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Radionuclide Metabolic Clinical Aspects, and Imaging

A Technologist’s Guide

Produced with the kind Support of Editors

Peștean, Claudiu (Cluj – Napoca) Veloso Jéronimo, Vanessa (Loures) Hogg, Peter (Manchester)


Berhane Menghis, Ruth (Liverpool) Mayes, Christopher (Liverpool) Bodet-Milin, Caroline (Nantes) Pallardy, Amandine (Nantes) Chiti, Arturo (Milan) Peștean, Claudiu (Cluj – Napoca) Cutler, Cathy S. (Missouri) Piciu, Doina (Cluj – Napoca) do Rosário Vieira, Maria (Lisbon) Rauscher, Aurore (Nantes) Faivre-Chauvet, Alain (Nantes) Silva, Nadine (Lisbon) Flux, Glenn (Sutton, Surrey) Sjögreen Gleisner, Katarina (Lund) Gorgan, Ana (Cluj – Napoca) Strigari, Lidia (Rome) Kraeber-Bodéré, Françoise (Nantes) Szczepura, Katy (Manchester) Larg, Maria Iulia (Cluj – Napoca) Testanera, Giorgio (Milan) Lowry, Brian A. (Liverpool) Vinjamuri, Sobhan (Liverpool) Lupu, Nicoleta (Cluj – Napoca) Williams, Jessica (Philadelphia) Mantel, Eleanor S. (Philadelphia) Imprint 153 Imprint III Section II Section I Section Acronyms 7 6 Introduction Foreword 5 Contents .Ftr esetvsi aincieTeay() 136 of andincooperation with: were support (*) Articles written withthekind 112 1. Future Perspectives inRadionuclide Therapy (*) 93 81 77 6. PainTherapy Metastatic Bone ofRefractory Alain Faivre-Chauvet, Françoise Kraeber-Bodéré Aurore Rauscher, Caroline AmandinePallardy, Bodet-Milin, 5. inLymphomas doRosário Nadine SilvaandMaria Vieira 4. inHepatocellular Carcinoma A.Lowry, Menghis, Brian Ruth Berhane Mayes Christopher andSobhan Vinjamuri 3. Radionuclide Therapy inNeuroendocrine Tumours PiciuDoina 2. Radionuclide Therapy inBenign Disease 41 PiciuDoina 54 1. Radionuclide Therapy in Thyroid Carcinoma Giorgio Testanera Chiti andArturo Preamble onaMultiprofessional Approach Metabolic inRadionuclide Therapy Claudiu Peştean IuliaLarg andMaria ExposureMinimising ofPatients, ofthePublic Staf andMembers 4. SpecialConsiderations Protection: inRadiation Sjögreen Gleisner,Katarina GlennFlux LidiaStrigari, Radiotherapy in Molecular 3. Dosimetry Szczepura Katy 2. Biological ofIonisingRadiation Efects Eleanor andJessica S.Mantel Williams 1. Principles inRadionuclide Therapy (*) Claudiu Peştean, Vanessa Veloso Jerónimo andPeter Hogg Cathy S.Cutler 129 LupuAna Gorgan, Nicoleta andClaudiuPeștean for8. NursingImplications Patients Metabolic Undergoing Radionuclide Therapy Mayes,Christopher A.Lowry, andSobhan Brian Menghis RuthBerhane Vinjamuri 7. Radiosynovectomy A.Lowry,Brian RuthB. Menghis, Mayes Christopher andSobhan Vinjamuri 3

105 121 61 29 18 9 Printed in accordance with the Austrian Eco-Label for printed matters. EANM Acknowledgements

The editors would like to express sincere gratitude to the following people, because without their generous help this book would not have come to fruition:

Reviewer: Lisa Bodei

English language editing: Rick Mills

Project management: Katharina Leissing

4 Foreword

Nuclear Medicine is a composite discipline Following the successful PET-CT Tech Guide in which radionuclide therapy has a role of series, this book is the joint work of many growing importance, with an increasing im- professionals from diferent nations and pact on clinical practice. Advances in radio- ields of interest within . pharmaceutical production and the imple- I want to really thank all those people who mentation of a multidisciplinary approach have contributed to this work as authors and in clinical medicine have propelled radio- reviewers, without whom the book would therapy methods and application not have been possible. I am proud to be towards personalised treatment, therapeutic able to welcome and thank our colleagues eicacy, patient comfort and safety. from the SNM (Society of Nuclear Medicine, Technologists are key igures in this process, United States) for their high-quality contribu- since their competencies allow them to play tions. I also wish to extend particular grati- an important role in every step necessary for tude to the EANM Dosimetry and Therapy EANM successful treatment, from radiopharmaceu- Committee for their availability and expertise tical preparation to administration. They are in the required ields. Special thanks are due also the main actors in pre- and post-thera- to Claudiu Peştean, Vanessa Veloso Jerónimo peutic imaging. The current book is specii- and Professor Peter Hogg, for their incredible cally aimed at radiographers and technolo- enthusiasm and competence in dealing with gists working in, or intending to work in, a the editorial duties and organisational work. Nuclear Medicine department with radionu- Finally, I remain extremely grateful to the clide therapy facilities, though it is also likely EANM Executive Committee, the EANM Exec- to be valuable for other healthcare profes- utive Secretariat, the Technologist Commit- sionals working in, or willing to work in, this tee and all the EANM committees involved in challenging environment. the project.

A successful radionuclide therapy unit is not With my warmest regards only fundamental for patient care in Oncol- ogy, Endocrinology and Orthopaedics, but Giorgio Testanera can also serve as a standard in an inter- Chair, EANM Technologist Committee professional and multidisciplinary approach to clinical medicine.

5 Introduction Claudiu Peştean, Vanessa Veloso Jerónimo and Peter Hogg

This year we have focussed on radionuclide the pathologies which it can treat and/or therapy for our book. For decades, radionu- where it can be used for palliation. This sec- clide therapy has been used to help manage tion contains signiicant input from those a range of malignant and benign diseases, who practice radionuclide therapy, especially and for many pathologies its utility is well nuclear medicine physicians and others who known and well documented. In the early have a range of relevant clinical skills. In Sec- years the radionuclide range and the pathol- tion III we consider the future, and particular ogies which could be managed (treatment emphasis is placed on molecular therapy. and/or palliation) were limited. However, The inal chapter considers new radionu- signiicant progress continues to be made, clides which may become valuable in the and there has been considerable expansion future. in the available therapeutic and the pathologies which can be managed We should like to thank the authors who by them. On this basis we feel it is timely for have taken the time to write the chapters this book to be published. The book brings and also the reviewers who have provided together experts in the ield of radionuclide constructive feedback to the authors. We therapy from Europe and America in order acknowledge that writing and reviewing that they can share their theoretical knowl- involves a considerable efort and we hope edge and clinical/practical experience. These that the readers will ind this book useful for experts emanate from a range of professional training and practical purposes. backgrounds and include medical physicists, nuclear medicine physicians, radiographers, nuclear medicine technologists and others.

The book commences with background information about radionuclide therapy (Section I). If you are new to radionuclide therapy, then we suggest that special atten- tion is paid to the irst four chapters as the information covered will give you a good theoretical grounding; with this in mind you can progress to read about the clinical and technical aspects of radionuclide therapy in Section II. Here, attention is paid to how to conduct radiotherapy procedures and also

6 Acronyms

AFP Alpha-fetoprotein EBRT external beam radiotherapy American Joint Committee on Eastern Cooperative Oncology AJCC ECOG Group ALARA as low as reasonably achievable ETA European Thyroid Association Alpharadin® in Symptomatic ALYSMPCA FBC full blood count clinical trial FIT irst-line indolent trial Anti-TPO anti-thyroid peroxidase FL folicular lymphoma ATA American Thyroid Association FNAB ine-needle aspiration biopsy AuNPs gold nanoparticles FPMs ine postmitotic cells BED biologically efective dose FT free T BRAF human gene precursor of B-Raf 3 3 EANM gene protein FT4 free T4 BRMs biological response modiiers FTC follicular thyroid BSA body surface area GFR glomerular iltration rate BT HAMA human anti-murine CCK cholecystokinin HBV hepatitis B virus CD20 B-lymphocyte HCC COX cyclo-oxygenase HCV hepatitis C virus CPPD pyrophosphate dihydrate HEGP high-energy general-purpose CR complete response HR homologous recombination International Atomic Energy CT Computed Tomography IAEA Agency disseminated intravascular DIC International Commission on coagulation ICRP Radiological Protection DIMs diferentiating intermitotic cells International Commission on ICRU DLBCL difuse large B-cell lymphoma Radiation Units and Measurements disease-modifying anti-rheumatic ITLC instant thin-layer chromatography DMARDS drugs LET linear energy transfer DNA deoxyribonucleic acid LQM linear quadratic model DSB double-strand break LSF lung shunt fraction DTC diferentiated thyroid carcinoma LT levothyroxine European Association of Nuclear 4 EANM Medicine MAbs monoclonal antibodies

7 multipotential connective tissue MCTs ROIs regions of interest cells RPMs reverting postmitotic cells MIBG metaiodobenzylguanidine Severe Combined Medical Internal Radiation Dose SCID MIRD Immunodeiciency Committee Single Emission Computed SPECT MRI Magnetic Resonance Imaging Tomograpy MRT Molecular radiotherapy Single Photon Emission Computed SPECT/CT Tomograpy with Integrated MTC medullary thyroid carcinoma Computed Tomography NCI National Cancer Institute SRS receptor

NETs neuroendocrine tumours SSTRs somatostatin receptors NHEJ and non-homologous end joining SWNT single-walled nanotubes NHL non-Hodgkin’s lymphoma triiodothyronine T3 NPs nanoparticles T thyroxine normal tissue complication 4 NTCP probability TACE transarterial chemo-embolisation OR overall response TAE transcatheter embolisation

PET Emission Tomography TCP tumour control probability Tomography Tg thyroglobulin PET/CT integrated with Computed Tomography THPAL trimeric phosphino alanine

PR partial response TNF tumour necrosis factor PRRT peptide receptor radionuclide therapy TRab anti-thyrotropin receptor antibodies Peptide receptor radionuclide PRRT therapy TSH thyroid stimulating hormone PTC papillary thyroid cancers TTP time to progression

PVNS pigmented villonodular synovitis US ultrasound

RA rheumatoid arthritis VIMs vegetative intermitotic cells

RAIU radioactive uptake test VOIs volumes of interest

RBE relative biological efectiveness WBS whole-body scanning Response Evaluation Criteria in RECIST Solid Tumours WFH World Federation of Hemophilia RIT Radioimmunotherapy WHO World Health Organization

8 ton stays is in the nucleusandelectron into aproton andanelectron. The pro- too high. An excess istransformed ratio ofneutrons to protons inthenucleusis emission occurs whenthe dose. Beta to deliver ahighlocalisedradiation are accomplishedby utilisingbeta-emitting All ofthetherapiesdiscussedinthischapter improve prognosis andoutcome. the patient’s tolerance to treatment andmay to a minimum. This, helps to in turn, improve thelevels oftoxicitywhich potentially keeps toattributed thepatient-speciic dosing, ological response from thepatient. This is processes whileeliciting alow ornophysi- cancerous disease plete ablationofcertain not onlyfor palliative therapy, butthecom- tumour. The cessation of cellgrowth allows throughout thebodyaswell astheprimary cell speciic, targeting distantmetastases ments are delivered systemically, are they them to stop growing. Althoughthesetreat- by damaging thecells’ DNA,whichcauses cellsandtumours abnormal orshrink to kill therapy usesionisingradiation Radionuclide hasstayedyears, thesame. thebasictheory radionuclide therapy hasevolved over the the progress inradionuclidetherapy. While ledto ofradiumthusdirectly The discovery been used to treat a multitude of diseases [1]. in 1903. Within 10years, radiumhadindeed predictedham Bell itsuseto treat tumours andPierreMarie in1898,AlexanderGra- Not long after thediscovery Not longafter Introduction Eleanor andJessica S.Mantel Williams 1. Principles inRadionuclide Therapy I Section ofradiumby 9 For patientsunableto adhere to certain sential for allradiotherapy administrations. safety ises- precautions and instructions breastfeeding [2-6].Adherence to radiation in female and patientsincludepregnancy cations. common contraindications Some own setofrelative andabsolute contraindi- Each speciicradionuclidetherapy hasits she isanidealcandidate for thetreatment. to whether determine he or medical history regimen, oneneedsto review thepatient’s aradionuclidetherapy When considering ratiothatmustbeconsidered.eit versus risk Generally, medicaltherapieshave aben- decay, shieldingmay beusedaswell. thathave acomponentofgamma However, orhigh-energy insomehigh-dose ofX-rays. andproduction lung interactions tempt to reduce thenumberofbremsstrah- ofchoiceforthe materials shieldinginanat- Lucite orplexiglass. Lucite andplexiglassare shielding is,Beta generally, achieved using tive emitters, beta emitters must be shielded. ergy itemitsto thetissue. As withallradioac- how far it can penetrate and how much en- has, mines how muchspeedabetaparticle duced. itselfdeter-The energy oftheparticle hasauniqueenergy thatispro- ery to treatment. prior purposes Ev- dosimetric at lower doses, to beusedfor diagnostic and ray emissionthatallows someoftheisotopes, follow isthisgamma thedecay ofthebeta.It Typically, ifthere are gammaemissions, they companies theemissionofabetaparticle. gamma-ray emissionac- expelled. Often,

EANM restraints following the treatment (for exam- metastatic disease by ablating any residual ple, patients with urinary incontinence [2]), tissue after partial or complete thyroidec- an in-patient admission might be necessary. tomy. 131I- is also used to treat Admission to the shielded isolation ward non-cancerous diseases such as hyperthy- may be required for patients receiving treat- roidism and non-toxic multinodular goitre. ments with certain high-energy isotopes or The dose is administered orally and can be in at high doses, depending on the regulatory capsule or liquid form since this radionuclide requirements [2]. is readily absorbed from the into the salivary glands, gastric mucosa Radioisotopes and their uses in and thyroid tissue. Because both malignant radionuclide therapy and benign disease processes are treated In this chapter, we will explore a number of utilising 131I, the dose will difer from one pa- isotopes that can be used for radionuclide tient to another. Doses generally range from therapy. Since each of the isotopes can be 1.11 to 11.1 GBq. used either independently or bound to an- other chemical compound, they are em- Prognosis following 131I therapy varies among ployed to treat diferent disease processes. cancer patients. While patient age, gender, pathology of the cancer, grading and size all Iodine-131 have an efect on how thyroid cancers be- A commonly used isotope for radiotherapy is have, they still have a favourable prognosis. iodine-131 (131I). 131I is a beta emitter with a The well-diferentiated types of thyroid can- principal of 364 keV (81% abun- cer, follicular and papillary, generally have dance) and beta with an energy of better outcomes than the other types (med- 0.61 MeV. Its half-life is 8.1 days and it has an ullary and anaplastic), with 10-year survival average range in tissue of 0.4 mm. 131I is pro- rates of between 92% and 98%. However, duced by the of -130 in a 5-20% of patients with well-diferentiated . While some patients may be will experience loco-regional treated on an out-patient basis, regulatory re- relapse that requires additional treatments quirements may necessitate those receiving and/or surgery [7]. high doses of 131I to have an extended stay in a lead-lined room as an in-patient. Patients Patients with that is treated receiving these higher doses require special with 131I-sodium iodide have a high response handling in an efort to minimise radiation rate. Those given a higher dose of 131I-sodium exposure to those around them. iodide (600 MBq) have a higher cure rate but also an increased incidence of hypothyroid- Given in its natural form, 131I-sodium iodide ism [8]. is used to treat residual thyroid cancer and

10 Section I 1. Principles in Radionuclide Therapy

131I-labelled metaiodobenzylguanidine et al. to have reduced tumour size in approxi- (MIBG) is an analogue of noradrenaline [2] mately 55% of those treated [9]. and therefore is taken up by the adrenergic nervous system. It is this uptake that makes 131I- is a murine monoclonal an- 131 I-MIBG the tracer of choice when treating tibody that is used to treat CD20-positive, fol- a number of diferent cancers and diseases. licular, non-Hodgkin’s lymphoma refractory When 131I is tagged to MIBG, it can be used to and in relapse. The therapy is ad- to treat stage III or IV , inoper- ministered intravenously. On the basis of the able phaeochromocytoma, inoperable carci- initial dosimetric calculations, most patients noid tumour, inoperable paraganglioma and receive a therapeutic dose of 2,590–3,330 metastatic or recurrent medullary thyroid MBq, but there is a wide variation in dose cancer [2]. The dose is administered via slow range. Patients who have previously received intravenous infusion and ranges between 3.7 murine antibodies must have a negative se- EANM and 11.2 GBq. Approximately 60% of patients rum human anti-murine antibody (HAMA) treated for phaeochromocytoma respond to result before proceeding with additional this therapy. Thirty percent see a regression treatment regimens. Use of 131I-tositumomab in tumour size while 30% experience symp- is also contraindicated in patients with hy- tom relief; unfortunately, however, about a persensitivity to murine (mouse) proteins. third of the patients have no response at all It has been found that patients undergoing [7]. this therapy have a 63% response rate with a median duration of 25.3 months [7]. 131I-Lipiodol is another form of 131I radiother- apy and is used to treat inoperable primary -90 hepatic carcinoma. Lipiodol is a naturally io- Yttrium-90 (90Y) is a beta emitter with a half- dinated fatty acid ethyl ester of poppy seed life of 2.7 days and an energy of 2.27 MeV. It oil. This iodine-labelled product consists of has an average soft tissue range of 3.6 mm. fat droplets of approximately 20–200 µm in 90Y is produced by high-purity separation diameter. Lipiodol is administered directly from -90 (90Sr), a ission product of into the hepatic artery in a volume of 2–3 ml. in a nuclear reactor. The standard dose administered is 0.9–2.4 GBq. 131I-Lipiodol targets cancer cells, causing 90Y- is a CD20-directed cytotoxicity in the tumour cells while spar- radiotherapeutic antibody used to treat pa- ing the normal cells and tissues surrounding tients with relapsed or refractory, low-grade the tumour. While a majority of the dose is or follicular B-cell non-Hodgkin’s lymphoma retained in the , lung ibrosis is a com- (NHL) and previously untreated follicular NHL mon complication when high lung uptake who achieve a partial or complete response to is identiied. 131I-Lipiodol was found by Raoul irst-line [6]. 90Y-ibritumomab

11 tiuxetan is contraindicated in patients with treatment in order to ensure that the micro- hypersensitivity to murine (mouse) proteins. spheres will localise in the intended tumour Four hours prior to administration of the 90Y- site and not end up in the stomach, lungs ibritumomab tiuxetan, the patient receives or small intestines. is also rituximab therapy with the goal of clearing taken into account in patients receiving the majority of normal B cells so that the consecutive treatments. Doses for patients therapeutic dose is more focussed on the with increased shunting or previous therapy tumour cells. 90Y-ibritumomab tiuxetan is ad- administrations will be decreased appropri- ministered intravenously through a 0.22-µm ately. low-protein-binding in-line ilter between the syringe and the infusion port. The dose There are two types of microsphere: resin itself is based on the patient’s platelet count and glass. Resin microspheres are 20–60 µm and actual body weight. Post-treatment eval- in diameter. The activity for a single resin mi- uation is an important component of this crosphere is 40–70 Bq, with a total number treatment as thrombocytopenia and neutro- of particles implanted of 30–60 x 106. Resin penia are common adverse events, occurring microspheres are routinely administered to in approximately 90% of patients. Seventy patients with liver metastases from colorec- percent of rituxan-refractory patients treated tal carcinoma. Response rates have been with 90Y-labelled rituxan showed an overall shown to be higher in patients receiving this response that lasted 7.7 months [7]. therapy in conjunction with a chemothera- py regimen as compared to those receiving 90Y-microspheres are utilised as a treatment just the chemotherapy regimen, and it has in patients with non-resectable hepatomas also been shown that the former group has and liver metastases [10,11]. Microspheres an improvement in time to progression [11]. are a single-use, permanently implanted The glass microspheres are 20-30 µm in di- radiotherapy source. The radioactive micro- ameter, with each milligram containing ap- spheres are delivered directly to the liver via proximately 22,000–73,000 microspheres. an intra-arterial catheter in the hepatic ar- The activity for a single glass microsphere tery that supplies blood to the tumour. The is 2,500 Bq. Glass microspheres are used for microspheres are not metabolised nor are compromised portal venous low or portal they excreted; therefore they remain within vein thrombosis and in patients diagnosed the tumour and continue to have a radio- with hepatocellular carcinoma (HCC), typi- therapeutic efect. Generally, the doses for cally secondary to viral hepatitis or cirrhosis. these therapies are 1.5–2.5 GBq but choice According to clinical studies, the median of dose is patient dependent. It is important survival rate depends on the dose adminis- to determine the percent of lung shunting tered. A 3.6-month median survival rate was present prior to the administration of the documented for patients receiving a dose of

12 Section I 1. Principles in Radionuclide Therapy

less than 80 Gy, while those receiving a dose -32 greater than or equal to 80 Gy had a median Phosphorus-32 (32P) is a reactor-produced, pure survival rate of 11.1 months [10]. beta-emitting radionuclide with a half-life of 14.3 days. The maximum energy 90Y-silicate/citrate as a colloid is suitable is 1.71 MeV. The particle range in tissue is 8 mm. for the treatment of inlammation of the synovium in the knee only [12]. This treat- 32P-sodium phosphate can be used for two ment is more commonly known as radiation diferent therapies: palliation of pain from synovectomy/radiosynoviorthesis. There are bone and myeloproliferative multiple indications for use of 90Y-silicate/ diseases (polycythaemia vera and essential citrate for the treatment of joint pain arising thrombocythaemia) [3,14]. from arthropathies, including: rheumatoid arthritis, spondylarthropathy (e.g. reactive Since 32P-sodium phosphate accumulates in EANM or psoriatic arthritis), inlammatory joint dis- the hydroxyapatite crystal of the bones in a eases (e.g. Lyme disease) , Behçet´s disease, similar manner to phosphate, it is an ideal persistent synovial efusion, haemophilic tracer for palliation of pain from bone me- arthritis, calcium pyrophosphate dihydrate tastasis. This therapy can be administered ei- (CPPD) arthritis, pigmented villonodular sy- ther intravenously or orally. The intravenous novitis (PVNS), persistent efusion after joint therapeutic dose is 117–370 MBq, while the prosthesis, undiferentiated arthritis where oral dose range is commonly 370–740 MBq. the arthritis is characterised by synovitis, sy- novial thickening or efusion. Another use for 32P is in the treatment of polycythaemia vera and essential thrombo- The route of administration is intra-articular cythaemia [3]. 32P has been used successfully injection. In order to avoid leakage of the ra- to treat polycythaemia vera since 1939. Doses diocolloid from the joint space and to ensure are based on the patient’s weight and blood that it is absorbed by the phagocytes within counts. Intravenously administered doses the joint, the particle size must be between range from 37 to 740 MBq, with an average 10 and 20 µm. The size of the particles is also dose range of 37–296 MBq. Some patients important in ensuring that the radiocolloid require repeat treatments and doses are ad- remains uniformly within the joint space justed as necessary depending on the patient. without causing an inlammatory response. The dose commonly used is 185–222 MBq. 32P-chromic phosphate as a colloid is used in It was found by Gencoglu et al. that 58% of several contexts: for treatment of malignant patients had a good clinical response to this efusions/malignant diseases of the serosal therapy, with the remainder having a fair or cavities and of cystic and for ra- poor response [13]. diosynoviorthesis.

13 While the treatment of choice for malignant of 1.1 mm and a 9% abundant gamma emis- efusions, in both the chest and the abdo- sion with a photopeak of 0.137 MeV. The half- men, is typically chemotherapy, 32P-chromic life is 3.7 days. phosphate does provide a possible alterna- tive for some patients. This radiocolloidal 186Re-etidronate is used for the palliation of suspension is administered via intracavitary pain from bone metastases, osteoblastic me- injection directly into the serosal cavity (pleu- tastases or mixed osteoblastic lesions seen ral, pericardial or peritoneal). Pre-treatment as areas of intense uptake on a bone scan, imaging with 99mTc-sulphur colloid is required with the primary malignancy being either to determine the overall distribution of the prostate or breast carcinoma. Low blood cell tracer as well as to quantify the loculation, if counts may be a relative contraindication present. Common dose ranges are depen- when deciding to utilise this therapy option dent on the area/cavity being treated. The and should be evaluated carefully. The rec- suggested dose range for intraperitoneal ommended dose is 1,295 MBq and it is ad- administrations is 370–740 MBq, while for ministered intravenously [4]. Patients should intrapleural administration it is slightly lower, be informed that their bone pain may actu- at 222–555 MBq, and pericardial doses range ally increase in the irst week after adminis- from 185 to 370 MBq. tration of therapy owing to a phenomenon called “pain lare”. This should subside within When 32P-chromic phosphate is used for 2–4 weeks post administration. radiosynovectomy/radiosynoviorthesis the size of the colloid is extremely important. A 186Re-sulphide as a colloid is used for radio- particle size of 2–10 µm is needed to ensure synovectomy/radiosynoviorthesis therapy. that the particles can be engulfed by the 186Re-sulphur colloid is best used for hip, phagocytes and do not leak from the joint shoulder, elbow, wrist, ankle and subtalar space, potentially causing an inlammatory joints [12]. The activity administered and the response. The dose, which is injected directly total volume administered are dependent into the synovial joint, is determined by the on the joint to be injected. As with the other size of the joint and ranges from 10–20 MBq radiosynoviorthesis therapies, the route of for proximal interphalangeal joints to 185– administration is intra-articular. Dose ranges 222 MBq for knee joints. vary depending on the joint of interest: A typ- ical hip and shoulder dose range is 74–185 -186 MBq with a recommended volume of 3 ml. Rhenium-186 (186Re) is produced in a high The wrist and subtalar dose range is 37–74 lux reactor and emits a beta particle with an MBq with a smaller dose volume of 1–1.5 ml. energy of 1.07 MeV, with a soft tissue range The elbow dose range is 74–111 MBq with

14 Section I 1. Principles in Radionuclide Therapy

a volume similar to that of the wrist volume radionuclide interacts within the body in a of 1–2 ml. The ankle dose is 74 MBq with a similar way to calcium analogues. It rapidly recommended volume of 1–1.5 ml. The total clears from the blood and is absorbed in activity of one session should not exceed 370 metastatic bony lesions. MBq [12]. 89Sr-chloride is another tracer utilised for pal- -169 liation of pain from metastasis to the bones Erbium-169 (169Er) is a beta emitter with an or mixed osteoblastic lesions from primary energy of 0.34 MeV that is produced in a high breast carcinoma or hormonally resistant lux reactor. The soft tissue range is 0.3 mm. prostate cancer or any other tumour pre- The half-life is 9.4 days. senting osteoblastic lesions seen as areas of increased uptake on bone scans [4,14]. The

169Er-citrate colloid is used primarily for ra- recommended dose is 150 MBq and admin- EANM diosynovectomy/radiosynoviorthesis and is istration is via slow intravenous infusion. Pa- most appropriately used for metacarpopha- tients will generally begin to feel some pain langeal, metatarsophalangeal and digital relief 7–20 days after administration of the interphalangeal joints. The dose is admin- therapeutic dose. Low blood counts are a rel- istered intra-articularly and the site deter- ative contraindication for this treatment. All mines how much volume can be injected: patients should be monitored for changes in the metacarpophalangeal dose is 20–40 blood counts following this therapy. MBq with a recommended volume of 1 ml, the metatarsophalangeal dose is 30–40 MBq -153 with a recommended volume of 1 ml, and Samarium-153 (153Sm) is a beta-emitting ra- the proximal interphalangeal dose is 10–20 dionuclide produced from neutron irradia- MBq with a recommended volume of 0.5 ml. tion of samarium-152 oxide. 153Sm has an en- The total dose injected should not exceed ergy of 0.81 MeV and a soft tissue range of 0.6 750 MBq at any one time [12]. In a double- mm. Its half-life is 1.9 days. blind study it was found that treatment with 169Er-citrate colloid had positive results 153Sm-lexidronam is another therapeutic ra- in 58% of cases through destruction of the diotracer used for palliation of pain from me- rheumatoid pannus [15]. tastases to the bones or mixed osteoblastic lesions from primary prostate or breast cancer Strontium-89 or any other tumour presenting osteoblastic Strontium-89 (89Sr) is a beta emitter with an lesions seen as areas of increased uptake on energy of 1.46 MeV and a half-life of 50.5 bone scans. The recommended dose is cal- days. The soft tissue range is 2.4 mm. This culated as 37 MBq/kg and it is administered

