone beam computed tomography . Ann 7 . Voisin P . Standards in biological dosimetry: A require- ICRP 2015;44(1 Suppl):229–235 . ment to perform an appropriate dose assessment . Mu- tat Res Genet Toxicol Environ Mutagen 2015;793:115– 15 . Nye JA, Dubose M, Votaw JR . A comparison of AAPM TG- 122 . 108 PET/CT shielding recommendations to measurements in an oncology center . Med Phys 2009;36:5017– 8 . Zimmerman BE, Herbst C, Norenberg JP, Woods MJ . In- 5021 . ternational guidance on the establishment of quality assurance programmes for radioactivity measurement in nuclear medicine . Appl Radiat Isot 2006;64:1142–1146 .

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