15 intravenously. Since the administration of decreasing or eliminating the need for opi- this radiotherapeutic agent can cause bone ate [16]. This therapy appears to marrow suppression, it is important that the be a safe and eicacious method for treat- patient’s blood count is monitored following ing patients with bone pain [17]. The shorter the injection. Each patient’s dose will be dif- half-life permits a high dose to be delivered ferent as it is weight based. Patients may be- over a short period; this allows for multiple gin to experience pain relief as soon as one therapies if the pain is recurrent, which pa- week after administration, and signiicant tients seem to tolerate well [18]. pain relief may last an average of 16 weeks,

16 3. 1. References References I,Chapter 1 Section 9. Syed N, Sheppard AA, Manji MC, Holder RL, K, Boelaert 8. 7. 6. 5. 4. 2. Graham LS, Kereiakes JG, Harris C,Cohen MB. JG,Harris Nuclear Graham LS,Kereiakes lipiodol. BrJSurg. 2003;90:1379-83. of131I-labelled injection carcinoma withintra-arterial Preoperative K. Boudjema treatment of hepatocellular E,Bretagne M,Boucher JL,Messner JF,Raoul Campion JP, 2009;70:129-38. roidism. (Oxf). ClinEndocrinol hypothyroidism inpatientsreceiving 131Ifor hyperthy- SC,FranklynGough JA. Prediction ofcure of andrisk cine, 2007. radionuclide therapies. ofNuclearMedi- The Society molecularimagingto and nuclearoncology–practical tiuxetan (Zevalin®). lymphomaand for B-cell EANM procedure guidelineofradio-immunotherapy tive compounds. radioac- cancer andliver metastases with intra-arterial EANM procedure guideline for the treatment of liver of myeloproliferative diseases. EANM procedure guidelinefor 1989; 9:118-202. medicine from Becquerel to thepresent. Radiographics. Alazraki NP,Alazraki Shumate MJ, DA. Kooby A clinician’s guide metastatic bonepain. EANM procedure guidelinefor treatment ofrefractory EANM procedure guidelines for guanidine ( 131 I-mIBG) therapy. 90 Y-radiolabeled ibritumomab 32 P phosphate treatment 131 I-meta-iodobenzyl- 17 11. 10. 18. 17. insert. Quadramet package 16. 15. 14. 13. EANM procedure guidelinesfor radiosynovectomy.12. insert. TheraSphere® glassmicrospheres yttrium-90 package Cancer. 2007;109:637-43. 153 lexidronam to patients with metastatic bone pain. ofrepeat Sm- administrationofsamarium and eicacy O,Sartor RH,BushnellDL,QuickDP, Reid Ell PJ. Safety 2000;88(12 Suppl):2934-9. liation of bone pain associated with metastases. Cancer. Sm-153lexidronam AN.Samarium forSeraini thepal- AcadSeances D. Sci 1977;284:1001-4. oftheingers. CRAcad Hebd Sci arthritis in rheumatoid by erbium-169 study, ofsynoviorthesis oftheeicacy F,Delbarre C,Le A.Proof, Go Menkes by adouble-blind Williams and 2009. Wilkins, and quickreference, 2ndedn.Philadelphia: Lippincott P.Shackett procedures Nuclear medicine technology: Med. 2002;27:395-400. synovitis.silicate ClinNucl therapy knee inrheumatoid lin Gscintigraphy ofyttrium-90 for assessingtheeicacy of et al. Utility Tc-99m humanpolyclonal immunoglobu- O, EA,ArasG,Kucuk Gencoglu Atay G, Tutak I,Ataman S, insert. package SirSphere® microspheres microspheres) (yttrium-90

EANM Section I 2. Biological Efects of Ionising Radiation Katy Szczepura

Introduction When the energy is absorbed in an it The biological efects of ionising radiation is known as organ dose and is deined as ab- are complicated and are inluenced by many sorbed dose averaged over the whole organ. factors, including the amount and rate of energy imparted to the tissue, the type of Kerma radiation, the cell and tissue type involved, Another quantity used is kerma, which is also age and gender, and variation in individual measured in Grays. Kerma is an acronym for sensitivity to radiation [1, 2]. kinetic energy released per unit mass (or in matter or material ). It describes the energy This chapter discusses the biological efects transferred per unit mass of irradiated mate- of radiation, the deinitions of patient dose rial. and the calculation of risk, the way in which radiation causes damage, the efects that For low-energy ionising radiation, D and may occur and the diferent efects on tissues kerma are approximately the same, but at according to tissue type. higher energies (>1 MeV) they start to dif- fer. This is due to the fact that at higher inci- Deinitions of dose in biological tissues dent energies, the secondary that When ionising radiation interacts with a ma- are produced may themselves have high terial, the ionisation and excitation that occur energy and so deposit their energy outside cause energy to be deposited within that the mass of interest, or may themselves pro- material, known as dose. There are diferent duce radiation. This energy deinitions of radiation dose, depending on is included in the kerma measurement, but the situation under consideration. not in absorbed dose. Therefore the energy released and the energy absorbed are not the Absorbed dose same in the mass of interest. Absorbed dose The energy that is deposited per unit mass is the most useful measurement when con- of a material during interactions of ionising sidering biological efects of radiation. radiation is known as absorbed dose. This is a measurable quantity and is deined as: Equivalent dose It is important to consider the type of radia- E D = m tion that is depositing the energy to the tis- sue. Even for the same amount of energy, where D = absorbed dose, E = energy (joules) diferent radiation types cause difering and m = mass (kg). Therefore the SI units of amounts of damage. absorbed dose are J kg-1; this is known as a Gray (Gy).

18 Section I 2. Biological Efects of Ionising Radiation

Non-charged ionising radiation, such as , are known as indirectly ionising radiation; this is because an interaction of a photon and an will only cause a single ionisation, and most of the ionisation that then occurs is due to the secondary that is released. Figure 1: High and low LET [3] The diference in biological efects due to Charged particles interact by means of the the radiation type is relected in the radia- coulombic forces between the moving tion weighting factor (W ), which is deined charged particle and the electrons in the R as the ratio of the biological efectiveness . With electrons only a small amount of one type of radiation relative to that of X- of energy is deposited per event and many EANM rays, for the same amount of absorbed dose. thousands of events can occur along the The higher the W , the more damaging the path of the charged particle, which is rela- R radiation [4]. For regulatory purposes, W has tively large compared to cellular dimensions; R been measured through experimentation the ionisation density is therefore considered and agreed internationally by governments to be low. Heavy charged particles, such as and regulatory bodies. Table 1 [5] shows the alpha particles, travel much shorter distances W for common ionising . and therefore the ionising events are more R closely spaced and within distances compa- rable to a single strand of DNA. Radiation Radiation type and energy weighting factor (W ) For these reasons, diferent types of radiation R cause diferent amounts of damage even Photons, all energies 1 for the same amount of energy deposited, Electrons, muons, all energies 1 with photons causing the least and heavy charged particles, the most. This is known Protons >2 MeV 2 as linear energy transfer (LET) and is deined Alpha particles, ission 20 as the sum of the energy deposited per unit fragments, heavy nuclei path length of the radiation (Fig. 1) [3]. Table 1: Radiation weighting factors [5]

19 The SI unit of equivalent dose is J kg-1, but publications 58 [6] and 92 [5] and Interna- it is given the unit (Sv) to distinguish tional Commission on Radiation Units and it from absorbed dose. Equivalent dose is Measurements (ICRU) report 67 [7]. mainly used for pur- poses. Efective dose Absorbed and equivalent dose take into ac- Relative biological efectiveness – weighted count the amount of energy, the mass of the dose tissue and the radiation used, but they do More useful in the context of radionuclide not take into account the type of tissue be- therapy is relative biological efectiveness ing irradiated. (RBE), deined as the ratio of a dose of a low- LET reference radiation to the dose of radia- Organs have diferent sensitivities to ra- tion that elicits the same biological response, diation, known as radiosensitivity, based on quantitatively and qualitatively. The RBE de- their tissue type, which will be discussed in pends on the radiation type, the dose rate, more depth later in this chapter. Efective dose the distribution of dose in time, the cells (or (E) is a calculation that takes into account this tissues) exposed and the type of injury inves- variation in radiosensitivity. It is a calculation tigated. of risk of the patient developing fatal cancer due to the irradiation. When considering radionuclide therapy, the ICRP recommends that the organ dose is Each organ is given a tissue weighting factor weighted by the RBE of the speciic biological (WT), based on that organ’s risk of developing response. It is important to recognise the dif- cancer. A WT for each organ has been calcu- ference between WR and RBE when consid- lated by the International Commission for Ra- ering dose to an individual: RBE is a quantity diological Protection (ICRP) and attempts to for deterministic endpoints measured under provide a single number that is proportional a speciic set of experimental conditions and to the overall detriment from a particular, is tissue and source location dependent, often inhomogeneous, type of radiation ex- whereas WR is a single set of values chosen posure. The overall detriment represents a by committee review and so has less value balance between cancer incidence, cancer when considering dose to an individual. mortality, life shortening and hereditary ef-

fects. Table 2 shows the most recent WT as Guidance on appropriate values for the RBE published by the ICRP [8]. for deterministic efects can be found in ICRP

20 Section I 2. Biological Efects of Ionising Radiation

Tissue Sum are variations in radiosensitivity that can af- fect the risk of radiation-induced cancer or, Organ weighting of WT at higher doses, tissue damage. A proportion factor (WT) values of this range is likely to be due to genetic Bone marrow (red), colon, lung, stomach, diferences, but recent studies demonstrate 0.12 0.72 breast, remainder that lifestyle factors, particularly tobacco use, tissuesa afect an individual’s risk [2]. Gonads 0.08 0.08 Efective dose calculation for radionuclides Bladder, oesophagus, 0.04 0.16 liver, thyroid A schema for calculation of absorbed doses has been developed by the Medical Internal Bone surface, brain, 0.01 0.04 salivary glands, skin Radiation Dose Committee (MIRD) and this

methodology has been widely adopted. In EANM Total 1.00 1.00 addition, the ICRP has introduced biokinetic a Remainder tissues: adrenals, extrathoracic (ET) re- models and data. This has resulted in estima- gion, gall bladder, heart, kidneys, lymphatic nodes, tion of the efective dose for a large num- muscle, oral mucosa, pancreas, prostate (♂), small in- testine, spleen, thymus, uterus/cervix (♀) ber of . The igures are given in mSv/MBq, meaning that an estima- Table 2: Recommended tissue weighting tion of the efective dose to a single patient factors [8] can be made simply by multiplying with the It is important to recognise that efective administered activity. It must be noted that dose is a measurement of risk to an average variations from patient to patient can be very person and is based on general populations; large; nevertheless, a rough estimation of the it should never be used to calculate the risk efective dose to the patient can be made. In to an individual as it does not take into ac- order to calculate absorbed dose and organ count the individual’s age, gender or radio- doses for an individual patient, one requires sensitivity. knowledge of the emissions of the radionu- clide, the activity administered, the activity Risk estimates are taken from groups of peo- in the speciic organ and in all other organs, ple with known exposures, such as the atom- the size and shape of the organ, the kinetic ic bomb survivors of Hiroshima and Nagasaki properties of the and its in 1945. Diferences in genetics, natural levels quality. These factors are not readily available of cancer, diet, smoking, stress and unknown for the individual patient. bias afect these results. The doses, and dose rates, during these events were much higher DNA damage than the regulated dose levels used medi- The energy that is transferred during ionising cally. There is growing evidence that there radiation interactions can be used to break

21 chemical bonds. In living tissue this breaking One of the most important features of DNA of bonds can be detrimental to cells, and can is that it can replicate and repair. During a kill the cell or cause it to reproduce abnor- process called mitosis, the cell divides and mally. replicates its genetic material, becoming two distinct cells, hence allowing growth and re- The biological efects of ionising radiation are production of the cell. mainly due to damage to the nuclear DNA chain. Ionising radiation can directly interact with DNA to cause ionisation, thus initiating the chain of events that lead to biological changes [9) (10]. This is called direct action, which is the main process for radiation with high LET, such as alpha particles or . Ionising radiation can also interact with mol- ecules within the cell, in particular , to produce free radicals, which are able to go on to interact with the DNA chain and cause damage. This is called indirect action (11].

Deoxyribonucleic acid (DNA) DNA is a complex macromolecule that con- tains the genetic instructions used in the de- velopment and function of all living tissues. Image published with courtesy of the owner It consists of bases attached to a “backbone” Figure 2: DNA double-helix structure [12] of alternating sugar and monophosphate molecules. The bases are: adenine (A), gua- It is well recognised that the most impor- nine (G), cytosine (C) and thymine (T). A and tant lesion caused by ionising radiation is G are purines and are the two larger bases. C the double-strand break (DSB), in which both and T are pyrimidines and are the two smaller strands in the DNA helix are severed. Once bases. Due to their size, a large base and a damaged, the DNA will attempt to repair it- small base combine opposite to each other self. There are two main mechanisms of re- to create the well-known double helix (C pair: homologous recombination (HR) and and T together would be too small, A and G non-homologous end joining (NHEJ). In HR together would be too big). Because of the an undamaged DNA chain, with the same in- chemical structure of the bases, C and G are formation, is used as a template to replicate always paired, and T and A are always paired the damaged part. The damage is removed (Fig. 2) [12]. and replaced by this replicated piece. NHEJ is

22 Section I 2. Biological Efects of Ionising Radiation

a rough form of repair in which the two dam- aged ends of the breaks are rejoined [11].

Once the repair mechanisms have been at- tempted, there are three main outcomes: the DNA has been repaired correctly and the cell becomes a viable cell; the DNA has been repaired incorrectly and the cell becomes a mutated cell; and the DNA was not able to be repaired and the cell becomes an unviable cell. If the DNA is repaired correctly, there is no lasting efect of the ionising incident, and so it needs no further consideration. EANM

There are two categories of efects: somatic ef- fects, where the damage afects the individual who has been exposed, and genetic or heredi- tary efects, where the damage occurs in the cells used for reproduction, known as germ cells, and so will afect subsequent generations. Image published with courtesy of the owner Mutation If the DNA has been repaired incorrectly, Figure 3: A damaged cell may undergo apop- then the “code” within the cell is no longer tosis if it is unable to repair genetic errors [12] correct. This is known as a mutation, and if The efects that occur due to mutation and this cell then replicates and multiplies, cancer apoptosis are generally divided into two cat- can result. On occasion the mutation to egories, deterministic and stochastic efects. the cell multiplying with no control and ex- ceeds the natural rate of cell death; this can Deterministic efects lead to the development of a tumour. Deterministic efects describe how the ra- diation causes a large amount of cells to Apoptosis die, resulting in damage to the organ. The Apoptosis is the regulated death that a cell body is naturally capable of replacing killed undergoes naturally once it has completed cells, but there is a critical value at which its life cycle. If a cell has become unviable, the body can no longer compensate for the then the cell may recognise this and go number of cells that are non-functioning or through apoptosis (Fig. 3) [12].

23 have died. Therefore there is a threshold ra- Cataracts. Cataract occurs due to accumu- diation dose below which deterministic ef- lation of damaged or dead cells within the fects are not seen, and as the dose increases lens, the removal of which cannot take place past this threshold value, the number of naturally. Cataracts may occur after 0.5 Gy cells that die, and so the severity of the ef- has been received, but may take years to de- fect, increases. velop [15].

Deterministic efects can be divided into two Sterility. Radiation can impair the female categories, acute and late efects. Acute ef- germ cell function, leading to impaired fer- fects occur in tissues that are rapidly prolif- tility or infertility. The dose required to have erating, such as in the epithelial surfaces of this efect decreases with age as the number the skin or alimentary tract. These cells are of cells decreases. Similarly, radiation expo- replaced by cells that are more tolerant to sure to the testes can result in temporary or radiation, and these efects therefore subside permanent limitations in sperm production. after 3-4 weeks. Late efects are typically not Permanent sterility occurs after 2.5-3.5 Gy has seen for 6 months after irradiation and devel- been received by the gonads. op through complex interacting processes that are not yet well understood [13]. (radiation sickness). Radiation sickness involves nausea, vomit- Efects are dependent on the area irradiated ing and diarrhoea developing within hours and the dose received. Acute efects include or minutes of a owing to skin erythema, epilation, fatigue, nausea and deterministic efects on the bone marrow, vomiting, while late efects include tissue gastrointestinal tract and central nervous necrosis, sterility, cataracts and secondary system [15]. cancers [13]. Deterministic efects on the foetus. Determin- Thresholds and timelines for deterministic istic efects during pregnancy depend not efects only on the radiation dose received but also Skin erythema/necrosis/epilation. Erythema on the gestational age at which it occurred. occurs within 1-24 hours of exposure to dos- The embryo is relatively radioresistant dur- es greater than 2 Sv. Breakdown of the skin ing its pre-implantation phase but highly surface occurs approximately 4 weeks after radiosensitive whilst organs are forming (at 15 Sv has been received. Epilation is revers- 2-8 weeks) and in the neuronal stem cell ible after 3 Sv but irreversible after 7 Sv and proliferation phase (at 8-15 weeks). Foetal occurs 3 weeks following exposure [14]. radiosensitivity falls after this period. High

24 Section I 2. Biological Efects of Ionising Radiation

levels of radiation exposure in pregnancy Radiosensitivity of cells can lead to growth retardation, in particular In 1906, experiments carried out by two microcephaly. The threshold dose for this ef- French scientists on rodents deined the ra- fect is high (>20 Gy), with other deterministic diosensitivity of cells based on their funda- efects (hypospadias, microphthalmia, retinal mental characteristics. The Law of Bergonie degeneration and optic atrophy) having a and Tribondeau [16] states that radiosensitiv- lower threshold level of >1 Gy [15]. ity is based on three factors:

Stochastic efects • The mitotic rate: The rate at which the cells Stochastic means statistical in nature, and divide and multiply: the higher the mitotic these efects arise through chance. Stochas- rate, the greater the radiosensitivity of the tic efects occur due to mutations in the DNA cell. chain and have no threshold value. As ab- EANM sorbed dose increases, the risk of observing • The mitotic future: How long the cell is able these efects increases, and the risk is consid- to divide for: the longer the mitotic future, ered proportional to the dose. The severity the greater the radiosensitivity of the cell. of the efect is not related to the absorbed dose; the person afected will either develop • State of diferentiation: An undiferentiated cancer or they will not. cell is an immature, embryonic or primitive cell. It has a non-speciic appearance with Stochastic efects are cancer if the efect oc- multiple non-speciic functions. A diferenti- curs in the person’s own cells (somatic cells) ated cell is highly distinct or specialised. Dif- and genetic mutations in subsequent gen- ferentiation predicts how vulnerable a cell erations if the efect occurs in the germ cells. will be to radiation. The more diferentiated a cell is, the more radioresistant it will be. The tissue weighting factors discussed previ- ously in this chapter are based on the risk of In 1968, Rubin and Casarett [17] deined stochastic efects occurring. The risk is based ive cell types with difering radiosensitiv- on the tissue type that the organ consists of. ity according to the characteristics shown in Table 3 [16].

25 Cell type Mitotic rate Example Radiosensitivity

Vegetative Mitotic rate: Erythroblasts Most radiosensitive intermitotic cells rapidly dividing Intestinal crypt cells (VIMs) Mitotic future: Basal cells of the skin short Diferentiation: undiferentiated

Diferentiating Mitotic rate: Spermatogonia Relatively radiosensitive intermitotic cells actively dividing (DIMs) Mitotic future: eventually mature into a diferentiated cell line Diferentiation: irst level of diferentiation

Multipotential Mitotic rate: Fibroblasts Intermediate connective tissue irregularly divide if the body Endothelial cells radiosensitivity cells (MCTs) needs to replace them Mitotic future: relatively long Diferentiation: more diferentiated than VIMs or DIMs

Reverting Mitotic rate: Parenchymal cells of Relatively radioresistant postmitotic cells do not normally divide, but the liver (RPMs) can do so if the body needs Lymphocytes to replace them Mitotic future: relatively long Diferentiation: diferentiated

Fixed postmitotic Mitotic rate: Some nerve cells Most radioresistant cells (FPMs) do not and cannot divide Muscle cells Mitotic future: Red blood cells can be long or short lived Diferentiation: highly diferentiated

Table 3: Cell types with difering radiosensitivity according to the criteria of Rubin and Casarett [16]

26 Section I 2. Biological Efects of Ionising Radiation

A more modern way of considering the bio- Dose calculation is complex and highly de- logical efects on a cellular level is the Micha- pendent on the individual circumstances. lowski classiication of cells. Under this clas- Diferent terms exist, and are used depend- siication, cells fall into three categories: ing on whether radiation protection or radio- therapy is under consideration. When con- • Stem cells – continuously divide and re- sidering populations, efective dose is useful produce to give rise to both new stem in generalising risk, but when considering an cells and cells that eventually give rise to individual one needs to look at the individual mature functional cells. organ dose and consider the RBE for the - ising radiation being used. • Maturing cells arising from stem cells that through progressive division eventually Recent studies have shown that radiosen-

diferentiate into end-stage mature func- sitivity is dependent on many factors when EANM tional cells. considering an individual, and that as well as age and gender, lifestyle factors and genetics • Mature adult functional cells that do not testing may inluence dose planning in the divide. future [2].

Summary Ionising radiation causes damage to tis- sues through ionisation, either directly with the cell or indirectly with water, leading to free radicals. The main target for damage is the DNA chain, where the ionisation causes breaks within the chain. Once damaged, the DNA will repair correctly, repair incorrectly or be so damaged that it will become non- functioning or die. Incorrect repair causes mutations, known as stochastic efects, whereas cell death leads to deterministic ef- fects such as necrosis, which is required for efective radiotherapy.

27 References Section I, Chapter 2

References 1. Wall BF, Health Protection Agency . Centre for Radiation 9. Valentin J. Low-dose extrapolation of radiation-related CaEH. Radiation risks from medical X-ray examinations cancer risk. Ann ICRP. 2005;35(4):1-140. doi: 10.1016/j. as a function of the age and sex of the patient. Didcot: icrp.2005.11.002. PubMed PMID: 16782497. Centre for Radiation Chemical and Environmental Haz- ards; 2011. iii, 66 p. 10. Lehnert S. Biomolecular action of . Bristol: Institute of Physics; 2008. 2. Radiation AGoI. Human Radiosensitivity - RCE 21. Ox- fordshire: Health Protection Agency, 2013. 11. Urbano KV. Advances in genetics research. Hauppauge, N.Y.: Lancaster : Nova Science ; Gazelle [distributor]; 2011. 3. Szczepura K. Linear Energy Transfer. 2013. xii, 290 p.

4. Allisy-Roberts P, Williams JR, Farr RFPfmi. Farr’s physics 12. Medicine UNLo. What is DNA? 2013. for . 2nd ed. / Penelope Allisy-Roberts, Jerry Williams. ed. Edinburgh: Saunders; 2008. 13. DeVita VT, Hellman S, Rosenberg SA. Cancer : principles & practice of oncology. 7th ed. Philadelphia, Pa.: Lip- 5. Task Group on Radiation Quality Efects in Radiological pincott Williams & Wilkins; 2005. 1 CD ROM p. Protection CoRE, I.ternational Commission on Radio- logical Protection. Relative biological efectiveness (RBE), 14. Balter S, Hopewell JW, Miller DL, Wagner LK, Zelefsky quality factor (Q), and radiation weighting factor (w(R)). MJ. Fluoroscopically guided interventional proce- A report of the International Commission on Radio- dures: a review of radiation efects on patients’ skin logical Protection. Ann ICRP. 2003;33(4):1-117. PubMed and hair. Radiology. 2010;254(2):326-41. doi: 10.1148/ PMID: 14614921. radiol.2542082312. PubMed PMID: 20093507.

6. International Commission on Radiological Protection C. 15. Stewart FA, Akleyev AV, Hauer-Jensen M, Hendry JH, RBE for deterministic efects : a report of a Task Group Kleiman NJ, Macvittie TJ, et al. ICRP publication 118: ICRP of Committee 1 of the International Commission on statement on tissue reactions and early and late efects Radiological Protection. Oxford: published for the In- of radiation in normal tissues and organs--threshold ternational Commission on Radiological Protection by doses for tissue reactions in a radiation protection Pergamon; 1990. v,57 p p. context. Ann ICRP. 2012;41(1-2):1-322. doi: 10.1016/j. icrp.2012.02.001. PubMed PMID: 22925378. 7. International Commission on Radiation Units and M. Absorbed-dose speciication in nuclear medicine. Ash- 16. Bushberg JT, Seibert JA, Leidholdt EM, Boone JM. The ford, Kent: Publishing; 2002. 120 p. essential physics of medical imaging. 3rd ed., Interna- tional ed. ed. Philadelphia, Pa. ; London: Wolters Kluwer/ 8. Wrixon AD. New ICRP recommendations. J Radiol Prot. Lippincott Williams & Wilkins; 2012. 2008;28(2):161-8. doi: 10.1088/0952-4746/28/2/R02. PubMed PMID: 18495983. 17. Rubin P, Casarett GW. Clinical radiation pathology. Phila- delphia: W. B. Saunders Co.; 1968.

28 sorbed doseisGray whichequals1J/kg. (Gy), sorbed and the mass of thevolume. imparted The unitofab- delivered. administered dosesubsequently ity ortheabsorbed avoided, asthiscanrefer to eitherthelevel ofactiv- The term The is thesumofallenergy depositsinagiven volume. and depositsenergy.interacts The energy imparted When ionisingradiationtravels through matter, it s,is Bq h. orBq occur inagiven region over oftime. aperiod The unit The equals 1/s. of decays persecond. The unitisBecquerel which (Bq) The 1. 1 Introduction Sjögreen Gleisner,Katarina GlennFlux LidiaStrigari, Radiotherapy inMolecular 3. Dosimetry I Section something which varies between patients between something whichvaries accumulates over time in diferent tissues, that the amountofradiopharmaceutical depends on thisdistribution vance, in MRT canbeplannedinad- dose distribution andhencetheabsorbed tion geometry andBT, inEBRT Unlike where theirradia- whereas inBT solidradiationsources are used. given systemically asaradiopharmaceutical, the source isdifuseandtherapy isnormally inside thepatient’s body. However, inMRT to BT inthattheradiationsource islocated similar isvery radiotherapy (MRT) Molecular delivered to target tissues and organs at risk. dose always oftheabsorbed madeinterms treatment planning, andprescriptions are without prior or brachytherapy (BT) (EBRT) treated beamradiotherapy withexternal It isunthinkable It Quantities activity absorbed dose cumulated activity ‘dose’ of a radioactive sampleisthemeannumber ofaradioactive alonecanbeconfusingandisbest isthequotientofmeanenergy thatapatient would be isthenumberofdecays that

29 tissue (Fig. Sjögreen Gleisner). 1,K. before losingitsenergy, inanother perhaps it wasemitted, oritmay travel somedistance point ofdecay, i.e. inthesametissuewhich to itsenergy the inclosevicinity may impart emitted decay atradioactive tient. A particle andthe individual pa- radiopharmaceutical speciicto the cording to pharmacokinetics in ceutical distributes the patient’s bodyac- Following administration, the radiopharma- dosimetry Internal specialised inoncologyornuclearmedicine. nologists, medicalphysicists, andphysicians gists, radiographers, nuclearmedicinetech- as teamwork biomedical technolo- between isregarded in MRT essential that dosimetry in otherradiationtreatment modalities, itis oftissues.diobiological As characteristics into considerationalongwithra- be taken prediction oftreatment efects, andhasto and the theadministeredtween activity be- constitutes thebridge dosimetry MRT administered.than on the level of activity doses delivered, andBT, asfor EBRT rather dependentontheabsorbed are primarily therapy, ofresponse interms andtoxicity, reasonable to assumethattheefects of dose ismore cumbersome. However, itis for MRT, ofthe the determination absorbed and therefore needsto bemeasured. Thus

EANM The basic equation is given by:

r r r r r D( T ← S ) = Ã( S ) · S( T ← S ) (Eq 1)

The quantity Ã(rS ) is called the cumulated activity. It represents (i) above and equals

the activity in a source region rS , integrated over time. The transport of radiation energy (ii) is diicult to calculate for every individual and therefore has been tabulated for stan- dardised reference geometries, speciic for radionuclide, age and gender. These so- r r called S-factors, S( T ← S ), describe the ab-

sorbed dose in a target region rT, from activ- r ity residing in a source region S , and are giv-

K. Gleisner Sjögreen en in units of mGy/(MBq s). The mass of the target tissue (iii) is implicitly included in the Figure 1: The standardised reference geometry S-factors since these are calculated for tissue used to calculate the factors S(rT ← rS) in weights according to standard geometries. the MIRD dosimetry schema. The igure In order to be applicable for an individual pa- mimics a situation where radiopharmaceutical tient, the S-factors need to be rescaled to the is located in the kidneys, which thus constitute tissue weight of the individual patient. rS . , illustrated in orange, mainly deposits energy locally, whereas Frameworks for calculation of the absorbed emitted gamma radiation, illustrated in blue, dose to individuals given a radiopharmaceu- reaches outside the patient’s body. tical are given by the Medical Internal Radia- The total amount of decays that occur within tion Dose (MIRD) Committee of the Society a tissue thus determines the totally emitted of Nuclear Medicine and the International radiation energy from that tissue. In order Commission on Radiological Protection to determine the distribution of absorbed (ICRP) [1], and guidance in reporting by the r Dosimetry Committee of the European Asso- dose, D, in a target region, T , knowledge is required concerning: (i) the total number of ciation of Nuclear Medicine (EANM) [2]. decays occurring in diferent tissues, (ii) the pattern with which the emitted particles Absorbed dose planning in MRT impart their energy and (iii) the mass of the Is it then possible to prescribe an MRT treat- tissues where the energy absorption takes ment based on absorbed dose? One pos- place. sibility is to perform a pre-therapy study

30 Section I 3. Dosimetry in Molecular Radiotherapy

using a tracer amount of radiopharmaceuti- as a factor describing the organ absorbed cal, and to determine the tumour and or- dose per administered activity, in units of gan absorbed doses that are obtained as a mGy/MBq (Fig. 2, K. Sjögreen Gleisner). result. Usually, this information is expressed K. Gleisner Sjögreen

Figure 2: Outline diagram for planning the absorbed dose in an MRT treatment.

If the therapeutic administration is then outside the patient’s body. Often, radionu- EANM given under similar conditions, this factor clides that emit both particles and gamma can be used to determine the activity that photons are preferable. Gamma photons be- needs to be administered in order to deliver have diferently from particles in that some a prescribed absorbed dose to a given organ interact whilst others penetrate the patient’s or tissue. A second possibility arises when body and thus allow measurement using an patients are given a series of administrations external counter or a scintillation camera. at intervals of a few weeks to a few months, Activity quantiication is based on determi- as is often the case for a radiopeptide or nation of the level of emitted gamma radia- for iodine-131 metaiodiobenzylguanidine tion inside the body, from measurement of (131I-mIBG) treatments of neuroendocrine the penetrating gamma radiation. Given the cancers. In that case it is possible to plan a level of emitted gamma radiation, the activ- treatment according to the biokinetics ob- ity and consequently the level of emitted tained from a previous therapy procedure. particle radiation can be calculated. These predictions in particular can be very accurate. On a photon’s passage from the site of decay to the detector or camera it travels through Measurement and quantiication of the tissue. The probability that a photon will in- activity distribution teract is mainly governed by two parameters: Radionuclides used for therapeutic purposes the atomic composition and the total thick- are those that emit particle radiation, such as ness of the tissue along the photon trajectory. electrons from beta-minus decay, or alpha Having interacted, the photon may continue particles. Such particles have a comparative- its passage, although in a diferent direction ly short range in tissue and rarely penetrate and with a lower energy. The photons that

31 provide correct information on the location of the retention curve and knowledge of the of decay are those that penetrate without amount of administered activity, the total- interaction, the so-called primaries. Photon body cumulated activity can be determined. attenuation is the reduction of the amount of It is important that the patient counter ge- such primaries. Scattered photons are those ometry is kept constant for all measurements that are detected but have interacted along that presence of metal near the patient or their passage and thus carry false informa- detector is avoided to keep the room scatter tion about the point of decay. Attenuation low and that care is taken to remove any pos- thus causes a loss of detected counts, so that sibly contaminated material in the room. For a factor used for attenuation correction must a gamma emitter such as 131I, the total-body have a value greater than one. Scatter causes retention curve can be used for estimation of a falsely increased count rate, and it is desir- the red marrow absorbed dose [3, 4]. able to remove such counts. Image-based activity quantiication Practically, there are several methods for de- In image-based activity quantiication the termining the amount of activity in a patient, underlying idea is that each image element and the choice of method depends on the can be viewed as a detector, so that the pixel level of accuracy required. All methods in- or voxel count rate relects the number of volve repeated patient measurements, since detected photons in a particular position. By the aim is to follow the activity retention over delineating a region or volume in an image, time. The timing of the measurements needs the total number of photons from a given to be distributed with regard to typical bioki- anatomical region can be determined. The netic behaviour of the radiopharmaceutical. delineation of organs and tissues is central It is an advantage if exactly the same equip- in the determination of the activity (Fig. 3, ment can be used for all measurements. It is K. Sjögreen Gleisner). also essential that clinical protocols are care- fully set up, and that patient positioning fol- lows agreed routines.

Probe-based measurements The activity retention in the body can be assessed by serial measurements using a standard probe dose-rate meter. The irst measurement will represent 100% of the ad- ministered activity if it is made shortly after infusion, but prior to voiding. By curve itting

32 Section I 3. Dosimetry in Molecular Radiotherapy

Activity in a region-of-interest, for instance, in one of the kidneys.

Time post injection Time post injection EANM K. Gleisner Sjögreen

Figure 3: Quantiication of the activity in organs from planar images. The left panel shows an example of images acquired during 177Lu-DOTATATE therapy for neuroendocrine tumours at diferent times after administration. ROIs used for organ activity quantiication are delineated in the images. For each ROI, a curve is itted to the activity versus time data (right panel), and the cumulated activity is determined by calculation of the area under the curve.

This task may seem trivial but there are several for activity quantiication [5-7]. The advan- aspects that need to be considered. Firstly, it tages of this method are that the whole body is essential that the operator has good knowl- is covered and that the acquisition time is edge of the intrinsic properties of nuclear comparatively short. A considerable draw- medicine images, where limited spatial reso- back is that a planar image is a two-dimen- lution produces an image intensity which is sional representation of a three-dimensional distributed over a volume or area that is larger activity distribution, and it is diicult to com- than the actual organ. Moreover, in order to pensate for activity residing in tissues lying achieve a good interpretation of the images it over or under the organ of interest. It is thus is important that the personnel who perform considered to be best suited for estimation delineation are trained in anatomy and physi- of the cumulated activity in the total body ology and have easy access to the patient and larger organs for radiopharmaceuticals history and the results of other image-based that exhibit a well-deined uptake with a examinations. low level of background activity. Attenuation correction can be performed based on trans- The most commonly employed method is mission studies, obtained using an external still to acquire anterior-posterior planar scans radionuclide lood source or using an X-ray and then apply the conjugate view method CT scout. It is then necessary for the patient

33 to maintain a similar position in the transmis- Radiopharmaceuticals used in radionuclide sion and radionuclide imaging sessions. To- therapies generally have a relatively long bio- mographic imaging with SPECT and PET en- logical half-life, which has to some extent lim- ables the activity distribution to be resolved ited more widespread use of luorine-18 PET in three dimensions. From such 3D images, imaging for dosimetry. However, an increas- measurements of the activity concentration ing number of research studies are using can be determined for the body region cov- longer-lived PET radionuclides for dosimetry ered by the scan. The preferred method for purposes, including iodine-124 (4.2 days), activity quantiication is to include it as part zirconium-89 (3.3 days), copper-64 (12.7 h) of the image reconstruction, provided that and yttrium-86 (14.7 h) [10-12]. Also it has re- corrections for attenuation and scatter can cently been determined that yttrium-90 can be included [8]. For such corrections, an at- be imaged using PET [13], and this is now the tenuation map is required, and can be ob- subject of many research studies. tained from a CT study which is registered to the SPECT or PET study. In this regard, Calculation of the absorbed dose hybrid SPECT/CT and PET/CT systems ofer From the values of the activity in a tissue at signiicant advantages for the purposes of diferent times, the cumulated activity is de- dosimetry. Although in principle SPECT and termined by integration, and the mean ab- PET images allow determination of the activ- sorbed dose can be determined using Eq. 1. ity concentration in a volume represented by Generally, this method is used when activity each voxel, tissues that are small in compari- measurements are made using a probe for son to the spatial resolution will be afected the total body, or when using planar imag- by resolution-induced “spill-out” of activity, ing for whole-organ dosimetry. Quantitative with an underestimated activity concentra- SPECT/CT or PET/CT allows for dosimetry in tion as a result. For SPECT the spatial resolu- smaller volumes using voxel-based methods tion can be in the order of 1 cm or more, and (Fig. 4, K. Sjögreen Gleisner). the activity concentration in smaller organs such as the kidneys and tumours may be underestimated. This is the so-called partial volume efect and it should also be corrected for. Methods involving a combination of pla- nar and tomographic imaging techniques have been explored, whereby the activity re- tention curve is measured by planar imaging and its amplitude is adjusted to absolute val- ues of the activity concentration or absorbed dose rate as determined from SPECT/CT [9].

34 Section I 3. Dosimetry in Molecular Radiotherapy EANM K. Gleisner Sjögreen

Figure 4: The left panel shows a transverse slice of a SPECT/CT study acquired during 177Lu- DOTATATE therapy for neuroendocrine tumours. If quantitative tomographic reconstruction is available, then quantiication of the activity, or activity concentration, in organs and tumours can be performed by delineating volumes of interest (VOIs) in SPECT/CT images. Such activity values can be used to calculate the absorbed dose according to the MIRD schema (Eq. 1). Another possibility (right panel) is to calculate the absorbed dose rate distribution on a voxel-by-voxel basis by using the SPECT/CT images as input to a Monte Carlo code that mimics the particle emission and subsequent interactions in the patient’s body. The VOIs are then applied in the resulting absorbed dose rate image.

From the 3D distribution of activity concen- dose calculation code. If co-registration is tration values, the absorbed dose rate dis- available, the dose rate maps from SPECT/CT tribution can be calculated using so-called or PET/CT images acquired on diferent occa- point dose kernels or voxel S values, describ- sions can be used to calculate a 3D map of ing the energy deposition pattern around a the absorbed dose [14] where organ delinea- point source located in water (or bone). This tion can be made. Otherwise, organ delinea- method assumes that the anatomical region tion needs to be performed in each separate is homogeneous in terms of density, such as image. Whichever dosimetry method is used, soft tissues within the trunk. For body regions a determination of the mass of the target re- where the density is heterogeneous, as in gion is required. The mass can be determined the lungs, a direct Monte Carlo calculation is using the CT image either on a voxel basis by preferable. Here, the activity distribution from applying a calibration relationship, such as is SPECT or PET is used as input to a Monte Carlo normally done in EBRT [14], or by delineating

35 the target region and assuming a reference • Repopulation: During MRT, the cells in value for the mass density. some tumours and some normal tissues grow, partially counteracting the cell kill- ing. Repopulation in normal tissues is also The aim of radiobiology is to establish rela- an important mechanism to counteract tionships between the absorbed doses de- acute side-efects. livered and the radiobiological efects in tis- sues and tumours. Currently in MRT few such • Redistribution: Cells have diferent ra- relationships have been established, but this diosensitivity at diferent parts of the cell is an area of intensive research. Radiobio- cycle. The highest radiation sensitivity is in logical models in MRT can be adopted from the early S and late G2/M phase. EBRT and BT through calculation of the bio- logically efective dose (BED). The BED takes All of these mechanisms can be included in into consideration the absorbed dose, the the linear quadratic model (LQM). absorbed dose rate and the capacity of tu- mours and tissues to repair induced radiation The linear quadratic model damage. Ideally the correlation between pre- The LQM applies to diferent treatment regi- and post-treatment dosimetry should be as- mens, including MRT, and allows the use of sessed to increase the predictive capability of BED, a quantity with the dimensions of Gy. absorbed dose-response relationships. This is useful to compare diferent irradiation schemes and to evaluate the impact of treat- The ‘four Rs’ of radiobiology ment in both tumours and normal tissues. The ‘four Rs’ of radiobiology summarise the The radiosensitivity of tumours and tissues main features of cell survival of tumours and can be considered using the parameters α, normal tissues [15]: which represents the radiosensitivity and is lower for radioresistant cells, and the α/β ra- • Repair: Powerful repair mechanisms coun- tio, which indicates the response to fraction- teract DNA damage induced by ionising ation and to diferent dose rates. This ratio is

radiation with a repair half-time, Trep, from approximately 10 Gy for tumours and 3 Gy for minutes to hours; late-responding tissues.

• Reoxygenation: stabilises the ef- Radiobiological models fect of radiation. Hypoxic cells are the The most commonly used radiobiological main obstacle to tumour curability, but, as models are the tumour control probability the radiation dose is usually delivered over (TCP) and the normal tissue complication several days, there is suicient time for its probability (NTCP). The TCP depends on N*, reoxygenation. the initial number of clonogenic cells, which

36 Section I 3. Dosimetry in Molecular Radiotherapy

is the fraction of cells that have the potential a few organs [16]. The maximum tolerated to proliferate and give rise to a tumour. Usu- dose depends on tissue and patient char- ally N* is considered proportional to the tu- acteristics and can be lowered by the use of mour volume. Palpable tumours are usually chemotherapy agents. characterised by 109 cells/cm3 (large masses may contain 1012 cells/cm3, while microscop- Normal tissues are more spared than tu- ic tumours/micrometastases contain about mours by a continuous low dose rate, and 106 cells/cm3). As expected, a TCP value cal- the LQM predicts a greater beneit due to culated at the same absorbed dose and with multifractionated treatments, using an α/β of the same radiobiological parameters (α and 3 Gy. However, full understanding of a dose- β) decreases when N* increases, as more cells efect relationship is limited by a lack of re- require a higher absorbed dose for eradica- ported clinical data. An improvement to the tion. Obviously, tumour response also de- dose-response models should include the EANM pends on concurrently given agents, such as efects of non-uniform dose distributions [17, chemotherapy. 18] as well as clinical risk factors.

Sparing of normal tissues is essential for a Clinical evidence for dosimetry good therapeutic outcome. This is largely A BED response curve for damage dependent on the tissue architecture, which has been reported after peptide receptor ra- is basically classiied as serial or parallel. In se- dionuclide therapy used for neuroendocrine rial organs (for example the spinal cord and tumours at high cumulative activities [19]. intestines) even a small volume irradiated The LQM supports the evidence that multi- beyond a threshold absorbed dose can lead ple-cycle schemes decrease the incidence of to whole organ failure. In parallel organs such nephrotoxicity. as the liver, kidneys and lungs the efect de- pends on the irradiated volume. Red marrow toxicity data have mostly been obtained from treatments with 131I for thy- NTCP models can predict the incidence of roid carcinoma and from 131I-mIBG therapy acute/late complications for serial/parallel of neuroblastoma. In many studies, red mar- organs. In EBRT early/acute reactions such row dosimetry is approached with great as tiredness, nausea, vomiting, skin redden- caution, and a maximum absorbed dose of ing, haematological toxicity and erythema 2 Gy to the blood (as a red marrow surro- occur typically during radiotherapy or within gate) is generally accepted [20] for radioio- 3 months, while late reactions, such as ibro- dine treatment of diferentiated thyroid can- sis and liver/kidney failure, could occur even cer. Recently a higher limit of 3 Gy has been 6 months thereafter. The majority of MRT proposed [21]. clinical data on toxicity are available for only

37 Lung toxicity data have also been mainly Conclusion derived from the treatment of metastatic After almost 70 years of the use of radionuclides thyroid carcinoma with 131I or from loco- to treat cancer, there is now a rapidly increasing regional liver treatments using 131I-Lipiodol awareness of the need to administer activities or 90Y-labelled microspheres. In the literature, according to a predicted pattern of absorbed lung-related constraints are based on difer- dose delivery, and to assess after a therapeutic ent criteria [21-23]. Radiation pneumonitis procedure whether that predicted absorbed has also been seen in patients receiving 90Y- dose has in fact been delivered. This funda- TheraSphere as single treatment at doses mental change in practice is being spurred ≥30 Gy. An empiric lung shunt [24] cannot on by the need for evidence-based medicine be considered a dosimetric constraint. Severe and the emerging interest in molecular imag- radiation-induced lung toxicity, expected ing and personalised treatment. Whilst there at doses of 25–27 Gy, were not observed in is evidently an opportunity for much research, some studies, probably due to the overes- it remains the case that only with this cancer timated normal lung absorbed dose [22]. therapy can the agent responsible for treat- In non-resectable primary or metastatic liver ment be imaged in vivo – this ofers a poten- tumours, radioembolisation is an increasingly tial for individualised treatment planning that used loco-regional treatment. The partition is unprecedented. The greatest challenges at model permits a distinction between tumour present are the need to quantify activity im- and normal liver doses [25], allowing the use aged by a gamma camera that is not well of constraints for normal tissues. Moreover, suited to the task (standardized uptake values TCP/NTCP models have been proposed [26]. have long been established for quantiication Pre-treatment imaging seems feasible and at- with PET) and the development of radiobiol- tractive for radiobiological treatment optimi- ogy to understand the clinical implications of sation [26-28]. Multi-cycle treatments would an absorbed dose. This ield has been the slow- allow administration of higher activities and est to develop of all cancer treatments, in part could improve the risk-beneit balance [29]. due to the relatively small numbers of patients Other organs that afect the quality of life treated at individual centres, but also due to should also be included in the evaluation of the need for a multidisciplinary approach to treatment. Cells that are actively dividing and what, in many centres, will be a new service. not as well diferentiated, such as gonads, As dosimetry is at the heart of molecular radio- haematopoietic cells and the gastrointestinal therapy, so imaging is at the heart of dosimetry. tract, are most susceptible to radiation dam- It is likely that changes in clinical practice will age. In young and long-surviving patients, the raise challenges and opportunities previously gonads should be considered for assessment not encountered, but that the outcome will be of temporary and permanent sterility risks. signiicantly greater beneit to patients.

38 10. Barone F, R, Borson-Chazot Valkema R, Walrand S, Ljungberg M,Sjogreen-Gleisner K, M, Garkavij 9. Dewaraja FreyYK, EC,Sgouros AB, P, G,Brill Roberson 8. JG. Thomas SR,Maxon HR,Kereiakes 6. Fleming JS.Atechnique for theabsolute measurement 5. LassmannM,Chiesa C,Flux G,Bardies M.EANMDosim- 2. Bolch KF,WE, Eckerman Sgouros G, Thomas SR.MIRD 1. References References I,Chapter 3 Section . SiegelJA, Thomas SR, Stubbs JB, StabinMG,Hays MT, 7. 4. Hindorf C,GlattingG,ChiesaLindenO, Flux Hindorf G.EANM 4. SE,Chittenden SJ, ST, SaranFH, Meller Buckley Flux GD. 3. relationship. JNuclMed. 2005;46Suppl 1:99S-106S. volume and doserate inindingadose-efect of kidney renalpredicting toxicity with (90)Y-DOTATOC: relevance Chauvin F, L, etal. Gogou Patient-speciic in dosimetry future therapeuticstrategy. Cancer. 2010;116:1084-92. on withimpact tumors:Analysisofdosimetry endocrine octreotate therapy inpatientswithdisseminated neuro- M, Ohlsson T, etal.Wingardh 177Lu- K, [DOTA0,Tyr3] radionuclidetherapy.internal JNuclMed.53:1310-25. in for dosimetry patient-speciic 3-dimensional SPECT Zanzonico PB, etal. MIRDpamphletNo. 23:quantitative estimates. JNuclMed. 1999;40:37S-61S. acquisition andanalysisfor use inhumanradiationdose data quantitative biodistribution radiopharmaceutical KF,Koral etal. MIRDpamphletno. 16: Techniques for Phys.Med 1976;3:253-5. countingmethods. usingexternal of lesionradioactivity Med Biol.Med 1979;24:176-80. usingagammacameraandcomputer.of activity Phys ing.37:1238-50. Imag- dosimetry. Mol Eur JNuclMed and whole-body Committee guidelines for bone marrowDosimetry roblastoma. JNuclMed. 2009;50:1518-24. planning of131I-MIBGradionuclidetherapy for neu- for individualized treatment dosimetry Whole-body ing. 2011;38:192-200. Imag- Mol Eur reporting. JNuclMed clinical dosimetry Committee of guidance document: good practice etry ture. JNuclMed. 2009;50:477-84. --standardization ofnomencla- maceutical dosimetry pamphlet No. 21:ageneralized schemafor radiophar- In vivo quantitation 39 17. A, Jackson ML, Ten JM,Kessler Robertson RK, Haken 16. M,ChiesaC,Cremonesi L,Benassi L, M,Bodei Strigari Withers HR. The four r’s ofradiotherapy.15. Biol. Adv Radiol D, Ljungberg Rueckert M.Registra- Sjogreen-Gleisner K, 14. J, HummJL,DivgiSchwartz CR,LarsonSM,O’Donoghue 12. SN, 11. Visser OJ,Rizvi Vosjan MJ, vanLingenA,Hoekstra 20. Benua RS, Cicale NR, Sonenberg M, Rawson RW. RS,CicaleNR,SonenbergBenua M,Rawson The rela- 20. 18. L,D’AndreaStrigari M. CL,Sciuto R,Benassi M,Maini 13. Lhommel R, van Elmbt L, Gofette P,13. Van den Eynde M, 19. Wessels BW, MW, Konijnenberg 19. Breitz DaleRG, HB, Cre- Imaging. 2011;55:205-21. radiobiology applicationandresults. Mol QJNuclMed D’Andrea innuclearmedicinetherapy: M.Dosimetry 1975;5:241-7. 2009;54:6181-200. inradionuclidetherapy.dosimetry Phys Biol. Med imagesfor three-dimensional SPECT/CT tion ofserial Imaging.37:1654-62. Mol Eur JNuclMed inliver metastasistherapy usingSIR-Spheres.dosimetry F,Jamar Pauwels S,etal. Feasibility of90Y TOF PET-based Med.53:615-21. using124I-PET. marrow JNucl JA. Bone dosimetry Imaging.39:512-20. Mol Med using 89Zr-ibritumomab tiuxetan andPET. Eur JNucl non-Hodgkin’spatients withrelapsed B-cell lymphoma and scoutingof90Y-ibritumomab tiuxetan therapy in OS, ZijlstraJM,etal. radiationdosimetry Biodistribution, J Roentgenol J Roentgenol Radium Ther NuclMed. 1962;87:171-82. tions inthetreatment ofmetastaticthyroid cancer. Am to results and complica- tion ofradioiodinedosimetry J NuclMed. 2008;49:1884-99. and response -- implications for radionuclide therapy. dosimetry the efect of model assumptions on kidney monesi M,Meredith RF, etal. MIRDpamphletNo. 20: 66. tions in systemic radiotherapy. Phys. Med 2006;33:1857- Biological optimizationofheterogeneous dosedistribu- Oncol BiolPhys.ture JRadiat model. 1995;31:883-91. Int tion data for radiation hepatitis using a parallelarchitec- Kutcher GJ, Lawrence TS. Analysisofclinicalcomplica-

EANM 21. Dorn R, Kopp J, Vogt H, Heidenreich P, Carroll RG, Gulec 26. Strigari L, Sciuto R, Rea S, Carpanese L, Pizzi G, Soriani A, SA. Dosimetry-guided radioactive iodine treatment in et al. Eicacy and toxicity related to treatment of hepa- patients with metastatic diferentiated thyroid cancer: tocellular carcinoma with 90Y-SIR spheres: radiobiologic largest safe dose using a risk-adapted approach. J Nucl considerations. J Nucl Med. 2010;51:1377-85. Med. 2003;44:451-6. 27. Ahmadzadehfar H, Sabet A, Biermann K, Muckle M, 22. Sgouros G, Song H, Ladenson PW, Wahl RL. Lung toxicity Brockmann H, Kuhl C, et al. The signiicance of 99mTc- in radioiodine therapy of thyroid carcinoma: develop- MAA SPECT/CT liver imaging in treatment ment of a dose-rate method and dosimetric implica- planning for 90Y-microsphere selective internal radia- tions of the 80-mCi rule. J Nucl Med. 2006;47:1977-84. tion treatment. J Nucl Med. 2010;51:1206-12.

23. Song H, He B, Prideaux A, Du Y, Frey E, Kasecamp W, 28. Lambert B, Mertens J, Sturm EJ, Stienaers S, Defreyne L, et al. Lung dosimetry for radioiodine treatment plan- D’Asseler Y. 99mTc-labelled macroaggregated albumin ning in the case of difuse lung metastases. J Nucl Med. (MAA) scintigraphy for planning treatment with 90Y mi- 2006;47:1985-94. crospheres. Eur J Nucl Med Mol Imaging. 2010;37:2328- 33. 24. SIR-Spheres® Yttrium-90 microspheres (package insert). In: Limited SM, editor. North Sydney, NSW, Australia; 29. Cremonesi M, Ferrari M, Bartolomei M, Orsi F, Bonomo 2009. G, Arico D, et al. Radioembolisation with 90Y-micro- spheres: dosimetric and radiobiological investigation 25. Ho S, Lau WY, Leung TW, Chan M, Ngar YK, Johnson PJ, for multi-cycle treatment. Eur J Nucl Med Mol Imaging. et al. Partition model for estimating radiation doses from 2008;35:2088-96. yttrium-90 microspheres in treating hepatic tumours. Eur J Nucl Med. 1996;23:947-52.

40 ciic parameters, including: to appropriately inluence spe- it is necessary radiation exposure from source, aradioactive al staf, patientsandpublic). To minimisethe where ionising radiation is used (occupation- ofindividuals involvedegories inprocedures forable (theALARAprinciple) allthecat- achieve adoseaslow asreasonably achiev- protection’sRadiation main target is to substances.when usingradioactive to implementspecialprecautions necessary the humanbodymay bedestructive, itis etc. theefects Because oftheradiationon administration, within thehumanbodyafter andeliminationoftheradiotracer tribution sources,radioactive thephysiological dis- ofemitted ofthe rays,the type theactivity man bodyindiferent ways dependingon its beneit,theradiationmay afect thehu- nostic andtherapeuticprocedures. Besides tracersforactive indiag- medicalpurposes • • • Nuclear medicine involves Introduction Claudiu Peştean IuliaLarg andMaria Exposure ofPatients,Minimising ofthePublic StafandMembers Protection:4. SpecialConsiderations inRadiation I Section radioactive sourcesradioactive are manipulated. to use when speciic shielding devices tory Shielding distance from patients, radioactive asafemote orkeeping handlingdevices tive source; thismightinvolve usingre- should bemaintainedfrom theradioac- Distance source.spent neararadioactive Time : as short atimeaspossibleshouldbe : asshort : themaximumpossibledistance : insomeinstancesitismanda- the use of radio- 41 • • • • • medicine facility [1]: medicine facility inanuclear ofactivity inallaspects lected protectionmust be re- concerns Radiation tent authorities. by needsto compe- beauthorised facility waste).of radioactive Anuclearmedicine tions (includingthestorage anddisposal specially designed spacesfor allopera- to have ismandatory number ofrooms. It should have enough space and a suicient wastesradioactive orsupplies. The facility tients andstaf, radiopharmaceuticals, and hospital, withappropriate circuits for pa- signed andsuitablylocated withinthe should be appropriatelyThe facility de- Potential forcontamination tration of radioactive tracers.tration ofradioactive oftheadminis- about allrelevant aspects Patients mustbeadequately informed minimal risk. with material with radioactive can work ceived special training to ensure that they All stafmustbecompetent andhave re- available asrequired by nationalregulations. instrumentsshouldbe diation monitoring for allprocedures;in thedepartment ra ment for safe handlingshouldbeavailable and meetstipulated speciications. Equip All the equipmentshould be authorised (internal and/or external) [1]. and/orexternal) contamination (internal of to minimisethepossibility necessary sourcessealed radioactive are used, itis : because un - - - EANM Regulations and principles in radiation images, while in therapeutic procedures, protection beta emitters are administered. In both situ- All activities that involve the use of ionising ations, radiation protection has an important radiations are performed under rules and place in daily practice and staf must be well guidance set out by regulatory bodies. In trained to respect the principles of radiation Europe, the European Commission issues protection. Special precautions are needed speciic directives for activities using ionising when therapeutic procedures are performed radiations. All member states have speciic in a nuclear medicine department because regulations which comply with the recom- high activities are administered and because mendations of the European Commission. of the high energy of emitted particles. It is These recommendations are designed to necessary to have speciic procedures that ensure the safety of all categories of individu- allow therapy to be performed in safe condi- als afected by activities using ionising radia- tions for patients and their families and also tions. Protection against ionising radiations for professional staf and the environment is the goal of activity of many representative generally. organisations at an international level, be- yond Europe. The International Commission Three categories of exposure may occur on Radiological Protection (ICRP) is the com- when a is performed us- mission that developed and elaborated the ing ionising radiation: international system of radiological protec- tion. This system is used all over the world as • Occupational exposure: exposure of work- a reference for all standards, legislation, pro- ers incurred during the course of their grammes and practice of radiation protec- work [2]. tion. Documents like the Euratom Basic Safe- ty Standards Directive [2], ICRP Publication • Medical exposure: this includes the expo- 103 [3], and Council Directive 97/43/Euratom sure of patients as part of their own medi- [4] are designed to ensure that activities (in cal diagnosis or treatment, the exposure of general) and medical practices (in particular) individuals as part of occupational health using ionising radiation are performed in a surveillance, the exposure of individuals way that respects the safety standards re- as part of health screening programmes, lated to radiation protection. the exposure of healthy individuals or pa- tients voluntarily participating in medical All procedures in a nuclear medicine depart- or biomedical, diagnostic or therapeutic, ment involve the use of radioactive trac- research programmes, and the exposure ers for the purpose of diagnosis or therapy. of individuals as part of medicolegal pro- In diagnostic procedures, gamma photon cedures [4]. or positron emitters are used to obtain the

42 it produces. ofthis Adetaileddescription that icient beneitagainstthedetriment medical exposure shalldemonstrate asuf- Euratom BasicSafety Standards Directive, a According 80,Justiication,ofthe to Article tional exposure) andpublic(publicexposure). applies:professionalsthe principle (occupa for ofindividualsto thosecategories whom basically refers to thelimitationofexposure radiation protection is procedures.emergency of Anotherprinciple care ofthehospitalisedpatientandadequate ily membersandthegeneralpublic, suitable tion, applicationofdoseconstraintsto fam administration, adequate patient informa as: safe sources, handling ofradioactive safe such nuclide therapy shouldincludeaspects tors into account” [5].Optimisation inradio socialandeconomicfac taking achievable atalevel must bekept “as low asreasonably that even whentheexposure isjustiied, it • Considerations4. Special Exposure Protection: inRadiation ofPatients, Minimising ofthePublic Staf andMembers I Section is ofradiationprotection principle The irstkey second principle is second principle diation, theexposure cannotbejustiied. The tic efect) canbeobtained withoutusingirra ofdiagnosticterms information ortherapeu continued, butwhenanequaloutcome (in cedures whichare appropriate needto be nuclear medicinepointofview, thosepro From causedby irradiation. the detriment a ied; thismeansthatthebeneitmustexceed justiication cupational exposure [2]. individuals, excluding any medical or oc- Public exposure: theradiationexposure to . Every exposure mustbejusti . Every optimisation. limitation This means means This . Limitation . Limitation ------43 achieved: optimisation inmedicalexposure isto be 81 ofthesamedocumentexplains how the into account.Article beingtaken etal factors reasonably achievable, economicandsoci- of individualsexposedare aslow as kept ofexposuresand likelihood andthenumber timised withtheintent thatthemagnitude situations, radiationprotection shallbeop- Safety Standard Directive states thatinall 5 of theEuratom Basic achievable. Article exposure shouldbeaslow asisreasonably ionising radiationmustbeoptimisedasthe Even when justiied, all procedures involving shall beprohibited [2]. that whenanexposure cannotbejustiied, it isto understand important isvery quired. It orconsequencesisac- about theireicacy evidence reviewed andimportant whennew also states thatexistingtechniques shallbe use of ionising radiation must be justiied; it opted, any technique new thatinvolves the Directive states thatbefore itisgenerallyad- other individuals. The BasicSafety Standard produceddetriment by exposure to stafand we shouldalsoconsiderthe about detriment, exposure to ionising radiation. When we talk agnostic or therapeutic), without or with less alternatives thathave (di- the same objective the eicacy, ofthe beneitsandalltherisks into account smaller thanthebeneitstaking shallbe thedetriments beneits to society; health orwell-being ofanindividualandthe peutic beneits, includingthebeneitsto clude allthepotential diagnostic andthera- isasfollows:principle thebeneitshouldin-

EANM • Doses applied for the purposes of radio- • In the case of treatment or diagnostic pro- diagnostic and interventional radiology cedures with radionuclides, the practitio- should be kept as low as is reasonably ner shall provide the patient with written achievable consistent with acquiring the information about the restriction of doses required imaging information, while in to persons in contact with the patient and radiotherapeutic procedures the doses about the risk of ionising radiation; this should achieve the intended result for the information shall be provided before the target volumes, while ensuring that expo- patient leaves the hospital or the depart- sure of non-target tissues is kept as low as ment. possible. We have already mentioned the term “dose • The national regulatory body and the gov- constraints”. According to the Euratom Basic ernment should promote the establish- Safety Standard Directive, a dose constraint ment, regular review and use of reference is “a constraint set as a prospective upper levels having regard to the available Euro- bound of individual dose used to deine the pean reference levels. range of options considered in the process of optimisation related to a given radiation • When research projects are performed source”. Constraints are a part of optimisa- and ionising radiation is used, individuals tion; they may be applied to a department, shall participate voluntarily and shall be to a procedure or to an individual patient. appropriately informed about the risk of The sum of doses from constraints must al- exposure; dose constraints shall be estab- ways be below the dose limit established for lished for individuals for whom no direct the category of individuals to whom the con- medical beneit is expected. straint is applied. In general, dose constraints are expressed as an individual efective dose • The optimisation process also covers the over a year or any other appropriate shorter selection of equipment, consistent pro- period of time [5]. duction of adequate diagnostic informa- tion or therapeutic outcome, and other “Limitation” refers only to the public and oc- “practical aspects” (e.g. quality control and cupational exposure, not the medical expo- the evaluation of patient and staf doses or sure [4]. According to the ICRP Publication administered activities). 103 (The 2007 Recommendations of the In- ternational Commission on Radiological Pro- • For carers and comforters, appropriate tection), and also according to the Euratom guidance and dose constraints shall be Basic Safety Standards Directive, in planned established. occupational or public exposure, dose limits apply to the sum of all planned individual

44 4. Special Considerations4. Special Exposure Protection: inRadiation ofPatients, Minimising ofthePublic Staf andMembers I Section aged onany cm is500mSv per yearlimit for (aver- theskin ICRP, according to ICRPPublication 103),the (this limitiscurrently beingreviewed by the eye is an equivalent dose of 150 mSv per year not exceed 1mSv. The limitfor thelensof shall thedurationofpregnancy during intotional limitsare account:exposure taken year. thecaseofpregnant In addi- workers, secutive years shallnotexceed 20mSv per able, but the average dose over any 5 con- 50 mSv inany singleyear isdeemedaccept- cial situationsamaximumefective doseof of 5 years, i.e. 100 mSv in 5 years. some spe- In year. This limit is mediated of time in a period (mSv) ina and thelimitshallbe20millisievert dose limitisexpressed asanefective dose exposures. For occupationalexposure, the recommendations regarding radiation These ofand are onlythemainaspects cording to theICRPPublication 103). limit iscurrently being reviewed by ICRP, ac- been established, i.e. 15mSv peryear (this for theequivalentdoseto theeye hasalso dose doesnotexceed 1mSv peryear. Alimit over any 5consecutive years, theaveraged exceed thislimit,butonlyonconditionthat tive dose for public exposure is allowed to inspecialcircumstances theefec-a year; limit oftheefective doseshallbe1mSv in recommendations, for publicexposure, the year. According to thesamedocumentsand The limit for public exposure is 1 mSv in a are more restrictive, aswould beexpected. is 500mSv peryear. For thepublic, thelimits (,extremities forearms, feet andankles) 2 of the skin) andthelimitfor oftheskin) 45 procedures radionuclide therapy performing protection indepartments Radiation into contact withthepatient). into contact ily (or membersofthepublicwhowillcome cedures, andto thepatientandhis/her fam- management,tointernal thestafandpro- and its relatingaspects to the department speciic ofvarious account needsto betaken formed in addition to diagnostic procedures, where metabolicradionuclidetherapy isper- anuclearmedicinedepartment necessary. In a suitableapproach to radiationprotection is regulations previously discussed, adoptionof sible, therecommendations respecting and order theexposure toIn aslow keep aspos- tive regarding innuclearmedicine. practice ing point for any radiationprotection perspec dents. These documentsrepresent the start and thedoselimitsfor apprentices andstu lactation dose limitsinpregnancy andduring information onthe provision ofimportant limitsareDose explainedingreat detail, with to practitioners. which mustbewell known recommendations aboutdoseconstraints mentioned documents contain important while inrelation to optimisation,theabove- regarding aspects responsibilities, important relation toIn thejustiication,there are other therapeutic procedures inparticular. ingeneralandradionuclide cine practice considered withreference to nuclearmedi- are mentioned tant aspects that must be ready been mentioned, many otherimpor- thedocumentsthathaveprotection. al- In - - - EANM The department and internal management with controlled access where special rules Departments where therapeutic procedures are necessary to ofer protection against ion- are performed need to have a special design ising radiation or to prevent the spread of in order to satisfy the special needs of ther- radioactive contamination) and a supervised apy. The minimum requirements for such a area (an area where appropriate supervision department, from a radiation protection per- is needed to ensure protection against ionis- spective, are: ing radiation).

• Special and separate designed circuits for Workers should be classiied in two catego- radioactive and non-radioactive patients ries: category A workers, liable to receive an efective dose greater than 6 mSv per year or • Specially designed storage room for iso- an equivalent dose greater than three-tenths topes of the dose limits for the lens of the eye, skin and extremities, and category B workers, who • Specially designed room and facilities for are liable to receive an efective dose exceed- administration of radioisotopes ing 1 mSv per year but do not reach the value of 6 mSv [2]. • Specially designed rooms for in-patients with separate facilities where the patient The internal rules, protocols and guidelines will remain after the therapeutic activity followed and used in the department should has been administered ensure that the procedures respect all radia- tion protection principles and that all activity • Specially designed storage rooms for ra- complies with international recommenda- dioactive waste tions and national legislation relating to ra- diation protection. • Special decontamination room: for wet and dry decontamination The staf and procedures Due to the complexity and the potential risk of • A separate system for collection and stor- radionuclide therapy procedures, it is impor- age of residual water and other household tant that the staf of the nuclear medicine de- waste until decontamination prior to its re- partment are well-trained specialists and that lease into the general waste system. procedures are performed safely and in accor- dance with good practice. The hazard for staf According to the Euratom Basic Safety Stan- is inluenced by the chemical form of the ra- dards Directive, where necessary, the work diopharmaceutical, by its physical properties area in a nuclear medicine department shall (half-life, radiation energy and type) and by its be designed as a controlled area (an area biological properties (after administration, the

46 • medical team: beneit andthatoftheothermembers order to reduce to the irradiation their own into accountin medicine stafshouldtake andexplanationofissueswhichnuclear view lations. The following list provides an over- and procedures andadhere to relevant regu- cine stafshoulduseappropriate techniques daily practice, nuclear medi- possible during order toIn reduce asfar theirradiation 4. Special Considerations4. Special Exposure Protection: inRadiation ofPatients, Minimising ofthePublic Staf andMembers I Section pharmaceuticals, e.g. administration, orinhalationofvolatile radio manipulationand during cidental punctures andhands, ac via contaminationoftheskin (due to irradiation ternal ingestionofnuclides patient hasbeenirradiated, etc.) andby in provided the situationsafter inemergency therapeutic assessment,whenhealthcare is tion, when patientsare examinedfor post- manipulated for preparation andadministra are radiation (when radiopharmaceuticals staf may ir be both determined by external The radiationexposure ofnuclearmedicine of the source. to the activity is proportional capsules, vialsoreven patients)and irradiated the time spent close to unsealed sources (e.g. cal half-life). The hazard is also inluenced by andbiologidepending onitsbiodistribution may afectradiopharmaceutical personnel nation). cidents (e.g. misadministration,contami- andwitha lower ofac- likelihood quickly proceduresnologist more willperform rate the exposure: tech- an experienced is invaluableExperience and may amelio- 131 I radioiodine). ------47 • • • • single-use shoesandspecialglasses single-use protectivegloves, coat,mask, asingle-use pharmaceuticals. This equipmentincludes preparation andadministrationofradio- trolled areas themanipulation, andduring protective con- equipmentwhenentering Technologists shouldwear appropriate administration. with the patients after minimise contact or doubts; in this way technologists can questions procedure andhasnofurther ofthe the patientunderstandsallaspects about theprocedure andto ensure that information patient withallthenecessary to provide the isalsomandatory clide. It administration ofthetherapeuticradionu- should beobtainedfrom to patientsprior ing documentationandbloodsamples, information,dures. includ- Allnecessary steps are followed for thediferent proce- shouldbeensured thatappropriate It sources withappropriate shielding. Most always to manipulate the ismandatory It maximum possibledistance. useful for technologists to maintainthe post-therapeuticduring assessment itis thesame way,creased by of4.In afactor doubled, willbede- theradiationintensity the distancefrom theradiation source is verse square law”, according to whichif tongs; thisisinaccordance withthe “in- vialsusinglongforcepsor radioactive or useful to manipulate unshieldedsources To reduce ofthehands, irradiation itisvery

EANM therapeutic radiopharmaceuticals are and electronic personal dosimeters using beta (β-) emitters, so the best way to shield as detectors G-M tubes or solid-state the source is to use low Z materials in or- diodes. When there is a risk of internal con- der to reduce the probability of producing tamination, measurements of internal con- bremsstrahlung X-rays (which are more tamination may be performed. penetrating than β- particles). Perspex is suitable for this purpose. When high ac- • In order to prevent any unnecessary expo- tivities are used, and in therapeutic admin- sure and to keep the exposure of person- istrations this is a common situation, or nel as low as possible, it is important that when, in addition to β- particles, the radio- scheduled environmental measurements nuclide emits gamma (γ) photons, it is use- are performed at representative points in ful to have a mixed shielding from Perspex the department to assess the environmen- and lead [6]. It is important that, when tal radiation level. Surfaces should be kept necessary, mobile shielding walls are used clean and decontamination procedures to ofer protection against the radiation should be appropriately performed. emitted by the patient (this depends on the energy and, implicitly, the radionuclide • Nuclear medicine staf should be suitably used and the activity administered). trained so that when accidental contami- nation occurs, they respect stipulated pro- Surveillance of personnel exposure is very cedures in order to minimise the radiation important; thus, all members of staf should exposure to themselves and others. wear personal dosimeters and be monitored in order to ensure that the limits established • When health care procedures are neces- by national regulations are respected. It is sary after therapy, the nursing or medical also important for technologists to wear staf should be instructed regarding radia- inger dosimeters during procedures that tion protection (e.g. permissible time and involve source manipulation and adminis- distance in proximity to the radioactive tration. The ideal dosimeter should be: inde- patient, special care regarding the risk of pendent of radiation energy and geometry contamination with radioactive saliva or of the irradiation, capable of distinguish- urine). ing doses from diferent types of radiation (β, γ, X), capable of detecting a large range • No pregnant person should work in areas of energies, easy to use, low cost, immedi- where the exposure is higher than 1 mSv ately readable, small, robust and indepen- over the period of pregnancy; no breast- dent of environmental conditions. Com- feeding person should work in areas where mon types of personal dosimeter are ilm there is risk of internal contamination. badges, thermoluminescent dosimeters

48 4. Special Considerations4. Special Exposure Protection: inRadiation ofPatients, Minimising ofthePublic Staf andMembers I Section should beinthe fastingcondition(for oral for thetherapy. When necessary, thepatient The patientmustbeprepared appropriately of radiationprotection. aspects ofthese the patientaware oftheimportance thepatientandofmaking ofinstructing ity and themedicalteam have theresponsibil special attention he/she to these aspects; of thetherapy. The technologist shouldpay administration withthepatient after contact of thepatientandpersonswhocomeinto exposure orminimisationofexposure essary relevant toeral aspects avoidance ofunnec nuclear medicine staf must be aware of sev From aradiationprotection pointofview, the the childshouldnotexceed 1mSv). tion ofthechild(e.g. theexposure limitof regardingspecial concerns radiationprotec ing to breastfeeding into account andtaking circumstances, constraints respecting relat undercertain the therapy canbeperformed thecase ofabreastfeedingpatient. In person, inapregnant istration shouldbeperformed thatnotherapeuticadmin iswell known It abolic radionuclidetherapy. for pathologies thatmay betreated by met dedicated protocols andclinicalguidelines justiied. For thispurpose, cliniciansfollow administration ofradionuclidesmustbe considered inthischapter, any therapeutic According to legalandguidancedocuments the patient) of thepublicwhowillcome into contact with The patientandhis/herfamily (or members ------49 to avoid e.g. malabsorption, for administration oftheradiopharmaceutical, ties (3.7–5.5 GBq) canbeadministeredties (3.7–5.5GBq) on thathigheractivi tions andstudiesassert ing hospitalisation;however, somepublica dur isperformed ceeds 30mCi(1.1GBq) any administration of radioiodine that ex conditions. Usually, for radioiodinetherapy, hospitalisation andsomeunder out-patient proceduresSome during are performed to respect them. and hygienic measures andshouldbeready regarding withotherpersons visits, contact conditions cedure andallthenecessary ofthetherapeuticpro stand allaspects The patientandhisfamilyshouldunder system. andurinary on thekidneys and to minimisetheefects oftheradiation ensure good clearanceoftheradiotracer and to beappropriately hydrated inorder to glands,sour candiesorlemonfor thesalivary of radiationonnon-target organs, e.g. to eat in ordermay be taken to minimise the efect measures that thepatientoncertain struct The nuclearmedicinestafmemberwillin containing iodineinexcess). disinfectants, foodrone, iodine-containing medicationssuchasamioda arrhythmic hormones, iodinated contrastmedia,anti- the following shouldbeavoided: thyroid radioiodine therapy, administration/use of or food are to berespected (inthecaseof pharmaceuticals, substances, treatments dine therapy). Contraindications to certain 131 I radioio ------EANM an outpatient basis with adapted radiation instructions regarding radiation protection, protection guidelines and proper oversight taking into account socio-economic and by professionals [7]. In other types of radio- environmental factors like the living space, nuclide therapy, hospitalisation is not neces- the number of rooms, the quality of sanitary sary, but the patient should remain under installation, the number of family members medical surveillance for up to several hours. etc. [8].

The decision to perform the therapy on an In the majority of therapeutic procedures, out-patient basis or to discharge a hospital- including those involving radionuclides that ised patient after therapy can be taken only emit only beta (β-) particles (e.g. metastatic if dose constraints and dose limits for family bone pain palliation with 89Sr), the patient members or close persons and the public needs to give special attention only to urine will not be exceeded due to residual activity. contamination (clothes and toilets) in order The values to be observed are established by to ensure the radiation protection of other competent authorities and national regula- persons [9]. The situation in respect of radio- tions [8]. In Europe, the situation regarding iodine therapy is more complex, and the pa- treatment delivery on an out-patient basis tient should respect some other instructions and time of discharge varies from country after discharge: to country. In some countries the activity of radioiodine that may be administered on • The patient should stay as far as possible an out-patient basis is up to 30 mCi, while in from other persons at home (more than 1 others even hyperthyroidism is treated dur- m and for extended periods of time, more ing hospitalisation of the patient. than 2 m).

During the hospitalisation, the patient will • The patient should urinate sitting down, be instructed how to use the toilet (e.g. the lush the toilet 2-3 times after urinating, toilet should be lushed 2-3 times, and men and wash the hands afterwards. should sit down to avoid spillage), how to maintain personal hygiene in order to mi- • Direct contact with children should be nimise contamination (hands should be avoided, and a greater distance should washed with soap and water after using the be maintained from them; in addition, ar- toilet), to wear footwear when leaving the rangements should be made for children bed and not to leave the room unnecessar- to be cared for in another house by other ily. individuals for the irst 2 days (if this is not possible for psychological reasons, con- A hospitalised patient should be discharged tact should be as brief as possible). only if he or she will be able to respect the

50 • Considerations4. Special Exposure Protection: inRadiation ofPatients, Minimising ofthePublic Staf andMembers I Section • • • • • • • should notbeagainstthesamewall. bedsinadjacentrooms at least2mapart; The patientshouldsleepalone, withbeds sex). about halfanhourperday (hugging and contraindicated, to itshouldberestricted While physical withadults is not contact are safe). used by washing other they persons (after andtowels mustnotbe Cutlery, crockery discouraged. young children andpregnant women are withthepatient;visitsby direct contact asafetors shouldkeep distanceandavoid For visits(upto afew hours),visi- short therapy4 monthsafter Conception shouldbeavoided for returning home therapy after and should not be restarted Breastfeeding mustbestopped before sonably achievable child dose toas low asisrea- theunborn should berespected inorder the to keep outlinedabovesleeping instructions thecaseofapregnantIn partner, the those measures thatare easyfor them. years only oldwillbeencouragedto take Regardingpersons, elderly those over 60 51 • • • • • point ofthepatient’s body[8]: tive dosemeasured at1mdistancefrom any oftheefec-has beenmadeasafunction in diferent ways. Oneoftheseestimations follow hasbeenestimated theseinstructions The lengthoftimefor whichpatientsshould stay athome. radioimmunoassay), thepatientshould (e.g. development ofphotographic plates, would be afected by ionising radiation similarly,must stay ofwork; ifthework children under10years old, thepatient the time; if the involveswork with contact maintained from otherindividuals mostof adistanceof2mshouldbe While atwork, events should beavoided.Social thetrip.should alsochangeseatsduring from otherpassengers, andthepassengers tient shouldmaintainasuitabledistance asfar as possible,2 hours per trip; the pa totion shouldberestricted amaximumof publictransporta theirstweek, During 2 weeks. for is period compliance withinstructions of<400MBq, therecommended activity corresponding to anestimated residual At anefective dose rate of<20 µSv h-1, 3 weeks. for is period compliancewithinstructions of<800MBq, therecommended activity corresponding to anestimated residual At anefective dose rate of<40 µSv h-1, - - EANM • At an efective dose rate of <10 µSv h-1, Radiation protection is a very important as- corresponding to an estimated residual pect of metabolic radionuclide therapy and activity of <200 MBq, the recommended it must be ensured not only that the patient period for compliance with instructions is beneits from the therapy but that the pro- 1 week. cedure is done properly, thereby minimising exposure of the patient, the medical staf, the • At an efective dose rate of <5 µSv h-1, cor- patient’s family and the public. responding to an estimated residual activ- ity of <100 MBq, the recommended period for compliance with instructions is 4 days.

• At an efective dose rate of <3 µSv h-1, corresponding to an estimated residual activity of <60 MBq, the recommended period for compliance with instructions is 24 hours.

52 . Horea HulubeiFoundation. The 2007Recommenda- 3. Euratom Draft BasicSafety Standard Directive. 2010[ac- 2. M,ed. Basicsciencesofnuclearmedicine, Khalil 1stedn. 1. References References I,Chapter 4 Section 6. Huggett S, ed. Best practice in Huggett S, ed.nuclear medicine. practice Best Part 2. 6. protection legislation. Eur Radiation JNucl Harding LK. 5. Council Directive 97/43Euratom. 1997[accessedDe- 4. Nuclear Medicine; 2007. Nuclear Medicine; A technologist’s guide. Vienna: European Association of radioprotection/doc/legislation/9743_en.pdf cember 2012].http://ec.europa.eu/energy/nuclear/ 2010. Protection. ICRPPublication 103.Bucharest: Anima; Commission onRadiological tions oftheInternational draft_euratom_basic_safety_standards_directive.pdf nuclear/radiation_protection/doc/art31/2010_02_24_ 2012].http://ec.europa.eu/energy/cessed December New York: 2011. Springer; Med. 1998;25:187–91. 53 7. Salvatori M,Lucignani Salvatori exposure, G.Radiation protection 7. . European Association ofNuclearmedicine. EANMpro- 9. European protection following Commission. Radiation 8. u5a99j92gahi2970g1c0 guidelines/gl_radio_treatment.pdf?PHPSESSID=t998d8 40. Available from: http://www.eanm.org/publications/ tion/doc/publication/097_en.pdf http://ec.europa.eu/energy/nuclear/radiation_protec- charged 2012]. in-patients).1998[accessedDecember therapy (exposure dueto out-patientsiodine-131 ordis- Med. 2010;37:1225-31. fromand risk nuclearmedicineprocedures. Eur JNucl bone pain. Eur J Nucl Med Mol Imaging. 2008;35:1934- Mol bone pain.Eur JNuclMed cedure guideline for metastatic treatment of refractory

EANM Section II Preamble on a Multiprofessional Approach in Radionuclide Metabolic Therapy Giorgio Testanera and Arturo Chiti

Introduction considerable variations in individual respon- Whilst the science of nuclear medicine con- sibilities exist between and within countries, tinues to be further perfected and described one thing all nuclear medicine departments within the literature, a signiicant limitation in have in common is the continued need for translating this knowledge into practice is as- a diverse range of professional groups. This sociated with the ways in which people work professional range is necessary to deliver a together to deliver a service which integrates service which draws expertise from diferent and collaborates efectively with relevant bodies of knowledge. medical and non-medical disciplines. Put simply, the science can be faultless but the Daily practice is a synergy between medical practice can be deicient because of human specialists, nurses, technologists, radiophar- limitations. As nuclear medicine has evolved, macists and physicists, with every profes- it has grown closer to those it provides ser- sional igure covering fundamental elements vices to. Clear examples of this include oncol- of the work lowchart, from radiopharmaceu- ogy for radiotherapy planning (PET/CT) and tical preparation to reporting. radionuclide therapy for treatment or pallia- tion of benign and malignant pathology. In In diagnostic nuclear medicine the goal is to both instances, personnel external to nuclear have an appropriate report on high-standard medicine have become centrally involved in quality images, while in radionuclide therapy the organisation and delivery of key aspects the goal is to achieve appropriate treatment of the nuclear medicine service to improve of the disease through delivery of a radia- the pathway and enhance the outcome tion dose at the desired cytotoxic level, with whilst addressing patients’ needs more sen- the deined endpoints being cure, disease sitively. With these considerations in mind, in control (stabilisation) or palliation. Likewise this preamble we recognise the importance it is fundamental to avoid or minimise toxic of efective inter-professional working both efects (spare normal organs), both in the within and external to the nuclear medicine acute time frame and as long-term complica- department and highlight some key human- tions [1]. These topics are discussed in more related factors that need to be considered for breadth and depth in dedicated chapters of the delivery of a successful multidisciplinary this book. externally integrated service. Facility and personnel Nuclear medicine comprises a broad pro- The facilities required depend on national fessional mix. Each professional group has legislation for the emission of beta- and a speciic formative training programme beta- and gamma-emitting therapy agents. and subsequently holds a range of respon- If required by law, the patient should be sibilities within the department. Whilst admitted to an approved isolation facility

54 Section II Preamble on a Multiprofessional Approach in Radionuclide Metabolic Therapy

comprising an appropriately shielded room radioactivity are two of the most scary events and en suite bathroom facilities. Radiopro- for people living within the “Western culture” tection issues are critical not only due to pa- and this has to be borne in mind in patient tient emission but also because of the rela- management. Treatment must be explained tively long half-life and the higher possibility to the patient by the physician, but in addi- of contamination. tion all personnel who deal with the patient (nurses, technologists) must be aware of the The facility in which treatment is adminis- procedure that he or she is undergoing in or- tered must have appropriate personnel and der to be able to answer questions properly. radiation safety equipment; procedures must Radiation safety measures must be orally ex- be available for waste handling and disposal, plained and presented to the patient in writ- handling of contamination, monitoring per- ten form (lealet). The ways in which these sonnel for accidental contamination and rules are explained will inluence patient EANM controlling contamination spread [2]. compliance with them. It is also important not to ask patients to do impossible things [3]. It is really important for all the personnel involved to have a good knowledge of the Patients and personnel have to follow the facility and of the principles and legislation same goals of efective therapy and respect underlying the facility structure in order to for radiation safety procedures within a good be able to interact eiciently. practice environment.

Facilities are considered not only the shield- Personnel and personnel ed hospital rooms, but also the radiophar- Generally speaking, each professional group macy laboratory for radiopharmaceutical has a lead person and together these people preparation, speciic patient circuits within manage the service. A medical lead (doctor) the department and the nuclear medicine specialised in nuclear medicine is necessary diagnostic department in which pre- and and holds medical responsibility for the ser- post-treatment dosimetry imaging is per- vice. The service usually also has a manager; formed. often the manager is a nuclear medicine technologist, physicist or radiographer. As Patients and personnel mentioned earlier, nuclear medicine is now Patients are the main subject of all radionu- integrated more closely with other disci- clide therapy procedures and it is important plines (e.g. oncology) and these disciplines that staf behave correctly in order to ensure will also have their professional groups and that they are introduced into a friendly and managerial systems. easy-to-understand environment. Illness and

55 The delivery of a successful patient-focussed choice of therapeutic modality (e.g. owing service will require good team working [4]. To to unexpected metastasis). The technolo- achieve this, all team members will require gist must be aware of the diagnosis and varying levels of skill and knowledge about prognosis of the patient as these are pre- other professional groups, in relation to their requisites for ensuring that the scan is per- areas of expertise and the roles they can fulil. formed adequately. One way of achieving efective inter-profes- sional working is through inter-professional • Pre-therapeutic dosimetry: Performed by a education. Leadership skills are also vital so physicist together with the technologist, that work gets done eiciently and all those after indication by a physician, using a involved contribute efectively. In the rest of tracer activity in order to assess individual this preamble we shall consider what team kinetics and plan efective treatment with- working, leadership and inter-professional in the dose limits for radiosensitive organs. working/education are and why they are so Good practice is fundamental since small important. errors in instrument calibration and mea- surements with the probe and gamma Some examples of team working procedures camera may lead to wide diferences in directly related to radionuclide therapy are therapeutic dose estimation. Technolo- as follows (these examples are not meant to gist cooperation is fundamental to ind be exhaustive, but only to illustrate concepts time slots in the diagnostic schedule for expressed in situations encountered in daily performance of dosimetry calculation, and practice): coordination with nurses is required for scheduling of blood sampling for analysis • Clinical audit: Carried out by physicians but of activity in the blood. with the cooperation of nurses, since the hospitalisation must be geared to speciic • Administration: The radiopharmaceutical is patient needs and special care may be re- prepared by radiopharmacists and given quired to ensure patient comfort. by a nurse, technologist or radiographer with appropriate skills, depending on na- • Pre-therapeutic scans: Performed by the tional regulations. Generally, physicians act technologist, after indication by a physi- as a support but they also can be the main cian, in order to simulate the biodistri- actors. All those involved, including the bution of radiopharmaceuticals using a patient, must be aware of the radiophar- diagnostic activity. This is very important maceutical characteristics, the dose to be in order to guarantee a high-standard administered, possible adverse events and scan and to identify possible abnormali- the level of radiation risk. ties in patient uptake that can change the

56 Section II Preamble on a Multiprofessional Approach in Radionuclide Metabolic Therapy

• Hospitalisation: Nurses monitor patients’ to enhance inter-professional practice and early symptoms and make patients as facilitate/publish research [5]; a multitude comfortable as possible without forget- of articles about this subject have been ting radiation protection and contamina- published in the medical, nursing and al- tion risks. Suitable advice and explanations lied health literature. Underpinning this is a must be given to patients to ensure that growing realisation that inter-professional they have a correct approach to the envi- education supports good inter-professional ronment and respect for radiation protec- working, and consequently medical, nursing tion rules. Physicists will cooperate with and allied health curricula have evolved to patients in minimising risk and teaching accommodate this; the relationship between them the best way to deal with patient inter-professional education and inter-pro- emergencies without increasing person- fessional collaboration in practice is well

nel exposure to radiation. documented [6,7]. Various deinitions have EANM been proposed on what constitutes inter- • Post-therapy dosimetry and follow-up: professional education, but an appropriate Physicists must perform evaluations and one is that put forward by the Centre for the controls before discharging patients. The Advancement of Inter-professional Educa- technologist’s role is to scan the patient tion: “when two or more professions learn with the gamma camera to evaluate bio- with, from and about each other to improve distribution. The technologist must know collaboration and the quality of care… and the administered dose and patient audit includes all such learning in academic and to perform a good scan for the indication work-based settings before and after qualii- requested. The patient needs to know the cation, adopting an inclusive view of profes- appropriate radiation safety procedures to sional” (2006). be followed at home, and it is important to have a printed lealet available as a sound Inter-professional learning is not simply means of explanation. about learning alongside other professionals in a classroom or lecture theatre. It concerns As stated above, legislation regulating radio- learning with other professionals to nuclide therapy may vary greatly between understand much more about them with countries, and competencies, skills and the intention of improving collaboration and knowledge of professional groups may difer mutual respect and ultimately the quality accordingly. of patient care. However, the importance of team skill development within hospitals The need for good inter-disciplinary work- seems to be culturally sensitive, so much so ing has been recognised for many years, and that while some countries (e.g. the United centres of excellence have been established States) attach high importance to team

57 working abilities, other countries have not yet Leadership is a poorly understood concept recognised their value. Numerous textbooks and often people misguidedly directly associ- have been published on team working, and ate leadership solely with management roles a tremendous amount of journal literature [9,10]. It is true to say that managers should exists on this topic, too [8]. be leaders; it is also true to say that leaders do not need to be managers – indeed, most It is important that, besides theories, the fo- leaders are not managers [11]. Leadership is cus is kept on treating the patient success- about getting things done with and through fully with the lowest dose possible and with other people: it concerns inluencing others the least possible radiation risk for operators. to do things. The purpose of leadership train- ing is clear – efective leadership has been Involvement of diferent medical specialists proven to enhance productivity, staf loyalty Medicine is increasingly becoming a multi- and performance, and many other important disciplinary science, and this enhances the factors. Many theories exist about leadership quality of care provided to patients. Radio- but perhaps the most pertinent for nuclear nuclide therapy is no exception, and agree- medicine would be transformational leader- ment among disciplines must be sought on ship [12], as this is ideally suited to peer lead- why, when and how the use of radionuclide ership. It is important to recognise the con- targeted techniques can be of value. Difer- cept of peer leadership within and external to ent diseases can be successfully treated with nuclear medicine as for many aspects of work nuclear medicine techniques, and diferent it is the team and speciic team members specialists should be involved in patient who take responsibility rather than one indi- management depending upon the disease vidual. For instance, when nuclear medicine under consideration. Most patients who can articulates with oncology for performance of beneit from radionuclide therapy are suf- radionuclide therapy procedures, the oncol- fering from cancer, but it should not be for- ogy team “work with” the nuclear medicine gotten that nuclear medicine therapy helps team to deliver the joint service in order to many patients afected by hyperthyroidism achieve the required outcomes. It might be and diseases of the joints. The clinical sce- that neither nuclear medicine nor oncology nario always requires careful evaluation of is “in charge”, but together they apply their all the possible therapeutic strategies that talents to achieve outcomes. Making sure a nuclear medicine physician can apply to these teams work efectively together can be his or her patients, and cases which do not diicult to achieve as conlict of role can arise it into existing guidelines should always be and confusion can ensue about who should discussed within multidisciplinary boards. In do what and who is capable of doing what. this context, some discussion about leader- Transformational leadership theory sits well ship may arise. in this context.

58 Section II Preamble on a Multiprofessional Approach in Radionuclide Metabolic Therapy

As you read our book on radionuclide meta- bolic therapy we hope you will remember that efective inter-professional working is essential for the delivery of an eicient and successful service.

At this point we acknowledge that the issues raised in our preamble have signiicant bod- ies of knowledge associated with them and we do not claim to be experts in these ields. In this preamble we appreciate that we have only skimmed the surface of the theory and practice that would support this, but we an- EANM ticipate that in the next Technologist's Guide an expert in inter-professional working will be invited to contribute an evidence-based chapter.

59 References Section II, Preamble

References 1. Thomas SR. Options for radionuclide therapy: from ixed 8. http://www.belbin.com/, accessed 5.4.2013 activity to patient-speciic treatment planning. Cancer Biother Radiopharm. 2002;17:71-82. 9. Hogg P, Hogg D, Henwood S. Consultant radiographer leadership – A discussion. 2008;14 Suppl 2. Giammarile F, Bodei L, Chiesa C, Flux G, Forrer F, Kraeber- 1:e39-45. Bodere F, et al.; Therapy, Oncology and Dosimetry Com- mittees. EANM procedure guideline for the treatment 10. Hogg P, Hogg D, Bentley HB. Leadership in the devel- of liver cancer and liver metastases with intra-arterial opment of the radiographic profession. Imaging and radioactive compounds. Eur J Nucl Med Mol Imaging. Oncology, 54-60, ISBN 1 871 101 360. 2011;38:1393-406. 11. Hogg P. The role of leadership in nuclear medicine. 3. Van Den Broek W. CTE session 7, EANM congress 2005. In: European Association of Nuclear Medicine Annual Conference. European Association of Nuclear Medicine, 4. Tutty L. Best practice in nuclear medicine, part 1. A tech- Birmingham, UK; 2011:S192. nologist guide. EANM 2006. 12. Kouzes JM, Posner BZ. The leadership challenge, 4th 5. http://www.caipe.org.uk/, accessed 5.4.2013 edn. San Francisco: Wiley

6. Wahlström O, Sandén I, Hammar M. Multiprofes- sional education in the medical curriculum. Med Educ 1997;31:425-9.

7. Learning together to work together for health (report of a WHO study group of multiprofessional education of health personnel: the team approach). Geneva: World Health Organisation, 1988.

60 dence of this pathology is continuing to rise dence ofthispathology iscontinuingto rise Various studieshave thattheinci conirmed with thyroid cancerintheUnited States [3]. women and15,000men willbediagnosed (NCI),in2013about45,000 Cancer Institute According to datapublished by theNational creasing incidencesamonghumancancers. it hasdisplayed oneofthemost rapidlyin tumour, thelastdecade and especiallyduring Thyroid canceristhe most frequent endocrine Epidemiology ofthyroid cancer The thyroid glandislocated The thyroid gland PiciuDoina 1. Radionuclide Therapy in Thyroid Carcinoma II Section feedback mechanism. hypothalamic-pituitary-thyroid axisnegative of thyroid isachieved through function the of thehuman body.librium The regulation mal thyroid isrelected intheequi- function metabolicpath,andnor- on every mones act cium level in the body [2]. The thyroid hor- system, digestive system, weight andcal- blood pressure, bodytemperature, nervous cells. rate, inluenceheart These hormones of calcitonin from the parafollicular thyroid thesis andrelease ofthyroxine (T The major role of the thyroid gland is the syn- elements situated inthethyroid area [1]. anatomical are themostimportant nerves thyroid glandsandtherecurrent laryngeal thefourthe common carotid artery, para- The jugularvein, internal thevagusnerve, thyroid andleft theright lies between lobes. side of the trachea, and an isthmus, which lobes, hastwo oneoneach area. It cervical dothyronine (T 3 ) from thefollicular cellsand in the anterior intheanterior 4 ) andtriio- - - 61 of Oncology, Cluj-Napoca,Romania. thyroid cancerinthedatabaseofInstitute Figure 1shows thetrend intheincidenceof sociated withhigherrates ofrecurrence [8]. discovered inadvanced stagesandare as inchildren arecurring more aggressive, are (PTC) andfollicular (FTC) thyroid cancers, oc thyroid cancers(DTC), whichincludepapillary diferentiatedin adults, theepithelial-derived mour inyoung people. Compared withcases most commonmalignant headandnecktu of allchildhoodtumoursandrepresents the females. Thyroid canceraccountsfor 0.5-1.5% [4-7], withaclearpreponderance ofcasesin cer, follicular thyroid so-called cancer. form ofdiferentiatedparticular thyroid can- are associated witha and iodinedeiciency opment ofthyroid cancer. Alow-iodine diet intheappearanceanddevel- as atrigger acts which of thyroid (TSH), stimulating hormone results inthechronictrophy”) hypersecretion Endemic goitre (or “thyropathic endemicdys- Endemic goitre Causes ofthyroid cancer of Oncology(IOCN),Cluj-Napoca,Romania. 1970 and 2012 at the “Ion Chiricuță” Institute Figure ofthyroid 1:Incidence cancerbetween 100 200 300 400 500 600 Number ofnewcases 0

1970 ← 2 1970 –2012 Years


553 ← - - -

Database of the “Ion Chiricuță” Institute of Oncology (IOCN), Cluj- Napoca, Romania, Dr.Piciu D. EANM Ionising radiation frequently associated with thyroid nodules; Ionising radiation is one of the most studied the long evolution of nodular thyroid and the causes of thyroid cancer, which scientiic and occurrence of chronic thyroid insuiciency clinical communities accept is directly relat- may lead to cancer. ed to a personal history of irradiation. The human environment accounts for up to Genetic factors 85% of the annual human radiation dose, the Genetic mutations are responsible for the sources being construction materials, food, development of medullary thyroid carcino- drink, soil and the cosmos. Human activities mas (MTC) in more than 25% of cases. If the account for the remaining 15%, the predomi- abnormal gene, usually located in codon 634 nant source being medical procedures (14% of chromosome 10, runs in the family, then of total); only a small amount of exposure is the individual may be at very high risk of de- due to fallout from past testing of nuclear veloping MTC. Such persons should consider weapons, though nuclear accidents have approaching a medical practitioner for infor- been associated with a clear increase in the mation on serum calcitonin tests and genetic incidence of thyroid cancer [9]. testing. People with certain inherited medi- cal conditions, including Gardner’s syndrome Chronic stimulation of TSH and familial polyposis (genetic disorders in As mentioned above, chronic TSH stimula- which large numbers of precancerous pol- tion is considered a trigger for the appear- yps develop throughout the colon and up- ance of metaplasia. This condition is also per intestine), are also at higher risk of PTC. important in the follow-up of patients with Cowden disease, a rare inherited disorder DTC, where the replacement dose of thyroid that causes lesions on the face, hands and hormone must produce suppression of TSH feet and inside the mouth, also increases the in order to decrease the probability of dis- risk of developing thyroid cancer and breast ease recurrence. cancer. In addition, mutations of BRAF genes, which may be determined even from the cy- Environmental factors tology specimen, are related to DTC. Environmental risk factors include radiation from soil, water, drinks, construction materi- Symptoms of thyroid cancer als and professional exposure, as well as low- The symptoms of thyroid cancer frequently iodine diet and intake. are not expressed for many years during the evolution of the disease. A nodule in the cer- Immunological factors vical area is the most common presenting The association of chronic lymphocytic thy- feature. A complete clinical examination is roiditis (Hashimoto’s thyroiditis) with thy- able to suggest the diagnosis of thyroid pa- roid cancer is well known. This pathology is thology, but the positive diagnosis of thyroid

62 Section II 1. Radionuclide Therapy in Thyroid Carcinoma

cancer is sometimes very diicult. The guide- taking into account the known pathways of lines published by clinicians and scientists lymphatic drainage: lateral cervical, supra- have sought to optimise working practice clavicular and submental. Inspection of the and procedures in order to assist in diagnosis. gland may reveal enlargement, asymmetry and a full, bounding pulse. The physician Only local compression and invasion are may observe mobility of the gland and dif- indings speciic to thyroid cancer. The fol- iculties in swallowing. Palpation will reveal lowing symptoms may be present owing to the texture (soft/irm), the surface (smooth/ thyroid dysfunction but they are not speciic seedy/lumpy) and the volume (increased in to thyroid carcinoma: diferent grades or decreased/atrophic). The • Respiratory insuiciency presence of regional pathological lymph • Hoarseness nodes should be noted, as should spontane-

• Deglutition diiculties ous pain or pain on palpation, mobility over EANM • Tremor the neck structures and mobility upon swal- • Sweating lowing. During the clinical examination it is • Diarrhoea/constipation important to note any history of irradiation • Anxiety, depression, lethargy and possible inherited associated patholo- • Heat/cold intolerance gies. • Coarse skin • Weight loss/weight gain Thyroid ultrasound • Pretibial oedema Thyroid ultrasound is a widespread tech- • Muscle weakness nique that is used as a irst-line diagnostic • Increased/reduced heart rate procedure for detecting and characterising • Dry hair nodular thyroid disease (more than 46% of • Swallowing diiculties thyroid nodules greater than 1 cm are not de- • Rarely, pain in the anterior cervical area tected by palpation). There are some special patterns on an ultrasound image that sug- These signs and symptoms may very seri- gest malignant transformation, the most im- ously afect the patient’s status. portant being a solid nodule, with peri- and Diagnosis of thyroid cancer intranodular circulation, a taller-than-wide Clinical examination shape (sensitivity, 40.0%; speciicity, 91.4%), The location of the thyroid gland in the ante- a spiculated margin (sensitivity, 48.3%; speci- rior neck region makes it very easy to inspect icity, 91.8%), marked hypoechogenicity the organ so as to determine the presence or (sensitivity, 41.4%; speciicity, 92.2%), micro- absence of disease. A large goitre may cause calciication (sensitivity, 44.2%; speciicity, tracheal deviation. Palpation of the cervi- 90.8%), and macrocalciication (sensitivity, cal lymph nodes should be done carefully, 9.7%; speciicity, 96.1%) [10].

63 Fine-needle aspiration biopsy routinely recommend preoperative serum Fine-needle aspiration biopsy (FNAB) is rou- Tg measurement. Serum Tg measurements tinely recommended for all nodules exceed- performed at 4-6 weeks after surgery have ing 1 cm in maximum diameter. Its sensitivity been shown to be of important prognostic has been reported to be 83%, with an associ- value. Antithyroglobulin antibodies interfere ated speciicity of 72–100% [11]. with the accurate measurement of serum Tg. Serial antithyroglobulin antibody monitor- FNAB is a simple, rapid, cost-efective di- ing necessitates the use of the same method agnostic method used in the evaluation of each time, because assays vary in sensitivity, the thyroid nodule. According to the latest speciicity and absolute values. studies [12], the use of various immunohis- tochemical markers in cytological samples Thyroid scintigraphy (BRAF, RAS, RET/PTC etc.) might increase the Thyroid scintigraphy uses radioactive trac- accuracy of the positive diagnosis. ers for imaging of the thyroid gland and for functional assessment during thyroid uptake Serum hormonal tests of the radiopharmaceutical. Diferent trac- Current guidelines [13,14] recommend that ers are in use for diferent purposes. Thyroid serum TSH be used as the irst-line test for scintigraphy is not the irst-line method for detecting both overt and subclinical hypo- the evaluation of thyroid nodules but it has a or hyperthyroidism in ambulatory patients very well established place in the diagnostic with stable thyroid status and intact hypo- protocol. Whole body radioiodine scintigra- thalamic/pituitary function. Thyroid hor- phy is the most important imaging method mone tests, [T4, T3, free T4 (FT4) and free T3 during the follow-up of DTC.

(FT3)] are conducted to determine the cause of an abnormal TSH test and to check how Computed tomography, magnetic well treatment of thyroid disease is working. resonance imaging and positron emission

In practice, measurement of FT4 and FT3 is a tomography more reliable test of thyroid function than These modalities are not usually indicated in measurement of total hormone levels. the evaluation of thyroid nodules and thyroid cancers; rather, they are reserved for speciic The tissue-speciic origin of thyroglobulin well-documented situations. (Tg) is used as a tumour marker for DTC. Be- cause Tg protein is tissue speciic, the detec- Overall, clinical examination, TSH determina- tion of Tg in non-thyroidal tissues or luids tion, thyroid ultrasound and FNAB are gen- (such as pleural luid) indicates the pres- erally suicient in permitting correct assess- ence of metastatic thyroid cancer (except ment of thyroid nodules and cancer. struma ovarii). Current guidelines do not

64 Section II 1. Radionuclide Therapy in Thyroid Carcinoma

Classiication of thyroid tumours T categories for thyroid cancer (other than anaplastic thyroid cancer) Well-diferentiated malignant neoplasms Note: All categories may be subdivided: (85% of thyroid cancers): • (s) solitary tumour • Papillary thyroid carcinoma (PTC) • (m) multifocal tumour (the largest focus • Follicular thyroid carcinoma (FTC) determines the classiication) Poorly diferentiated malignant neoplasms: TX: Primary tumour cannot be assessed • Medullary thyroid carcinoma (MTC) T0: No evidence of primary tumour • Anaplastic thyroid carcinoma T1: Tumour 2 cm or smaller, limited to the thyroid Other thyroid tumours: T1a: Tumour 1 cm or smaller, limited to the • Teratoma thyroid EANM • Primary lymphoma and plasmacytoma • Ectopic thymoma T1b: Tumour larger than 1 cm but not larger • Angiosarcoma than 2 cm, limited to the thyroid • Smooth muscle tumours T2: Tumour between 2 and 4 cm in greatest • Peripheral nerve sheath tumours dimension, limited to the thyroid • Paraganglioma T3: Tumour more than 4 cm in greatest • Solitary ibrous tumour dimension, limited to the thyroid; any • Follicular dendritic cell tumour tumour that displays minimal extrathy- • Langerhans cell histiocytosis roidal extension (e.g. extension to the • Secondary tumours of the thyroid sternothyroid muscle or perithyroid soft tissues) The TNM Staging System T4a: Tumour of any size that has grown ex- The most common system used to describe tensively beyond the thyroid gland into the stages of thyroid cancer is the American the nearby tissues of the neck, such Joint Committee on Cancer (AJCC) TNM as the larynx, trachea, oesophagus or Staging for Thyroid Cancer [15], where T in- recurrent laryngeal nerve (also called dicates the size of the main (primary) tumour moderately advanced disease) and whether it has grown into nearby areas, N describes the extent of spread to nearby T4b: Tumour of any size that has grown ei- (regional) lymph nodes and M indicates ther back toward the spine or into near- whether the cancer has spread (metasta- by large blood vessels (also called very sised) to other organs of the body. (The most advanced disease) common sites of spread of thyroid cancer are the lungs, the brain, the liver and the bones.)

65 T categories for anaplastic thyroid cancer Papillary or follicular thyroid cancer in All anaplastic thyroid cancers are considered patients aged 45 years old and older T4 tumours at the time of diagnosis. Stage I (T1, N0, M0) T4a: Tumour still within the thyroid Stage II (T2, N0, M0) T4b: Tumour has grown beyond the thyroid Stage III: • T3, N0, M0 N categories for thyroid cancer • T1 to T3, N1a, M0 NX: Regional (nearby) lymph nodes cannot Stage IVA: be assessed • T4a, any N, M0 N0: No spread to nearby lymph nodes • T1 to T3, N1b, M0 N1: Cancer spread to nearby lymph nodes Stage IVB (T4b, any N, M0): N1a: Spread to pretracheal, paratracheal and Stage IVC (any T, any N, M1) prelaryngeal lymph nodes Medullary thyroid cancer N1b: Spread to other or Age is not a factor in the staging of medullary to lymph nodes behind the throat (ret- thyroid cancer ropharyngeal) or in the upper mediasti- Stage I (T1, N0, M0) num Stage II: M categories for thyroid cancer • T2, N0, M0 M0: No distant metastasis • T3, N0, M0: M1: Spread to other parts of the body, such Stage III (T1 to T3, N1a, M0) as distant lymph nodes, brain, internal Stage IVA: organs and bones • T4a, any N, M0 • T1 to T3, N1b, M0 Thyroid cancer staging Stage IVB (T4b, any N, M0) Papillary or follicular thyroid cancer in Stage IVC (any T, any N, M1) patients younger than 45 years old All people younger than 45 years old hav- Anaplastic (undiferentiated) thyroid cancer ing these types of cancer are considered to All anaplastic thyroid cancers are considered have stage I cancer if they have no distant to be stage IV, relecting the poor prognosis spread, and stage II cancer if they have dis- of this type of cancer. tant spread: Stage IVA (T4a, any N, M0) Stage I (any T, any N, M0) Stage IVB (T4b, any N, M0) Stage II (any T, any N, M1) Stage IVC (any T, any N, M1)

66 Section II 1. Radionuclide Therapy in Thyroid Carcinoma

Prognostic factors lymph node group (level VI, Delphian lymph The majority of thyroid cancers are not ag- nodes) and the selective resection of lateral- gressive and have an excellent prognosis. cervical lymph nodes. The type of surgical pro- Prognostic factors include: cedure is dictated by the type of tumour and • Age the risk category, as follows [14]: • Sex Diferentiated thyroid carcinoma (DTC) – • Histological type nodules with undeined cytology from FNAB: • Histological grade • undeined solitary nodule <4 cm – total • Tumour size lobectomy • Extrathyroidal extension • undeined solitary nodule >4 cm or per- • Distant metastases sonal history of irradiation or familial histo- EANM ry of thyroid cancer – total thyroidectomy • Lymph node involvement • undeined multiple nodules or bilateral • Multicentricity nodules – total thyroidectomy • Incomplete resection

Depending on histology and stage, dif- Diferentiated thyroid carcinoma (DTC) – nod- ferent treatment approaches are adopted ules with suggestive cytology for malignancy: for thyroid carcinoma. There are multiple • thyroid cancer >1 cm – total thyroidctomy guidelines for diagnosis and therapy, many • total lobectomy only if: of them published by national and interna- - tumour <1 cm tional committees of experts in endocrinol- - low risk histology ogy, endocrine surgery, nuclear medicine and oncology. All of these algorithms have - unifocal been reviewed frequently with the intention - intrathyroid papillary carcinoma, of minimising suboptimal diagnosis, surgery without previous irradiation and or irradiation and providing the best option without lymph node metastases or for multimodal treatment. local invasion.

Surgical Treatment The type of lymphadenectomy depends on Surgery is the most important treatment op- the tumour type, tumour size and presence tion in thyroid cancer management. It consists of lymph node metastases. in total thyroidectomy, total lobectomy or pro- phylactic total thyroidectomy in MTC. Lymph- Medullary thyroid carcinoma (MTC) is treated adenectomy in thyroid cancer is well deined by total thyroidectomy and level VI lymph regarding the ablation of the pretracheal node dissection; uni- or bilateral cervical

67 lymph node resection is also recommended Recommendations depending upon presence of the sporadic The European Thyroid Association (ETA) [14] or hereditary form, tumour size and lymph recommendations are: node involvement. 1. Very low risk group – no indication for postoperative 131I Anaplastic thyroid carcinoma requires total • Unifocal diferentiated microcarcinoma thyroidectomy and level VI lymph node dis- (≤1 cm) section, assuming that the staging indicates • these to be appropriate; frequently, however, No extension beyond the thyroid capsule this cancer is classiied as being at a stage un- • No lymph node metastases suitable for surgical resection. • Complete surgery 2. Low-risk group – probable indication – no Thyroid hormone treatment consensus Synthetic levothyroxine is typically adminis- • tered in a dose of 2-2.5 µg/kg body weight; ac- Less than total thyroidectomy, no lymph cording to the risk group and time since thera- node dissection py, the dose might be suppressive, with the aim • Age <18 years of maintaining the TSH level below 0.1 mIU/L. • Unfavourable histology, T1 >1 cm, T2, N0, M0 Radioiodine therapy 3. High-risk group – deinite indication Radiopharmaceutical • T3, T4, N1, M1 Iodine-131 (131I) sodium iodide capsules are used for oral administration, with a speciic • Incomplete surgery activity of 1.11 GBq, 1.85 GBq, 2.59 GBq, 3.7 • High risk of recurrence GBq or 5.55 GBq at calibration time, as clearly stated by the producer. The American Thyroid Association (ATA) [13] categorised their recommendations into Principle seven ratings (A–F, plus I for recommenda- 131I-sodium iodide is administered systemi- tion neither for nor against) according to the cally for selective irradiation of post-surgical strength of the available medical evidence. thyroid remnants of DTC or other suitable For assessment of risk recurrence, they pro- cases of DTC not treated by surgery, or for the posed a three-level stratiication into low-, irradiation of iodine-avid metastases. intermediate- and high-risk groups.

68 Section II 1. Radionuclide Therapy in Thyroid Carcinoma

According to the ATA, radioiodine ablation is Risk of second malignancies: recommended for: • ETA – the risk of second malignancy • Patients with stage III or IV disease is signiicantly higher at a dose above 131 • All patients with stage II disease who are 22.2 GBq I [14]. younger than 45 years • ATA – the risk of second malignancy is • Most patients with stage II disease who dose related, and long-term follow-up are 45 years old or older studies demonstrate a very low risk. There appears to be an increased risk of • Selected patients with stage I disease breast cancer, but it is unclear whether who have higher risk factors, i.e. multi- this is a result of screening, radioiodine focal (>2 foci) disease, nodal metastases, therapy or other factors. extrathyroid and vascular invasion and/

or aggressive histology. EANM Protocol There are multiple choices for establishing ETA/ATA recommendations for management the necessary dose for radioiodine therapy, of metastatic and recurrent disease but administration of a ixed dose of 131I is the For local and regional recurrence: simplest and most widely used method. • Surgery and 131I • External beam therapy of 40-45 Gy in The indications for radioiodine are as follows: 25-30 sessions only if surgery is not pos- sible and there is no 131I uptake a) Remnant ablation. The dose for remnant For distant metastases: ablation may be 1.1, 1.85, 2.59 or 3.7 GBq, according to the volume of the tissue, the • Lungs: 3.7-7.4 GBq every 4-8 months uptake and the level of Tg. during the irst 2 years • 131 Bones: surgery and I, external beam b) Lymph node metastases may be treated therapy with 3.7–6.475 GBq of 131I. Cancers that • Brain: surgery and external beam ther- extend through the thyroid capsule and apy, 131I only after external radiotherapy have been incompletely resected are • Doses are repeated until the disease is treated with 3.7-7.4 GBq. cured • Radioiodine therapy is stopped if there c) Patients with distant metastases are usu- 131 are signs that the tumour is no longer ally treated with 7.4 GBq of I, which typi- iodine avid cally will not induce radiation sickness or produce serious damage to other struc- tures but may exceed generally accepted

69 safety limits for the blood in the elderly cameras. Upon discharge, the patient is ad- and those with impaired kidney function. vised how to minimise the radiation risk to other persons and for what period of time, d) Difuse pulmonary metastases are treated depending on the dosimetry measurements with 5.55 GBq or less of 131I to avoid lung at the time of discharge. injury, which may occur when more than 2.96 GBq remains in the whole body 48 h Post-treatment whole-body 131I scan after the treatment. Whole-body radioiodine imaging should be performed several days (1-3) following treat- The administered activity of radioactive io- ment to document 131I uptake by the tumour dine therapy should be adjusted for paediat- and to assess the extent of the disease. ric patients. Special recommendations: After the administration, the patient remains • Do not use CT with contrast media for in a fasting condition for two more hours staging; it is reserved for speciic situations and after that he/she is advised to hydrate where the 131I therapy is not scheduled. consistently and to use “chewing drops” to • Avoid 131I whole-body scan before radioio- stimulate saliva production and thereby re- dine treatment unless distant metastases duce the impact of irradiation on the salivary are suspected and an important active gland. thyroid remnant must be removed by sur- gery. The administration of 131I for the treatment of • Do not use any (blocking DTC is typically performed under hospitali- agents with iodine, amiodarone etc.) that sation and patients are discharged in accor- may inluence the radioiodine uptake. dance with national radioprotection regula- • tions; however, in some countries the treat- Use the lowest eicient radioiodine activity. ment may be done on an ambulatory basis • At discharge it is necessary to give the pa- even at doses of 131I higher than 1.1 GBq. tient information regarding radioprotec- tion issues. All patients receive paper and electronic in- formation about the diagnosis, the treatment A total response and disease-free state are options, follow-up, side-efects and personal indicated by the absence of tumour mass indications about individual medication. on clinical examination and ultrasound, ab- sence of symptoms, undetectable Tg in the The rooms must have separate washing and presence of high TSH and absence of anti-Tg toilet facilities and the patient is under con- antibodies. tinuous surveillance by the staf, on separate

70 Section II 1. Radionuclide Therapy in Thyroid Carcinoma

Strict follow-up is very important for early The role of supporting staf in detection of disease recurrence and rapid in- administering radionuclide therapy stitution of appropriate treatment. Patient preparation Patients must have undergone total or near- External beam radiotherapy total thyroidectomy and have a conirmed External beam radiotherapy (EBRT) has only pathological diagnosis of DTC. a limited indication in DTC, being appropri- ate when the tumour is inoperable or there is For successful radioiodine therapy, the TSH local invasion without a favourable response value must exceed 40 mIU/L. This value may to radioiodine therapy. Similarly, in MTC, EBRT be obtained: is limited to inoperable tumours and cases • At 4-6 weeks after surgery in the absence with regional invasion. In anaplastic thyroid of thyroid therapy replacement carcinoma, by contrast, EBRT is frequently EANM • After 2-4 weeks of thyroid hormone with- used owing to the very severe outcome of drawal, in the case of replacement thyroid the disease and the lack of other therapeutic hormone therapy; options. • After administration of recombinant TSH Chemotherapy in two intramuscular injections of 0.9 ml Thyroid carcinoma is widely considered to solution on two consecutive days, if the be radio- and chemoresistant. In DTC, che- patient is under hormonal treatment. motherapy is reserved for those situations in which the tumour loses ainity for radioio- It is important to be familiar with the TSH dine, while in MTC it is used in some forms of stimulation procedures and to be able to ver- abdominal metastasis. Anaplastic thyroid car- ify that the patient has understood and con- cinoma shows rapid and aggressive growth, sented to the procedure. The recombinant and response rates to systemic chemothera- TSH stimulation method will involve a range py are very limited. of clinical professionals in ensuring accurate dose preparation and administration. Clinical trials When DTC shows continued evolution, but Patients must fast before therapy and must no longer responds to radioiodine and pres- be checked carefully by all the staf. It must ents a negative 131I whole-body scan, new be ensured that the patient is not taking drugs undergoing clinical trials might repre- any of an extensive inventory of long-term sent a reasonable treatment choice. medications that might interfere with iodine uptake. During the preceding 3 months, the

71 patient must not have received blocking relevant to physicians, nurses, technologists agents or iodinated contrast media used in and others. Radiation protection-related X-ray examinations. Dietary restrictions con- problems are very important for both pa- sist in avoidance of iodised salt, seafood, nuts tients and staf, and have already been dis- and other foods rich in iodine for 1 week cussed in Chapter 4 of this book. prior to therapy. Contamination and vomiting, as well as vari- Precautions ous prostheses and metallic clips (which may In the case of female patients of childbearing be contaminated by the iodine from the potential, a routine pregnancy test must be bloodstream), are factors that may inluence done within 72 h prior to the administration the accuracy of scanning results [16] and of 131I. No radioiodine therapy may be admin- therefore it is very important that staf pay at- istered in pregnant patients. tention to such circumstances.

All institutional and departmental documen- Whole-body scanning (WBS) – technical tation must be explained and signed before issues therapy in order to limit the exposure after 131I-NaI is absorbed from the gastrointestinal iodine administration. tract after oral administration. The process of organiication consists in trapping of 131I in In order to avoid or reduce the stunning ef- the thyroid gland and in all DTC cells dissemi- fect, pretherapy 131I whole-body scan is not nated in the body. routinely recommended. It is possible to: • Use 123I or low doses (74 or 111 MBq) of 131I The whole-body acquisition allows data to be acquired from a patient who is larger than • Use a shortened interval (of not more than the ield of view of the gamma camera. The 72 h) between the patient’s bed is moved into/out of the gantry diagnostic 131I dose and the therapy dose. during acquisition of the image. A close relationship between all staf mem- The scan is performed at 24, 48, 72 h or some- bers involved in the diagnostic and treat- times even 5-7 days after administration of ment of this pathology is essential in achiev- the radioiodine capsule, the time interval ing an optimal outcome for patients. depending on the activity of the radioiodine dose and the amount of remnant tissue. The Patient surveillance patient’s position for scanning is supine, with Patient surveillance in the period follow- slight neck extension. Scanning technique ing radioiodine administration is an issue entails use of the following:

72 Section II 1. Radionuclide Therapy in Thyroid Carcinoma

• Gamma camera (single head or dual head) • Calibration and valid quality control tests • Large ield rectangular head • High-energy general-purpose (HEGP) col- limator • Anterior-posterior (AP) and posterior-ante- rior (PA) scanning over the patient’s body, as close to the patient as possible, ensur- ing that suicient distance is maintained in order to avoid any inluence on resolution • Acquisition: whole body EANM • Selected energy: 364 keV • Window: 15–20% • Matrix: 1,024 × 256 • 750,000–1,000,000 counts/image “Ion Chiricuță” Image the Department from of Nuclear Medicine of the D. Institute of Oncology (IOCN), Cluj-Napoca, Romania, Dr.Piciu Figure 2: 131I WBS at 24 h post therapy. • Acquisition of lateral or oblique-lateral im- ages (optional) It is essential to obtain the best possible im- • Special PC programs for processing the age, yielding the most accurate information images. on uptake and distribution of radioiodine in the patient’s body. As the technologist is the Figure 2 shows the normal distribution of irst member of the clinical staf to observe the radiopharmaceutical in the body: there the image showing radioiodine distribution, is uptake in the thyroid remnant, the mouth he or she must be well prepared and aware and salivary glands, the stomach, the diges- of possible artefacts and radioiodine con- tive tract and the urinary bladder. tamination. Figure 3, showing high uptake in

73 the ocular areas due to contact lens contami- Figures 4 and 5 further serve to illustrate the nation, illustrates how a mistake may occur sort of mistake that may arise if inadequate and the importance of recognising artefacts precautions are taken to limit possible con- and taking appropriate corrective action. tamination. Figure 4 shows a 131I WBS at 48 h post therapy that demonstrates thyroid rem- nant uptake in the thyroid area; in addition, pathological uptake is evident in the lower right lobe of the lung. This image was highly suggestive for a macronodular right lung me- tastasis. Because the value of Tg (28.5 ng/L, N.V. <0.1 ng/L in athyreotic patients) was not very high, as is usually the case in patients with lung metastasis, we supposed that ei- ther the lung tumor was not related to the thyroid pathology or that this was a metasta- sis of the thyroid carcinoma with low expres- sion of Tg. Before testing other pathologies, it was important to double check the pos- sibility of radioiodine contamination of the patient. In this second inspection we found that the patient had placed a handkerchief in the pocket of the disposable robe. Figure 5 was obtained immediately after changing the disposal robe, and we observed that the

Image from the Department of Nuclear Medicine of the “Ion Chiricuță” “Ion Chiricuță” Image the Department from of Nuclear Medicine of the D. Institute of Oncology (IOCN), Cluj-Napoca, Romania, Dr.Piciu uptake from the right lung has disappeared. Figure 3: 131I WBS post therapy: high uptake is seen in the ocular areas due to contact lens contamination.

74 Section II 1. Radionuclide Therapy in Thyroid Carcinoma EANM Image from the Department of Nuclear Medicine of the “Ion Chiricuță” “Ion Chiricuță” Image the Department from of Nuclear Medicine of the D. Institute of Oncology (IOCN), Cluj-Napoca, Romania, Dr.Piciu “Ion Chiricuță” Image the Department from of Nuclear Medicine of the D. Institute of Oncology (IOCN), Cluj-Napoca, Romania, Dr.Piciu Figure 4: 131I WBS at 48 h post radioiodine Figure 5: Same patient as in Figure 4. 131I therapy: there is suspicion of a right lung WBS at 48 h post radioiodine therapy. metastasis. After changing the disposable robe, the contamination responsible for the apparent metastasis was eliminated. Radioprotection issues Clinical staf must know and respect the ra- basic requirements that must be respected diation protection measures relating to staf in daily medical practice involving the use protection, handling of radiopharmaceuti- of ionising radiation are justiication, opti- cals and patient safety. Chapter 4 in this book misation and adherence to the International describes extensively the radioprotection is- Commission on Radiological Protection sues related to radioiodine therapy. The three (ICRP) dose limits.

75 References Section II, Chapter 1

References 1. Bliss RD, Gauger PG, Delbridge LW. Surgeon’s approach 10. Wémeau JL, Sadoul JL, d’Herbomez M, Monpeyssen H, to the thyroid gland: surgical anatomy and the impor- Tramalloni J, Leteurtre E, et al. Guidelines of the French tance of technique. World J Surg. 2000;24:891-7. Society of Endocrinology for the management of thy- roid nodules. Ann Endocrinol 2011;72:251-81. 2. Piciu D. Thyroid gland. in Piciu D, ed. Nuclear endocri- nology. Berlin Heidelberg New York: Springer; 2012, pp 11. Wojtczak B, Sutkowski K, Bolanowski M, Łukieńczuk T, 53-163. Lipiński A, Kaliszewski K, et al. The prognostic value of ine-needle aspiration biopsy of the thyroid gland - 3. National Cancer Institute. 2013. http://www.cancer.gov/ analysis of results of 1078 patients. Neuro Endocrinol cancertopics/wyntk/thyroid. Lett. 2012;33:511-6.

4. Enewold L, Zhu K, Ron E, Marrogi AJ, Stojadinovic A, 12. Koperek O, Kornauth C, Capper D, Berghof AS, Asari R, Peoples GE, Devesa SS. Rising thyroid cancer incidence Niederle B, et al. Immunohistochemical detection of in the United States by demographic and tumor char- the BRAF V600E-mutated protein in papillary thyroid acteristics, 1980–2005. Cancer Epidemiol Biomarkers carcinoma. Am J Surg Pathol. 2012;36:844-50. Prev 2009;18:784–91. 13. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, 5. Davies L, Welch HG. Increasing incidence of thy- Mandel SJ, et al. Revised American Thyroid Associa- roid cancer in the United States, 1973–2002. JAMA tion management guidelines for patients with thyroid 2006;295:2164–7. nodules and diferentiated thyroid cancer. Thyroid 6. Colonna M, Guizard AV, Schvartz C, Velten M, Raverdy 2009;19:1167-214. N, Molinie F, et al. A time trend analysis of papillary and 14. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, follicular cancers as a function of tumour size: a study Wiersinga W. European consensus for the management of data from six cancer registries in France (1983–2000). of patients with diferentiated thyroid carcinoma of the Eur J Cancer 2007;43:891–900. follicular epithelium. Eur J Endocrinol 2006;154:787-803.

7. Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. 15. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti Pediatric thyroid carcinoma: incidence and outcomes in A, eds. AJCC Cancer Staging Manual, 7th edn. New York: 1753 patients. J Surg Res 2009;156:167-72. Springer, 2010:1-646..

8. Piciu D, Piciu A, Irimie A. Thyroid cancer in children: a 16. Piciu D, Piciu A, Irimie A. Cerebral false-positive radio- 20-year study at a Romanian oncology institute. Endocr iodine uptake. Acta Endocrinologica (Buc) 2012;8:495. J. 2012;59:489-96.

9. Sources of radiation exposure. http://www.epa.gov/ radiation/sources/index.html

76 future malignant transformation. in whichthere isahighindexofsuspicion of and for thosepatientswiththyroid nodules for large, compressive, unaestheticgoitres irst-line therapy. isusuallyreserved Surgery United States, as where radioiodineisstarted however, centres intheworld, mainlyinthe dine therapy may beproposed. There are, orradioio- holding ofmedication,surgery ofhyperthyroidism uponwith- otherwise to diseaseevolution andtherecurrence or 3-6months,gies. according the next During assessment ofdeinitive therapeuticstrate- lising symptoms andallowing for aproper therapy, intention ofstabi- withtheprimary treatment (drugs) isfrequently theirst-line upon thespeciiccircumstances. Medical surgery, andthechoiceoftherapy depends thyroidism includeantithyroid drugsand treatment optionsforThe hyper- further efect). dioiodine therapy (shrinkage from a reduction in thyroid volume ra- after those withaeuthyroid status, may beneit with large non-toxic goitre, includingeven of excessive thyroid Patients action. hormone is hyperthyroidism, whichisaconsequence A frequent indicationfor radioiodinetherapy formed the1940s. during thyroid gland, theirstprocedure beingper- for the treatment of benign conditions of the to beusedinhumans radiopharmaceutical Radioiodine (iodine Radioiodine 131, 131I) Introduction PiciuDoina 2. Radionuclide Therapy inBenign Thyroid Disease II Section wastheirst 77 of the patientswithhyperthyroidism, theaim In Indications andcontra-indicationsIndications for Indications for Indications therapy tions ment ofradionuclide therapy. should beinformed to thecommence- prior exist. doexist,thephysicianWhen they determine whether any contra-indications patient care, appropriate steps shouldtake to Clinical staf, including all those involved with tive thyroid orbitopathy (especially insmokers). dition islife threatening. cessation ofbreastfeeding ifthepatient’s con treatment and ofpregnancy termination after cian may, however, advisetheradioiodine are andbreastfeeding; pregnancy thephysi solute orrelative. medication, suchaslevothyroxine (LT treated by thyroid substitutive hormone hypothyroid, thelatter beingsubsequently status,perthyroid whichcanbeeuthyroid or Contra-indications for • • • • • • induced hyperthyroidism With specialprecautions, amiodarone- Goitre recurrence surgery after Non-toxic multinodulargoitre nodule hyperfunctioning Solitary Toxic multinodulargoitre roidism) Graves’ disease(autoimmune hyperthy- are uncontrolled hyperthyroidism andac 131 I treatment is to achieve a non-hy- 131 I

therapy are: Absolute contra-indications 131 I therapy may beab Relative contra-indica

4 ). 131 I - - - - -

EANM Facility requirements • In female patients of childbearing poten- In some countries the national regulations tial, a routine pregnancy test should be dictate that radionuclide treatments may be performed before the administration of conducted only in in-patients while in oth- 131I. ers they may be permitted on an ambulatory out-patient basis. The clinical facility in which • Antithyroid drugs must be stopped 5–7 thyroid disease is to be treated with radionu- days before radioiodine therapy. clides must have appropriate authorisation. It must also have appropriate personnel, ra- • Beta-blockers, e.g. metoprolol, atenolol diation safety equipment and clear, well-de- and propranolol (drugs used to manage ined procedures for handling and disposal heart problems) should be stopped 24 h of waste. This facility may be an endocrinol- before therapy. ogy department or a nuclear medicine de- partment or any other specialised unit that • Propylthiouracil (a drug to reduce thyroid respects the above requirements. metabolism) should be stopped at least 2 weeks before therapy. The involvement of technologists in radionu- clide therapy procedures varies signiicantly, • In patients with Graves’ ophthalmopa- from no involvement to leading adminis- thy, if the patient is already taking steroid tration procedures. At the minimum they therapy, oral prednisolone (a drug used to should have knowledge and skill in the cor- treat auto-immune and inlammatory con- rect use of the equipment and the radiation ditions) is administered. It is not routine to safety of the facility. start corticotherapy.

Patient preparation • In patients with thyrotoxicosis induced by • Written informed consent must be ob- amiodarone (an anti-arrhythmic drug) or in tained from the patient before the pro- those receiving compounds that contain cedure commences. Special recommen- iodine (e.g. radiographic contrast agents), dations and radioprotection information radioiodine can be administered as deini- must also be discussed/given to patients tive therapy if the drug has been stopped before commencement. suiciently long for the excess iodine load to be eliminated – at least 3–6 months. • Depending upon national regulations, recommendations relating to conception Assessment of disease may have to be provided. Generally, it is • Laboratory testing, including free thyroxine 131 suggested that after I therapy, contra- (FT4), free triiodothyronine (FT3), thyroid- ception should be used for 4 months. stimulating hormone (TSH), anti-thyroid

78 Section II 2. Radionuclide Therapy in Benign Thyroid Disease

peroxidase antibodies (anti-TPO) and anti- The ixed dose method is usually based on an thyrotropin receptor antibodies (TRab). estimation of the size of the gland, which can be achieved by ultrasound. Frequently • 99mTc thyroid scintigraphy or a radioactive the recommended activity is 3.7-5.55 MBq/ iodine uptake test (RAIU, with scanning 24 gram of thyroid, adjusted with the 24-h 131I h after intake of the radioactive iodine) can RAIU (radioiodine uptake). In patients with be undertaken according to availability. autonomous nodules, the activity currently Uptake measurements are not usually re- prescribed varies between 200 and 800 MBq, quired when ixed activities are used. with the intention of achieving an irradiation dose of 200-300 Gy at nodule level. • Determination of the thyroid target vol- ume can be done using ultrasonography, The calculated dose method might be used

while evaluation of intrathoracic exten- in the selection of a more accurate dose of EANM sion in those with a large goitre can be radioiodine for treatment. There are multiple achieved using magnetic resonance im- methods for dose calculation, but the sim- aging or computed tomography (without plest formula is as follows: contrast agents).

MBq= (V×25×Gy) ÷ [(RAIU (24h) x Tef ] • Fine-needle aspiration biopsy (FNAB) is performed when nodules meet criteria where MBq = the calculated activity in MBq, suggestive of malignancy. V = the gland volume estimated at ultra- sound in ml (cm3), Gy = the estimated dose • In patients with Graves’ ophthalmopathy, at thyroid level, RAIU (24h) = % of thyroid up-

the status of thyroid eye disease activity take at 24 h, Tef = efective half-time, and 25 is established by an experienced ophthal- is a constant. mologist. Those involved with performing or assisting • For children between 5 and 15 years of with radionuclide therapy procedures must age, radioiodine therapy may be consid- be able to use and calculate this and similar ered. The side-efects should be clearly dis- basic formulas. cussed by all staf involved in the treatment of a young patient with Graves’ disease. Side-efects of 131I therapy Patients with a large goitre may notice tran- Radiopharmaceutical and administration sient swelling of the goitre and dyspnoea. In Radioiodine is available in solid (capsules) some patients a thyroid storm may develop. and liquid forms, both of which can be used This rare condition must be treated with for oral administrations. intravenous infusion of antithyroid drugs,

79 corticosteroids and beta-blockers. This situa- Follow-up after radioiodine treatment tion is extremely rare and does not represent As mentioned above, regular review of thy- a reason for not recommending the therapy. roid function tests in patients who have un- dergone radioiodine treatment for thyroid Hypothyroidism is the main side-efect of ra- disease is essential to assess the eicacy of dioiodine treatment. Its rate varies and its inci- the treatment and for timely detection of dence continues to increase over time, so that development of hypothyroidism. The level of life-long follow-up is essential. According to serum TSH increases slowly, so determination published literature, the rate of hypothyroidism of TSH is less useful for monitoring during the at 1 year after radioiodine therapy is very similar irst 3-6 months, when determination of FT4 to the rate following the surgical approach. should be used instead. In those with persis- tent hyperthyroidism, radioiodine treatment Administration of prednisone (a drug used to can be repeated after 6–12 months. Annual treat allergic reactions) helps prevent exacer- laboratory tests (including TSH) are necessary bation of ophthalmopathy, and this is now throughout life, even in patients with euthy- the standard approach in patients who have roidism after 131I therapy. clinically active ophthalmopathy at the time of treatment.

The determination of periorbital inlamma- tory tissue by nuclear testing with 99mTc-DTPA may identify the cases that will beneit from steroid treatment.

Further reading Stokkel MP, Handkiewicz Junak D, Lassmann M, Dietlein Riccabona G. Use of radionuclides in the diagnosis and M, Luster M. EANM procedure guidelines for therapy treatment of thyroid diseases. Wien Med Wochenschr. of benign thyroid disease. Eur J Nucl Med Mol Imaging. 1977;127:97-101. 2010;37:2218–28. ATA/AACE guidelines. Hyperthyroidism and other causes Piciu D. Thyroid gland. in Piciu D, ed. Nuclear endocrinology. of thyrotoxicosis: management guidelines of the American Berlin Heidelberg New York: Springer; 2012:53-163. Thyroid Association and American Association of Clinical Endocrinologists. Endocrine Practice 2011; 17 no. 3:11-13.

80 in 2004and2010. The 2010updated ogy, thisclassiicationwasupdated in2000, ordertumours. to In standardise terminol term “carcinoid” most wasusedto describe thisclassiicationthe published in1980.In The irst WHO classiication of NETs was andinsulinoma). vipoma, gastrinoma secretion orsymptomatic presentation (e.g. whichresults inhormonebiological activity caecum) andto includeinformation on origin (e.g. duodenumandtion ofprimary NETsis to describe according to theirloca NETs. Optimalandrevised current practice consideration thebiological diferences of classiication doesnot,however, into take gut (distal large bowel andrectum) [2]. This caecum andascendingcolon)hind and pancreas), midgut(appendix,ileum, (oesophagus, lungs, stomach, duodenum ological origin into tumoursoftheforegut NETs are classiiedaccording to theirembry [1]. tracts gestive andrespiratory cellsinthedi the disseminated endocrine isletsinthepancreaticdocrine tissue, and and theadrenal medulla,aswell astheen resented by thepituitary, theparathyroid conined neuroendocrine systems are rep neuroendocrine system. The difuseand neuroendocrine system andtheconined of tumoursthatoriginate from thedifuse slow growing andheterogeneous group Neuroendocrine tumours(NETs) neuroendocrine tumours andclassiication of Deinition A.Lowry, Menghis, Brian Ruth Berhane Mayes Christopher andSobhan Vinjamuri 3. Radionuclide Therapy inNeuroendocrine Tumours II Section are arare, ------81 TNM staging [3]. tiated), proliferative (G1, G2,G3)and activity thology (well diferentiated/poorly diferen classiication isbasedontumourhistopa NETs; however, there isconsiderable varia are theones mostcommonlyexpressed in ofSSTR,SSTR2andSSTR5 major subtypes the ive out in nuclear medicine.carried Of the foundation for imaging the functional number ofNETs express SSTRs andthisforms interest thatalarge isthefact particular Of sst2, sst3,sst4andsst5[5]. acterised. haveThey beencode namedsst1, geneshavesubtype beenclonedandchar andprostate.ach, lungs, kidneys Five SSTR body, includingthepancreatic islets, stom system anddiferentnervous tissuesinthe a widespread inthehuman distribution SSTRs are receptors Gprotein-coupled with diferentiated aspoorly scribed NETs. become highlymalignant. The latter are de present withanaggressive behaviour and therapy ofNETs. However, NETs canalso used for theidentiication,localisationand tostatin receptors (SSTRs),whichcanbe tors at the cell membrane, such as soma mechanismsand/orspeciicrecep uptake tures include the possession of neuroamine potent diferentiation features [4].Suchfea (well diferentiated) orretain many multi are eitherbenign orrelatively slow growing oftumoursAt presentation thevast majority Pathology ------EANM tion in SSTR subtype expression among the involving the endocardium, primarily on diferent tumour types and among tumours the right side. of the same type [6]. Non-functioning NETs are not associated It is also particularly important to evaluate with any speciic syndrome and are more the proliferation index of neoplastic cells by diicult to detect than functioning NETs; for measuring the percentage of tumour cells this reason, patients generally present late, with Ki-67 positivity. Ki-67 is an antigen ex- with large primary tumours and advanced pressed during the G1 and M phases of the disease. In the case of non-functioning cell cycle. Determination of the Ki-67 plays NETs, there can be some degree of hormon- an important role and allows selection of al secretion, but the secretion may be at the most appropriate and efective treat- subclinical levels or there may be secretion ment, reserving chemotherapy for NETs of inactive compounds. Non-speciic symp- with a high proliferative index which are toms such as weight loss, abdominal bleed- likely to respond better when treated with ing and pain can be related to increased antiblastic drugs [7]. In contrast, NETs with tumour mass producing mass efect symp- a low Ki-67 respond less well to chemother- toms and/or metastases [9]. apy and are more responsive to treatment with somatostatin analogues, either cold Diagnosis somatostatin or possibly radiolabelled ana- The diagnosis of NETs is best carried out by logues (radiometabolic therapy) [8]. a multidisciplinary approach and is based on clinical symptoms, hormone levels, his- Presentation tological characterisation, and radiological Clinically, NETs can be symptomatic (i.e. and functional nuclear medicine imaging “functioning”) or silent (i.e. “non-function- assessment. ing”). The functioning NETs can give rise to clinical syndromes, such as the one called Nuclear imaging has played an important “carcinoid syndrome”, which is character- role in the diagnosis, staging and follow-up ised by nausea, flushing and diarrhoea. of NETs and, as mentioned above, has al- Other clinical manifestations include lowed appropriate and optimal functional wheezing or asthma-like symptoms as well assessment of NETs. Scintigraphic imag- as pellagra-like skin lesions. These symp- ing with indium-111 (111In)-labelled SST toms arise due to specific production, stor- (Octreoscan®) has been a useful tool in age and secretion of polypeptides, amines diagnosing SSTR-positive tumours for de- and hormones, like serotonin. Cardiac in- cades (Fig. 1). A recent development which volvement can occur as a result of fibrosis marked an important step forwards in the

82 Section II 3. Radionuclide Therapy in Neuroendocrine Tumours

diagnostic work-up of NETs is the introduc- contrast and a higher sensitivity for 68Ga- tion of novel somatostatin-based positron DOTATOC PET/CT than for somatostatin re- emission tomography (PET) tracers labelled ceptor scintigraphy (SRS) [10, 11]. The study with generator-produced radiometal gal- with the largest patient population (84 pa- lium-68 (68Ga). tients with NETs) reported DOTATOC to have a superior sensitivity (97%) compared with Visualisation of NETs is obtained on 68Ga-DO- CT (61%) and SRS (52%) for the detection of TA-peptide PET/CT scans as PET tracers such NET lesions, with special value in the detec- as 68Ga-DOTA-peptides bind to the SSTRs tion of small tumours and lesions localised in overexpressed on the surface of NET cells. the nodes [12]. Several diferent DOTA-peptides (DOTATOC, DOTANOC and DOTATATE) have been used Moreover, further studies have been carried in the clinical setting for either diagnosis out to compare 68Ga-DOTATOC with con- EANM or therapy (Fig. 2). Basically the diference ventional imaging to assess the accuracy of among these compounds is due to diferent PET for the detection of bone lesions. In 51 peptides having diferent ainity for SSTR patients with well-diferentiated NETs, PET subtypes. with 68Ga-DOTATOC performed better than CT or SRS for the early detection of second- Many studies have found a high target/back- ary bone NET lesions (sensitivity of 97% and ground ratio which results in better image speciicity of 92%) [13].

83 Images by courtesy of Prof. Sobhan Vinjamuri Vinjamuri Sobhan Images courtesy by of Prof.

Figure 1: Octreoscan® image obtained with 111In in a patient with thymic carcinoid.

84 Section II 3. Radionuclide Therapy in Neuroendocrine Tumours

of tumour. The main secondary goals are symptom control and limitation of tumour growth where possible. Surgery to remove the primary malignancy and adjacent in- volved lymph nodes is currently the only possible cure and it represents traditional irst-line therapy. Curative surgery is, how- ever, not an option for patients presenting with metastases at diagnosis, which are the majority.

When curative surgery is not feasible owing

to metastases, patients are ofered medical EANM management to relieve symptoms, espe- cially diarrhoea and lushing, and to a lesser extent to suppress tumour growth. An im- portant class of drugs ofered in this setting is the somatostatin analogues, which are endogenous inhibitors of various hormones secreted by the endocrine system. They exert

Image courtesy by of the Imperial Hospital London College their efect by binding with high ainity to the ive SSTR subtypes (SSTR1–5) on secre- Figure 2: 68Ga-DOTATATE scan in a patient with tory endocrine cells [15]. metastatic NET.

Therapy Radiolabelled somatostatin analogues are Therapeutic management of NETs after thor- a fairly new treatment modality for patients ough diagnostic work-up includes medi- with SSTR-positive tumours and with inoper- cal and surgical strategies. The therapeutic able or metastasised endocrine gastro-en- recommendations are mainly based on tero-pancreatic tumours. Radiopharmaceu- retrospective studies, and the optimisation ticals used for diagnostic purposes can be of diverse management strategies is best modiied for therapeutic use by substituting achieved by multidisciplinary assessment a gamma-emitting radioisotope with a beta- and consensus-based therapy [14]. emitting one. Thus, SSTR analogues used for diagnostic scintigraphy labelled using 111In The optimal tumour therapy is curative treat- are replaced by the radiometal, yttrium-90 ment, and the primary treatment goal for pa- (90Y) or -177 (177Lu). tients with NETs is in fact complete resection

85 The rationale for the targeted therapy is Radionuclides for therapeutic purposes the selective irradiation of tumoral cells by should emit beta particles because it is these means of transportation of radioactivity in- particles which have greater therapeutic po- side the tumour cell, following internalisa- tential since have suicient energy to cause tion of the complex formed by the SSTR and cell damage and deliver higher radiation the beta-emitting particle. Suitable radionu- doses to a larger part of the tumour without clides are 90Y, a pure, high-energy beta emit- penetrating very far into the surrounding tis- ter (2.27 MeV), 177Lu, a medium-energy beta sue [17]. emitter (0.5 MeV) with a low abundance, and 111In [16]. The irst radiopharmaceutical used in pep- tide receptor radionuclide therapy (PRRT) was 111In is a gamma-emitting isotope with a half- 111In-DTPA-octreotide, already used in the life of 2.8 days. The energy of this gamma- medical setting as a diagnostic agent with emitting isotope ranges from 171 to 245 keV, activities ranging between 10 and 160 GBq making it suitable for scintigraphic imaging. [18, 19]. The therapeutic eicacy of 111In- DTPA-octreotide was initially promising but 177Lu is a beta- and gamma-emitting isotope several studies arrived at the conclusion with a maximum energy of 0.49 MeV, a tis- that 111In-coupled peptides are not ideal for sue penetration range of 2 mm and a half- PRRT because of the small particle range and life of 6.7 days. The gamma emission enables therefore short tissue penetration and poor performance of imaging and dosimetry cal- energy delivery to tumour cells. culations at the same time. Its short tissue penetration range allows targeted therapies Limitations of 111In were overcome when for small lesions and its longer half-life makes researchers came up with a modiied so- it suitable for cases where a longer “tumour matostatin analogue, [Tyr3]octreotide, with residence time” is a clinical requisite. a higher ainity for SSTR2, and a diferent chelator, DOTA instead of DTPA (which was 90Y is a pure beta-emitting isotope with high used in 111In therapy), to ensure more stable energy (2.3 MeV), a half-life of 2.67 days and binding of the intended beta-emitting radio- a tissue penetration range of 11 mm. Its high nuclide, 177Lu or 90Y. therapeutic potential derives from the emis- sion of high-energy beta particles causing Clinical applications, contra-indications damage to large tumours. The absence of and limitations of PRRT gamma ray emission, however, makes im- Targeted radionuclide therapy ofers sev- aging and dosimetric calculation with 90Y eral advantages compared with the con- diicult. The latter is an important factor for ventional management options ofered for therapeutic planning. NETs. Selective tumour localisation allows

86 Section II 3. Radionuclide Therapy in Neuroendocrine Tumours

treatment to be administered systemically potentially be delivered by administration of while minimising potential toxicity to non- 177Lu-octreotate or 90Y radiopeptide therapy. target, healthy tissues. The fact that potential The intensity of uptake is assessed visually toxicity to healthy tissue is spared means that and considered adequate if lesion uptake is targeted therapies are usually better toler- of greater intensity than that of normal liver. ated than other, systemic treatments such as Once adequate uptake has been conirmed, chemotherapy and deliver higher absorbed further suitability criteria include the con- radiation doses to the tumour than can be irmation of a histopathologically proven, achieved by external beam irradiation. This relatively well diferentiated NET with a Ki-67 applies mostly to NETs, which are relatively score <10 [8]. radioresistant compared with other solid cancers. This kind of therapy relies on the The kidney is the major critical organ dur- administration of appropriately radiolabelled ing therapy with 90Y or 177Lu. Once iltered EANM somatostatin analogues and is intended to by glomeruli, radiolabelled peptides are re- control symptoms due to hormonal secre- absorbed by proximal tubular cells and re- tion. Indeed, symptomatic improvement tained in the interstitium [21]. Another critical may be achieved with all 90Y- and 177Lu- organ to be taken into consideration is the labelled somatostatin analogues that have bone marrow. been used for PRRT. However, several studies that have assessed objective responses have In summary, the inclusion criteria for PRRT yielded encouraging results as well. Kwekke- are: boom et al. reported that despite diferences • Adequate tumour uptake on octreotide in protocols, complete plus partial responses scan or 68Ga-DOTA-peptide PET/CT in diferent studies with 90Y-octreotide have • ECOG performance status of 2 or less ranged from 10% to 30%. According to the • same authors, the overall objective tumour Life expectancy of at least 6 months response rate with 177Lu-octreotate, compris- ing complete and partial responses, was al- Absolute contra-indications for PRRT are: most 30% [20]. • Pregnancy and lactation

A prerequisite for PRRT is the demonstration Relative contra-indications for PRRT are: that tumoral lesions have suicient uptake • Severe liver impairment when a diagnostic 111In-octreotide or 68Ga-la- • Renal impairment belled somatostatin analogue scan is carried • out. Adequate uptake of the above-men- Impaired haematological function tioned tracers is an essential indicator that • Severe cardiac impairment therapeutic levels of internal radiation could

87 Pre-therapeutic evaluation Ki-67 and correct histopathological evalua- PRRT uses radiolabelled somatostatin ana- tion of the tumoral lesion, as well as correct logues with high ainity for SSTR2, which is biochemical assessment, in order to better expressed by the majority of NETs. Currently categorise the patient. the most frequently used radiopharmaceu- ticals for PRRT of NETs are 90Y-DOTA-Tyr3- As mentioned above, radionuclide therapy octreotide (90Y-DOTATOC), 90Y-DOTA-Tyr3-oc- is contraindicated in pregnant and lactating treotate (90Y-DOTATATE) and 177Lu-DOTA-Tyr3- women and patients with less than 6 months’ octreotate (177Lu-DOTATATE). life expectancy. Patients with carcinoid heart disease should be monitored closely be- Adequate tumour uptake on 111In-DTPA- cause these patients are at high risk of right- octreotide (111In-pentetreotide) scintigraphy sided heart insuiciency. (Octreoscan®) is an essential prerequisite when considering PRRT as a therapeutic Therapeutic procedure option. Novel somatostatin-based PET im- Prior to therapy administration, each patient aging techniques such as 68Ga-DOTATOC has to undergo a consultation with the nu- or 68Ga-DOTATATE are also used to evaluate clear medicine physician in order to obtain a adequate tumour uptake before PRRT. In the thorough medical history, perform a physi- pre-therapy imaging evaluation setting, false cal examination, conirm appropriateness negatives may be due to the small size of le- for treatment and acquire formal written in- sions (knowledge of the spatial resolution of formed consent. the imaging modality used is important) or poorly diferentiated forms, which express Targeted therapy is administered intrave- fewer receptors. nously in subsequent cycles (usually three or four) in order to reach an adequate cumula- Other imaging modalities that can be con- tive activity to efectively irradiate the tu- sidered before radionuclide therapy adminis- mour. According to several dosimetric stud- tration are chest X-ray, CT or MRI of the lesion ies, to obtain the disappearance of tumoral and echocardiography (the latter can be con- lesions or, at least, a reduction in lesion size, sidered in patients in whom carcinoid heart an absorbed dose of at least 70-80 Gy must disease is suspected). be provided. Such an absorbed dose can be delivered by giving the patient a cumulative Further pre-therapy evaluation for PRRT con- activity of at least 20 GBq of 177Lu-DOTATATE sists in reviewing the blood tests in order [22]. Based on a prospective phase I-II study, to exclude patients with important renal, Bodei et al. reported cumulative activities of hepatic and haematological impairment. up to 29 GBq of 177Lu-DOTATATE to be well Of vital importance is the determination of tolerated. In this study, cumulative renal

88 Section II 3. Radionuclide Therapy in Neuroendocrine Tumours

absorbed doses ranged from 8 to 37 Gy with The cycles are separated by at least no major acute or delayed renal toxicity. A 8-12 weeks, such intervals being necessary median decrease in creatinine clearance of to ensure adequate recovery from any hae- 27.9% was recorded after 2 years, with higher matological or other toxicity. reductions in patients with hypertension and diabetes [23]. The side-efects of radionuclide therapy can be divided into acute side-efects and more An example of the precautions taken to re- delayed efects caused by radiation toxicity. duce the renal absorbed dose is to give pa- The most common acute efects, occurring tients an intravenous infusion of positively at the time of injection or up to a few days charged amino acids, such as lysine and/ after therapy, include nausea, vomiting and or arginine, 30 min before administration of increased pain at tumour sites [26]. These

177Lu or 90Y and in the 4 h following therapy. side-efects are generally mild, are minimised EANM The infusion aims to optimally by a slow infusion and can be prevented or hydrate the patient and competitively inhibit reduced by symptomatic treatment. Severe the renal proximal tubular reabsorption of toxicity includes liver, kidney or haematologi- the radiopeptide [24]. This precaution has cal failure and may occur as a result of the been shown to reduce the absorbed dose radiation absorbed dose in healthy organs. to the kidneys by between 9% and 53% [22]. Post-therapy evaluation As nausea and vomiting are some of the Follow-up of patients who undergo targeted common side-efects of radionuclide thera- radiopeptide therapy consists in anatomical, py, an intravenous injection of an anti-emetic functional, biochemical and clinical response is also administered. The radiopeptide is then evaluations. administered in a saline bag through slow in- travenous infusion. As ascertained by phase The anatomical response is evaluated by I studies, the recommended dose per cycle means of radiological imaging (Fig. 3), most of 177Lu-DOTATATE is about 5.5-7.4 GBq, while notably CT or MRI. The image response cri- the cumulative dose is around 22.2-29.6 GBq teria used when applying CT are based on [25]. The subsequent doses can be ixed or the RECIST criteria (Response Evaluation Cri- escalated according to patient response and teria in Solid Tumors), according to which re- post-therapy image evaluation. sponse can be subdivided into: • CR (complete response) The unsealed source should be administered • PR (partial response) in designated facilities incorporating appro- • priate lead shielding, en suite washing facili- PD (progressive disease) ties and radiation monitoring equipment. • SD (stable disease)

89 Images courtesy by of Imperial Hospital London College

Figure 3: Pre- (bottom) and post-PRRT therapy (top) imaging in a patient with metastatic NET.

Functional imaging modalities with somatosta- recorded by the patient in a special diary and tin analogues labelled with 111In or 68Ga play subsequently evaluated by a doctor. an important role in the follow-up of patients treated with radionuclide therapy. More com- In conclusion, treatment with 90Y- or 177Lu- prehensive information may be gained by eval- labelled somatostatin analogues has been uating factors such as tumour uptake intensity, associated with considerable symptomatic together with the image response on CT. improvement and, to a lesser extent, disease stabilisation with limited side-efects that are Clinical response evaluation is carried out mainly related to reduction in kidney func- in symptomatic patients. Any change in the tion [20]. frequency or intensity of the symptoms is

90 9. Metz DC, Jensen RT. DC,Jensen Metz Gastrointestinal neuroendocrine 9. BajettaE,Catena L,Procopio G,BichisaoE 7. Herder De WW, SW. HolandLJ, vanderLely Lamberts AJ, 6. JJ, Plowman G,Mukherjee PN,Grossman AB. Kaltsas The 4. FT, R,Bosman, G,Arnold Rindi DS, Capella C,Klimstra 3. R, Frank Arnold U. M, of gastroen-Kajdan Management 1. References References II,Chapter 3 Section 10. Herder De WW, HolandLJ, Van derLely Lamberts AJ, 8. Hoyer D, pharmacology H,BrunsC.Molecular Lubbert 5. Williams ED, Sandler M. The classiication of carcinoid 2. preliminary data.Eur JNuclMed. 2001;28:1751–7. preliminary matostatin 68Ga-DOTATOC: receptor PET ski P ski 2003;10:451-8. atic neuroendocrine tumours. Cancer. EndocrRelat SW. Somatostatin receptors ingastroentero-pancre treatment? AnnOncol. 2005;16:1374-80. tumours useful fordocrine an appropriate selecting Torre S,etal, Isthenew WHO classicationofneuroen- Clin Gastroenterol. 1996;10:571–87. Peptide receptors tumours. ingutendocrine Bailliere’s Pharmacol. 1995;350:441–53. of somatostatin receptors, Naunyn Schmiedeberg’s Arch 2001;55: 575-87. of malignant neuroendocrine tumours. ClinEndocrinol. role ofchemotherapy inthenonsurgical management for Agency Research onCancerInternational 2010:13-14. FT,Bosman Carneiro F, RH, Hruban Theise D, eds. Lyon: WHO classiicationoftumoursthedigestive system. neuroendocrine neoplasmsofthedigestive system. In: G, et al. NomenclatureKlöppel and classiication of tostatin analogues. Digestion.1994;55Suppl3:107–13. teropancreatic tumors:theplaceofsoma- endocrine Hofmann M 2008;135:1469–92. tumors: pancreatic tumors. endocrine Gastroenterology. tumours. Lancet.1963;I:238–9. , Oei L, et al. Biokinetics andimaging withtheso- L,etal.Oei Biokinetics , Maecke H Maecke , Börner R Börner , Weckesser E , Ferrari L , Schöf- , , Della -

91 16. 16. 15. B, HolstJJ. LN,StidsenCE,Hartmann Somatosta- Moller 14. Pavel M,BaudinE,Couvelard E,Öberg A, Krenning K, 13. 11. J, HR,Hof- Henze J, M,Schuhmacher Kowalski Macke 18. 12. M,Decristoforo D,Gabriel C,Kendler Dobrozemsky G, 17. Smith MC, Liu J, Chen T, H, Schran Yeh F CM, et Jamar Breeman WA Putzer D mediated imaging and therapy: basicscience, current mediated imaging andtherapy: R, tin receptors. BiochimBiophys 2003;1616:1–84. Acta. 2011. ence participants Steinmüller T, andallotherBarcelona Consensus Confer- 2009;50:1214–21. and . toin comparison CT J Nucl Med. 68Ga-DOTA-Tyr3-octreotideneuroendocrine tumor: PET Dobrozemsky G,etal. metastases inpatientswith Bone 2007;48:508–18. matostatin receptor scintigraphy andCT. JNuclMed. withso- inneuroendocrine tumors:comparison PET Heute D, Uprimny C,etal. 68Ga-DOTA-Tyr3-octreotide Biol.tumors. Imaging 2003;5:42–8. Mol irst results inpatientswithneuroendocrine SPECT: Tyr(3)-octreotide to [111In]-DTPAOC incomparison tomography imaging using[68Ga]-DOTA-D Phe(1)- U.mann M,Haberkorn Evaluation ofpositron emission 1996;37:1519–21. treotide inmidgutcarcinoid syndrome. JNuclMed. nuclide therapy usingindium-111-DTPA-D-Phe1-oc dóttir J Fjälling M, Andersson P, Forssell-AronssonGrétars E, plastic therapy. Digestion.2000;62Suppl1:69–72. somatostatin-receptor-targeted radionuclideantineo- al. OctreoTher: clinicaldevelopment ofa ongoingearly Nucl Med. 2001;28:1421-9. limitationsandfutureknowledge, perspectives. Eur J Bakker WH Bakker , , Johansson V Johansson Gabriel M Gabriel , , de Jong M de Jong Kooij PP,Kooij et al. Somatostatin receptor , Henninger B , Tisell LE,etal. Systemic radio , Kwekkeboom DJ Kwekkeboom , Kendler D Kendler , Uprimny C , Valkema , - - - , EANM 19. De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom 23. Bodei L, Cremonesi M, Grana GM, Fazio N, Iodice S, Baio DJ, Breeman WA, et al. Somatostatin receptor-targeted SM, et al. Peptide receptor radionuclide therapy with radionuclide therapy of tumors: preclinical and clinical 177Lu-Dotatate: the IEO phase I-II study. Eur J Nuc Med. indings. Semin Nucl Med. 2002;32:133–40. 2011;38:2125-35.

20. Kwekkeboom DJ, de Herder WW, van Eijck CHJ, Kam 24. Bernard BF, Krenning EP, Breeman WA, Rolleman EJ, Bak- BL, van Essen M, Teunissen JJM, Krenning EP. Peptide ker WH, Visser TJ, et al. D-lysine reduction of indium-111 receptor radionuclide therapy in patients with gastro- octreotide and yttrium-90 octreotide renal uptake. J enteropancreatic neuroendocrine tumours. Semin Nucl Nucl Med. 1997;38:1929-33. Med. 2010;40:78-88. 25. Cybulla M, Weiner SM, Otte A. End-stage renal disease 21. Behr TM, Goldenberg DM, Becker W. Reducing the after treatment with 90Y-DOTATOC. Eur J Nucl Med. renal uptake of radiolabeled antibody fragments 2001;28:1552–4. and peptides for diagnosis and therapy: present sta- tus, future prospects and limitations. Eur J Nucl Med. 26. Waldherr C, Pless M, Maecke HR, Schumacher T, Craz- 1998;25:201–12. zolara A, Nitzsche EU, et al, Tumor response and clinical beneit in neuroendocrine tumors after 7.4 GBq (90) 22. De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom Y-DOTATOC, J Nucl Med. 2002;43:610–6. DJ, Breeman WA, et al. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical indings. Semin Nucl Med. 2002;32:133-40.

92 cases are related , while31% to HBV isestimated that54%ofHCC [1,3,4].It intake infection, alcoholism andalatoxintion, HCV The infec- are predominant factors HBV risk factors Risk Each year, cases thenumberofnew Epidemiology doRosário Nadine SilvaandMaria Vieira 4. Radionuclide Therapy inHepatocellular Carcinoma II Section annually [1]. incidence inEurope cases will be78,000new wide, anditisestimated thatby 2020,the The incidence of HCC isincreasing world- infection [3]. for HCC appears to behepatitis C virus (HCV) factor risk theprimary andJapan Spain, Italy dueto alcoholabuse[3],whilein cirrhosis France, theprevalence ofHCC isrelated to theUnited States infection and [3].In (HBV) graphical areas ischronic hepatitis B virus inthesegeo- factor and thedominantrisk [1], Africa occur inEastAsia and sub-Saharan highest incidencerates, approximately 85%, to [3,4]. factors theprevalence ofrisk The ofHCCThe distribution worldwide isrelated cancers [1]. liverrepresents more than90%ofprimary annually [2].Hepatocellular carcinoma (HCC) cancer-related deaths, with695,245cases per year, andisthethird leadingcauseof cancer worldwide, cases with 749,000 new mostcommon [1]. Liver canceristhesixth related deathsaround eachyear theworld cancer diagnoses and6.7millioncancer- is estimated thatthere are 10.9millionnew cer andcancer-related deathsincreases. It ofcan- 93 rhotic patientswilldevelop HCCrhotic [1]. ofcir- [4].One-third deposition andcirrhosis regeneration, leadingto collagen and further necrosisis capableofcausinghepatocyte duce aprocess ofchronic inlammationthat All theaforementioned canin- factors risk are dueto othercauses[1]. are related infection and almost 15% to HCV with a higher risk ofHCCwith ahigherrisk [4,7]. values canbehelpfulinidentifying patients vated serumAFP. this, Despite increased AFP other tumours may be associated with ele- in about30%ofHCC patients[7]andsome However, serum levels of AFPremain normal protein thatmay beincreased inHCC [4,7]. Alpha-fetoprotein (AFP) isaserumglyco- plying potentially curative procedures [1,4]. sized ofap- lessthan2cmwiththepurpose Nowadays, thegoalisto diagnose tumours Diagnosis less than5%[5,6]. without rate for5-year HCC survival is below 10%, and to detect tumours early [1,4,5]. to tumoursearly detect programmesHCC into inorder surveillance to ofdeveloping enter patientsathigherrisk nosed at an advanced stage, it is important initially is typically “silent”, beingdiag- often are factors recognisedSince therisk andHCC of treatments [1]. gressive diseaseandinluencesthesuccess isrelated to asitisapro- cirrhosis, survival

treatment the 5-year survival treatmentrate is the 5-year survival

The overall


EANM It is possible to detect HCC at an early stage several months and this may lead to tumour with ultrasound (US), but also with dynamic progression, resulting in exclusion from the imaging techniques such as four-phase com- transplantation list [4]. puted tomography (CT) or dynamic contrast- enhanced magnetic resonance imaging For both of the aforementioned approach- (MRI) [1,4,8]. es there are some neo-adjuvant therapies which may be helpful by delaying disease Liver biopsy is not necessary if clinical, labo- progression, such as transarterial chemo- ratory and radiography are positive for HCC embolisation (TACE) and transcatheter em- [7] but is recommended for tumours occur- bolisation (TAE) [1,4]. ring in non-cirrhotic [1]. Local ablation by percutaneous ethanol in- Therapeutic approach jection or radiofrequency achieves good re- The therapeutic approach to HCC will de- sponses in patients with tumours less than 2 pend on the tumour size, the extent of liver cm, with a 90% complete response rate [1]. disease and the presence of metastases [9]. Staging the disease is the irst step in achiev- Although there are options which provide a ing an appropriate therapeutic approach. high complete response rate for HCC at early There are several potential curative therapies, stages, there is a lack of efective options for such as surgical resection, liver transplanta- unresectable HCC associated with liver dis- tion and percutaneous ablation [4,5]. ease [3]. For most such patients, treatment options are palliative [9]. Surgical resection is the irst-line treatment option for patients with well-deined and HCC has a poor response to systemic chemo- solitary liver tumours, as well as good liver therapy [3,6,9]. TACE and TAE are the most com- function [4]. Selected candidates may have monly used options for patients with interme- a positive outcome with resection, with a diate stage HCC [1,4]. Although these proce- 5-year survival rate of 30-50% [1]. Unfortu- dures can achieve partial responses in 15-55% nately, this is an option for only 10-20% of of patients, both are often associated with mild HCC patients, and recurrence after resection to moderate adverse events, such as abdomi- is a possibility [1,3,9]. In cases of recurrence, nal pain, fever, nausea and vomiting [1,3]. patients need to be re-staged and treatment based upon the results of that re-staging [1]. Some patients with advanced stage HCC may beneit from therapy with sorafenib, Liver transplantation ofers less risk of re- which is the only systemic approach with currence, with the same chance of survival. demonstrated value in the management of On the other hand, the waiting list is often HCC [1].

94 Section II 4. Radionuclide Therapy in Hepatocellular Carcinoma

External beam has a limited neuroendocrine tumours, due to the unique role in the treatment of HCC as for patients inlow characteristics of these tumours [13- with normal liver function the maximum tol- 15]. This local liver-directed therapy may re- erated dose is 30-35 Gy, which is below the duce tumour burden, provide palliation and required dose for tumoricidal efect [3]. increase survival, while having a low toxicity proile [3]. Radionuclide therapy is an approach which aims to deliver radioactive substances, such Physical characteristics of 90Y as iodine-131 (131I)-Lipiodol or yttrium-90 90Y is a beta particle emitter which has no (90Y) microspheres, by the use of intra-arterial gamma photon emission (Table 1) but does percutaneous techniques [1,10]. Radioem- have secondary bremsstrahlung radiation bolisation techniques are based on tumour emission [10,16]. This secondary emission hypervascularisation, as most unresectable does not imply burdensome radiation safe- EANM liver tumours receive their blood supply al- ty precautions because it does not exceed most totally from the hepatic artery, whilst 1 mSv for twhe general public [12]. the normal liver parenchyma receives its blood supply mainly through the portal Emission Pure beta emission (β-) vein [1,10,11]. This diferential low between tumour and normal tissue allows the admin- Mean energy (MeV) 0.9367 istration of high-energy and low-penetration Decay product Zirconium-90 (stable) radionuclides in order to obtain highly selec- Physical half-life (h) 64.2 tive tumour uptake while delivering tolerable Average penetration doses to the normal liver tissue [1,10-12]. 2.27 range (mm) 90 Maximum penetration Radioembolisation with Y-microspheres 11.3 Some positive outcomes from cohort studies range (mm) [1] indicate that radioembolisation with 90Y- Nuclear reactor Production 89 90 microspheres is an option for patients with Y(n,p) Y an intermediate or advanced tumour stage. Table 1: Biophysical characteristics of 90Y Patients with intermediate and advanced [10-12,17] stage disease showed median survival times of 17.2 and 12 months, respectively [1]. Radiolabelled microspheres Currently, two types of 90Y-microsphere are This therapeutic approach is a reported op- available: resin microspheres (SIR-Spheres; tion not only for HCC patients, but also for Sirtex Medical, Lane Cove, Australia) and patients with secondary hepatic tumours glass microspheres (TheraSphere; MDS Nor- from , pancreatic cancer and dion, Kanata, Ontario, Canada) [10,12]. These

95 two types of microsphere have diferent pro- but dose calculations have shown that these duction methods, but also diferent charac- impurities do not exceed the medical event teristics, as shown in Table 2. limits [12].

Glass Resin Resin microspheres are produced by the Characteristics 90 microspheres ricrospheres chemical incorporation of Y in the carbox- ylic group after the production of the micro- No. of spheres spheres [10]. Trace amounts (up to 0.4% of per dose 3-8x106 30-60x106 90 (range) the administered dose) of Y may be present and excreted by urine during the irst 24 h. Speciic Resin microspheres have been shown to activity per 2500 50 88 sphere (Bq) have detectable amounts of Y [12]. Activity 3, 5, 7, 10, 3 Both types of microsphere are biocompat- available (GBq) 15, 20 ible, non-biodegradable devices and are not Size (µm) 20-30 20-60 excreted or metabolised. These devices de- Splitting one cay to ininity, delivering 94% of their radia- vial for two or Not possible Possible tion in 11 days [17]. more patients Solution used Radiation safety considerations for suspension Saline (0.9%) Sterile water Patients treated with 90Y-microspheres will of the spheres have the activity conined to the liver, though Associated 88Y, 152Eu, 154Eu, some may have shunting activity in the lungs 88Y impurities 57Co, 60Co or the gastrointestinal tract. As 90Y is a pure beta emitter, the only considered dose to an Table 2: Summary of general characteristics of individual likely to be in contact with the pa- glass and resin microspheres (adapted from tient is the bremsstrahlung radiation [12]. Giammarile et al. [10], Murthy et al. [17] and Vente et al. [18]) Patient instructions are only required if the Glass microspheres are obtained by neutron dose to other individuals is likely to exceed bombardment of the glass matrix of the 1 mSv [12]. For health care workers, no bur- spheres, in which 89Y is embedded; in this densome radiation safety precautions need way, 89Y is converted to radioactive 90Y and be taken: the shielding of this radiopharma- the radioisotope cannot be leached from the ceutical is achieved by the use of plastic and glass [11,12]. This procedure may enhance acrylic materials and lead should be avoided the production of detectable amounts of im- due to the bremsstrahlung radiation produc- purities, such as 88Y, 152Eu, 154Eu, 57Co and 60Co, tion that may arise [12].

96 Section II 4. Radionuclide Therapy in Hepatocellular Carcinoma

As some free 90Y may be excreted by urine SIR-Spheres® TheraSphere® during the irst 24 h after administration (particularly with the resin microspheres), Abnormal excretory Severe hepatic instructions may be issued with a view to en- liver function tests dysfunction suring careful bathroom hygiene [10,12]. Tumour volume ≥70% of the target liver Contra-indications and eligibility criteria Ascites volume or multiple Pregnancy and breastfeeding are two ab- tumour nodules (“bulky disease”) solute contra-indications to this therapy, as with almost all nuclear medicine-related pro- Abnormal hepatic Abnormal hepatic cedures. Another important absolute contra- vascular anatomy vascular anatomy (if it would induce (if it would induce indication, for radioprotection reasons, is a radiopharmaceutical radiopharmaceutical life expectancy of less than 1 month [10]. relux to other organs) relux to other organs) EANM

There are relative contra-indications that Lung shunt fraction Lung shunt fraction ≥20% (determined which results in should be analysed speciically for each pa- by 99mTc-MAA delivery of ≥610 MBq tient. Lab tests are required, generally to as- scintigraphy) sess liver function, renal function, pulmonary disease and contra-indications to hepatic ar- Extrahepatic malignant Iniltrative tumour type disease tery catheterisation [9,10]. It is also important to determine the extension of the disease Portal vein thrombosis as disseminated extrahepatic malignant dis- ease and extensive intrahepatic disease are Table 3: Speciic contra-indications to relative contra-indications [10]. each type of microsphere (adapted from Giammarile et al. [10]) For each type of microsphere there are spe- Dosimetry and administered dose ciic contra-indications, which are reported in In order to calculate the necessary activity to Table 3. deliver the required dose to the tumour, ei- ther dosimetric or empirical methods may be used. For SIR-Spheres®, empirical models are proposed that are based on the estimated tumour involvement of the liver [10,16]. This method implies that the greater the tumour burden, the higher the dose to the tumour, as reported in Table 4 [10,16].

97 Tumour involvement Recommended Reduction in the LSF (%) activity (GBq) administered activity (%) <25% 2.0 <10% No reduction

25-50% 2.5 10-15% 20%

>50% 3.0 15-20% 40%

Table 4: Recommended activity for SIR- >20% The technique is contra-indicated Spheres®, accordingly to tumour involvement Table 5: Adjustment in the administered [10,16] activity according to LSF, for SIR-Spheres® [10] Another empirical model suggested for SIR- In order to detect and quantify LSF, techne- Spheres® relates to the body surface area tium-99m (99mTc)-labelled albumin macro- (BSA), using Eq. 1 to calculate the activity to aggregate (MAA) scintigraphy is performed be delivered to the patient [10]: [10]. The LSF is determined using Eq. 3 [10]: tumor volume A(GBq) = (BSA – 0.2) + lung counts total liver volume (1) Lung Shant fraction = lung + liver counts (3) The dosimetric models, which consider the Procedure lung shunt fraction (LSF), are usually used for As mentioned previously, a pre-therapy eval- TheraSphere® [10,16]. The delivered dose for uation must be performed in order to assess TheraSphere® is between 80 and 150 Gy [16]. patient eligibility for this speciic treatment. With glass microspheres the activity required This evaluation consists in a complete history to deliver the prescribed dose is calculated and physical examination, chest radiography using Eq. 2 [16]: and assessment of pulmonary function, liver [Dose(Gy)] [Liver mass(kg)] sonography or CT, evaluation of serum liver A(GBq) = 49.8 (2) enzymes, complete blood count, coagula- tion testing, determination of creatinine lev- Whichever type of microsphere is used, the els and assessment of tumour markers [9-11]. vendors recommend adjustments in order to reduce the fraction of activity shunting to the Positron emission tomography (PET)/CT with lungs (the LSF). For TheraSphere, the dose to luorine-18 (18F) luorodeoxyglucose (FDG) the lungs should be less than 30 Gy [10,16]. can be performed to exclude extrahepatic For SIR-Spheres®, the adjustments are shown disease and also to evaluate the extension in Table 5 [10]. of hepatic disease. Usually, HCCs have very low-grade FDG uptake, or even no uptake,

98 Section II 4. Radionuclide Therapy in Hepatocellular Carcinoma

unless the tumour is of an aggressive type; acquired [9-11]. Visual evaluation of lung and nevertheless, 18F-FDG uptake has prognostic gastrointestinal shunt and lung shunt quan- value and is used to check the therapeutic tiication are performed, which may lead to outcome [10,19]. dose adjustment. Assessment of the tumour uptake within the liver is also performed [10]. A CT scan allows accurate calculation of the It is important to note that imaging with liver volume, which is essential for dose cal- 99mTc-MAA may entail visualisation of the thy- culation [10,11]. roid, stomach and urinary bladder because of free pertechnetate [10]. Angiography by high-speed multi-slice CT is usually performed 4-6 weeks before the After LSF assessment and evaluation of the therapy with 90Y-microspheres [11]. Angiog- presence or absence of gastrointestinal raphy visualises the hepatic arterial anatomy shunt and of whether patients are suiciently EANM and the haemodynamics of the hepatic cir- well to undergo the therapy, dose calculation culation [11]. Anatomical variations are as- proceeds [10]. 90Y-microsphere administra- sessed, as is the presence or absence of por- tion is carried out in the interventional radi- tal venous thrombosis [10]. Angiography also ology department as it involves intra-arterial permits the placement of coils in order to oc- catheter manipulation. Administration is clude aberrant hepatic arteries and embolise performed by a nuclear medicine physician collateral vessels, to ensure that the micro- using the vendor’s device and with gentle spheres remain conined to the liver [11]. Coil infusion in order to prevent backlow of the embolisation of the gastroduodenal artery radiopharmaceutical [10]. may be of use in preventing shunting activity to the gastrointestinal tract [10]. A few hours after administration, in order to locate the administered activity, bremsstrah- During angiography, a catheter is placed in lung planar images (anterior and right later- the hepatic artery or in any branch of the al) may be acquired using a gamma camera hepatic artery (depending on the hepatic with an energy peak of 100 keV and a wide- arterial anatomy or on selective treatment energy window in order to increase sensitiv- options) [10,11]. This procedure allows intra- ity [20]. Alternatively, 30-min PET images may arterial administration of 99mTc-MAA, which be acquired, which have the advantage of have a comparable size to 90Y-microspheres. better spatial resolution [10]. These images Thus, scintigraphic acquisition is performed are essential to assess the administered ac- as soon as possible after the administration tivity, as this may be unexpectedly located of 75-150 MBq of 99mTc-MAA. Planar views outside the liver despite the indings on (anterior and lateral) of the upper abdomen, 99mTc-MAA scintigraphy and the previous liver anterior chest image and hepatic SPECT are embolisation [20]. They are also important in

99 localising the activity in order to prevent and demonstrated good tolerance by patients manage side-efects if there is extrahepatic [21]. Compared with 90Y-microspheres, 131I- activity [20]. Lipiodol is approximately 10 times less ex- pensive [19]. Side-efects and follow-up The overall incidence of complications and 131I-Lipiodol is an option in patients with por- side-efects after the therapy is low [17]. Even tal vein thrombosis and those who have al- though prophylactic hepatic embolisation ready been surgically treated. 131I-Lipiodol is is performed in order to prevent shunting also under study for application in patients and to guarantee maximum tumour uptake, with liver metastases and as a neoadjuvant some side-efects may be experienced by therapeutic before resection and liver trans- patients because inadvertent deposition of plantation [10]. 90Y-microspheres is a possibility despite an- giographic occlusion techniques [9]. Com- Physical characteristics of 131I monly, patients experience fatigue, nausea, 131I is a beta emitter but it is also character- abdominal pain, fever and transitory eleva- ised by high gamma ray emission (Table 6). tion of the transaminases [10]. Some other This allows image acquisition but constrains possible side-efects occur at lower rates the administered activity owing to radiation (2-8%), such as chronic abdominal pain, ra- exposure [10,21]. diation gastritis, gastrointestinal ulceration, upper gastrointestinal ulceration, haemor- Emission Beta, gamma rhage, pancreatitis, radiation pneumonitis and radiation-induced liver disease [9,10]. In β (0.61, 89% Mean energy (MeV) abundance), γ (0.36, addition to careful assessment of extrahepat- 81% abundance) ic shunting, appropriate selection of patients is essential to minimise side-efects [9,17]. Decay product -131 (stable) Physical half-life (days) 8.04 Post-therapeutic follow-up is performed in Average penetration order to detect any possible side-efects but β: 0.9 mm range (mm) also to evaluate tumour response. It is con- ducted 30 days after the therapy and at 2- to Maximum penetration β: 2.4 mm 3-month intervals thereafter [10]. range (mm) Production Nuclear reactor 131I-Lipiodol therapy Treatment with intra-arterial injection of Table 6: Biophysical characteristics of 131I 131I-Lipiodol was developed in the 1990s [10,19,21] and has yielded valuable clinical results and

100 Section II 4. Radionuclide Therapy in Hepatocellular Carcinoma

131I-Lipiodol It is important to note that 131I-Lipiodol is This radiopharmaceutical is available in a eliminated mainly via the urinary tract (30- commercial form as Lipiocis (IBA, Brussels, 50% of the administered activity at day 8) Belgium) [10]. Lipiodol is an oil compound [19]. A small amount of the activity is elimi- with 38-40% iodine fatty acid ethyl esters of nated in faeces (<3% at day 5) [19]. In this re- poppy seed oil [10,19]. This compound con- spect, it is important to verbally instruct the tains stable iodine-127 (127I), and by a simple patient on efective bathroom hygiene to isotopic change it is substituted by 131I [10,19]. prevent contamination.

After intra-arterial injection, 131I-Lipiodol mi- Thyroid gland blockage with stable iodine or grates towards the tumour region. There perchlorate is usually not recom- may be some unspeciic uptake in non-ma- mended [10]. lignant endothelial cells, but this compound EANM is highly selective for malignant cells [10,19]. The health facility in which the procedure is It is estimated that 24 h after the administra- performed must be fully equipped in order tion, more than 75% of Lipiodol is trapped in to guarantee radiation safety for both staf the liver, though the remainder reaches the and patients (i.e. shielding rooms, adequate lungs [10,19,22]. The tumour/non-tumour protection during transportation of the pa- uptake ratio is about 15-20:1 and it tends tient within the institution, implementation to increase with time, possibly because of of appropriate contamination procedures the lack of macrophagic cells in the tumour, and suitably trained staf) [10]. leading to slow Lipiodol clearance from the tumour [19]. Contra-indications and eligibility criteria Pregnancy and breast-feeding are again two Other tissues show very little uptake of this absolute contra-indications to this therapy. compound, this being true even of the thy- Another important absolute contra-indica- roid gland [22]. tion, for radioprotection reasons, is a life ex- pectancy of less than 1 month [10]. Radiation safety considerations Because of the gamma emission of 131I, hospi- There are relative contra-indications that talisation is required in order to safeguard in- should be analysed individually for each pa- dividuals likely to come into contact with the tient. Lab tests are required, generally to ac- patient [22]. This hospitalisation can be from cess liver function, renal function, pulmonary 4 days to a week, in a shielded room [22,23]. disease and contra-indications to hepatic ar- Discharge will depend on the measured re- tery catheterisation [10]. It is also important maining activity, and this limit is usually less to determine the extension of the disease, than 1 mSv to other individuals. as disseminated extrahepatic malignant

101 disease and extensive intrahepatic disease creatinine levels and assessment of tumour are relative contra-indications [10]. markers [10,19].

Appropriate patient selection with respect to As previously mentioned, PET/CT with 18F- hepatic reserve and overall functional status FDG may be of use, especially in order to will maximise the therapeutic outcome and evaluate extrahepatic disease [10,19]. minimise the risk to normal hepatic paren- chyma [10]. Angiography is performed to assess the he- patic vascular anatomy and to place an intra- Administered dose arterial catheter. Due to anatomical variations The administered activity of 131I-Lipiodol is the catheter may be placed in other, distally 2.22 GBq, which corresponds to a hepatic located hepatic branches [10,19,23]. dose of approximately 50 Gy [10]. Although this is a ixed activity, it is possible to adjust The activity is administered slowly in the it according to tumour load if necessary [10]. catheter to prevent relux and consequent retrograde low into the gastroduodenal Radiopharmaceutical preparation must be artery [10,23]. This procedure is done under performed in an adequately ventilated cabi- luoroscopic control [10,23]. After the admin- net in the Nuclear Medicine Department in istration, the patient is taken to the shielded order to prevent iodine aerosol inhalation room [19,22,23]. [19]. Whole-body scintigraphic images are ac- As this compound is a viscous oil, it might quired one week after the administration of ofer some resistance to syringe dispensing 131I-Lipiodol. A CT scan may be performed and catheter injection [10]. based on the high iodine content of the ra- diopharmaceutical as this dispenses supple- Procedure mentary contrast administration [10,23]. As previously mentioned, a pre-therapy eval- uation must be performed in order to assess Some patients may beneit from one or sev- the patient’s eligibility for this speciic treat- eral treatments [19] that can be performed ment. This evaluation consists in a complete 2, 5, 8 and 12 months after the irst injection history and physical examination, pulmonary [10]. function assessment, three-phase contrast CT, -enhanced MRI, assessment Side-efects and follow-up of extent of extrahepatic disease, evalua- Serious adverse efects are rare [19,22]. tion of serum liver enzymes, complete blood Early side-efects, which occur rarely, may count, coagulation testing, determination of be moderate and temporary pyrexia (29%),

102 Section II 4. Radionuclide Therapy in Hepatocellular Carcinoma

moderate and temporary alteration on bio- logical liver test (20%) and hepatic pain on injection (12.5%) [10,19,22]. The delayed side efects, which occur more rarely, are moder- ate and reversible leucopenia (7%) and inter- stitial pneumopathies (2%) [19].

Follow-up should be performed using the same modalities as have been employed to assess the disease (three-phase CT, MRI, PET/CT, lab tests) and this should be done 1 month after therapy and then at 2- to

3-month intervals [10,19]. EANM

103 References Section II, Chapter 4

References 1. Llovet J, Ducreux M, Lencioi R, Di Bisceglie AM, Galle PR, 14. Arslan N, Emi M, Alagöz E, Üstünöz B, Oysul K, Arpaci F, Dufour JF, et al. EASL-EORTIC Clinical Practice Guidelines; et al. Selective intraarterial radionuclide therapy with management of hepatocellular carcinoma. J Hepatol. yttrium-90 (Y-90) microspheres for hepatic neuroen- 2012;56:908-43. docrine metastases: initial experience at a single center. Vojnosanit Pregl. 2011;4:341-8. 2. IARC. http://www-dep.iarc.fr/;2013 [accessed 23/03/2013] 15. Cao C, Yan T, Morris D, Bester L. Radioembolization 3. Geschwind J, Salem R, Carr B, Soulen MC, Thurston KG, with yttrium-90 microspheres for pancreatic cancer Goin KA, et al. Yttrium-90 microspheres for the treat- liver metastases: results from a pilot study. Tumori. ment of hepatocellular carcinoma. Gastroenterology. 2010;96:955-8. 2004;127:S195-205. 16. Dezarn W. Quality assurance issues for therapeutic ap- 4. Bruix J, Hessheimer AJ, Forner A, Boix L, Vilana R, Llovet plication of radioactive microspheres. Int J Radiat Oncol JM. New aspects of diagnosis and therapy of hepatocel- Biol Phys. 2008;71:S147-151. lular carcinoma. Oncogene. 2006;25:3848-56. 17. Murthy R, Nunez R, Szklaruk J, Erwin W, Madof D, Gupta 5. Clark H, Carson W, Kavanagh P, Ho C, Shen P, Zagoria R. S, et al. Yttrium-90 microsphere therapy for hepatic Staging and current treatment of hepatocellular carci- malignancy: device, indications, technical consider- noma. Radiographics. 2005;25:S3–24. ations and potential complications. Radiographics. 6. O’Brien T, Kirk G, Zhang M. Hepatocellular carcinoma: 2005;25:S41-55. paradigm of preventive oncology. Cancer. 2004;10:67- 18. Vente M, Wondergem M, Van Der Tweel I, Van Der Bosch 73. M, Zonnenberg B, Lam M, et al. Yttrium-90 radioem- 7. Bialecki E, Di Bisceglie A. Diagnosis of hepatocellular bolization for the treatment of liver malignancies: a carcinoma. HPB (Oxford). 2005;7:26-34. structured meta-analysis. Eur J Radiol. 2009;19:951-9.

8. Dufy J, Hiatt J, Busuttil R. Surgical resection of hepato- 19. Ahmadzadehfar H, Sabet A, Jürgen H, Risse, Risse J. cellular carcinoma. Cancer. 2008;14:100-11. Therapy of hepatocellular carcinoma with iodine- 131-Lipiodol. In: Lau JWY, ed. Hepatocellular carcino- 9. Dancey J, Sheperd F, Paul K, Sniderman K, Houle S, Ga- ma - Clinical research. ISBN: 978-953-51-0112-3, InTech, brys J, et al. Treatment of nonresectable hepatocellular Available from: http://www.intechopen.com/books/ carcinoma with intrahepatic 90Y-microspheres. J Nucl hepatocellularcarcinoma-clinical-research/therapy-of- Med. 2000;41:1673-81. hepatocellular-carcinoma-with-iodine-131-lipiodol.

10. Giammarile F, Bodei L, Chiesa C, Flux G, Forrer F, Kraeber- 20. Elschot M, Vermolen BJ, Lam MG, de Keizer B, van den Bodere F, et al. EANM procedure guideline for treatment Bosch MA, de Jong HW. Quantitative comparison of of liver cancer and liver metastases with intra-arterial PET and bremsstrahlung SPECT for imaging the in vivo radioactive compounds. Eur J Nucl Med Mol Imaging. yttrium-90 microsphere distribution after liver radioem- 2011;38:1393-406. bolization. PLoS One. 2013;8:e55742.

11. Andrews J, Walker SC, Ackermann RJ, Cotton LA, Ens- 21. Ruyck K, Lambert B, Bacher K, Gemmel F, De Vos F, Vral minger WD, Shapiro B. Hepatic radioembolization with A, et al. Biologic dosimetry of 188Re-HDD/Lipiodol ver- yttrium-90 containing glass microspheres: preliminary sus 131I-Lipiodol therapy in patients with hepatocellular results and clinical follow-up. J Nucl Med. 1994;35:1637- carcinoma. J Nucl Med. 2004;45:612-8. 44. 22. Raoul J, Boucher E, Roland Y, Garin E. 131-iodine Lipiodol 12. Gulec S, Siegel J. Posttherapy radiation safety consider- therapy in hepatocellular carcinoma. Q J Nucl Med Mol ations in radiomicrosphere treatment with 90Y-micro- Imaging. 2005;53:348-55. spheres. J Nucl Med. 2007;48:2080–6. 23. Marelli L, Shusang V, Buscombe JR, Cholongitas E, Sti- 13. Gulec S, Fong Y. Yttrium 90 microsphere selective inter- gliano R, Davies N, et al. Transarterial injection of 131I- nal radiation treatment of hepatic colorectal metastases. Lipiodol, compared with chemoembolization, in the Arch Surg. 2007;142:675–82. treatment of unresectable hepatocellular cancer. J Nucl Med. 2009;50:871-7.

104 (<60-65 years). The of rituximab introduction young people transplantation inhigh-risk dose chemotherapy coupledwith stem cell chemotherapy, of high- with the possibility of disseminated NHLincludes multi-agent 50-60% ofpatientsbeingcured. Treatment The prognosis ofDLBCL is diferent, with ranges fromrelapses. 5 to 15 years. Survival with response to chemotherapy, butalways FL generallyshows indolentprogression ofindolentNLH(22%). most commontype (31%), andfollicular lymphoma (FL) isthe ofaggressivethe most common type NHL NHL(DLBCL)is (35%) [2].Difuselarge B-cell gressive (65%ofNHLs)andindolentforms classiication, andcanbeseparated into ag- ing to the World HealthOrganisation (WHO) more than25histological accord- subtypes indication for RIT. NHLscanbeclassiiedinto spond to coldmAbsandrepresent arelevant ,terised are highlyradiosensitive, re- lymphoma (NHL)cellsexpress well-charac- munological processes. non-Hodgkin B-cell of RITinvolve bothradiobiological andim- techniques [1]. The cytotoxic mechanisms stable chelates for labellingandpretargeting the development humanised mAbs,of new years, RIThasprogressed signiicantly, with thelast20 against atumourantigen.Over monoclonal antibodies(MAbs) directed clides isdelivered to tumourtargets using therapy whereby from irradiation radionu- Radioimmunotherapy (RIT) Radioimmunotherapy Introduction Alain Faivre-Chauvet, Françoise Kraeber-Bodéré Aurore Rauscher, Caroline AmandinePallardy, Bodet-Milin, inLymphomas5. Radioimmunotherapy II Section isatargeted 105 apy inthefront-line treatment ofFL patients. chemother- induction as consolidationafter FL or of patients with relapsed or refractory foring non-ablative activities thetreatment RIT canbeintegrated us- into clinical practice Clinical application limitations to RIT Clinical application andcontra-indications/ pecially targeting antigensotherthanCD20. RITandotherMAbsment, fractionated es- chemotherapy,after RITinirst-line treat- treatment, RITasconsolidation or high-dose myeloablativeor otherlymphomasubtypes: cols are inFL beingassessedinclinicaltrials treatment of FLpatients. Diferent RIT proto- usingnon-ablative dosesforclinical practice RITcanbeintegratedGlaxoSmithKline). into tigen hasbeenapproved inEurope for RIT: Today, one product targeting the CD20 an- FL ortreatment ofresidual massesofDLBCL. diation can beproposed for limited stage chemotherapy alone[3].Involved-ield ra- chemotherapy), ascompared withuseof with diferent chemotherapy regimens (R- or indolentB-NHLwhenitwascombined ment in outcome in patients with aggressive antibody,anti-CD20 resulted inanimprove- Basel, Switzerland), amonoclonalchimeric (MabThera, Ltd., Roche Rituxan, Genentech, Pharmaceuticals, Henderson,NV, USA). 90 the United States: other product targeting CD20 is available in Y-ibritumomab tiuxetan, (Zevalin, Spectrum 131 I-tositumomab, (Bexxar,

An- EANM Contra-indications Yttrium-90 is a beta-emitter, with a physical Exclusion criteria for treatment with Zevalin® half-life of 64 h, a maximum particle energy are: of 2.27 MeV and a maximum range of 11 mm in soft tissue. • Pregnancy and continuing breast-feeding

• Known hypersensitivity to 90Y-ibritumom- Preparation procedure ab tiuxetan, yttrium chloride, other murine Zevalin® is supplied as a kit for the prepara- 90 proteins or any of their components tion of Y-radiolabelled ibritumomab tiux- etan. The kit contains one antibody vial with • Children and adolescents under 18 years 3.2 mg ibritumomab tiuxetan (1.6 mg/mL), of age one 2-mL sodium vial, one 10-mL formulation bufer vial and a 10-mL empty • Marked bone marrow suppression (<1.5 x reaction vial. The kit must be stored at 2-8°C 109/L leucocytes; < 100 x 109/L thrombo- and should not be frozen. The radioactive cytes) component, 90Y, must be obtained separately • Greater than 25% of bone marrow iniltra- upon order from the manufacturer. Only tion by lymphoma carrier-free 90Y of pharmaceutical grade qual- ity must be used for antibody labelling, since • Previous external beam radiation involving metal contamination has a detrimental efect >25% of the active bone marrow on the labelling eiciency. • Prior bone marrow or stem cell transplan- Labelling must be performed only by quali- tation ied staf (radiopharmacist, chemist or tech- • Detectable human anti-murine antibody nician with qualiication in radiopharmacy) (HAMA), depending on titre with appropriate authorisation for the use and manipulation of radionuclides. Appro- The peripheral blood cell count should not priate facilities for shielding, calibration and be lower than the limits stated above. While quality control should be in place. Proper lower blood counts do not constitute an ab- aseptic technique and precautions for han- solute contraindication, they do increase the dling radioactive materials must be em- risk of severe and prolonged bone marrow ployed during the preparation procedure. suppression. Vial rubber stoppers must be cleaned with a suitable alcohol swab and sterile syringes Therapeutic procedure must be used. Waterproof gloves, protective Radiopharmaceutical shields for syringes and containers, forceps Approved name: 90Y- ibritumomab tiuxetan and tongs as gripping tools must be used or Zevalin® for the preparation. Owing to the 9.2 mm

106 Section II 5. Radioimmunotherapy in Lymphomas

length of 90Y beta emission [4], at least 1-cm- chromatography (ITLC) is recommended for thick Perspex or lead-loaded Perspex shields this purpose with sodium chloride solution should be used during labelling. (0.9%) as mobile phase. DTPA-90Y is carried by the solvent and has a chromatographic ratio The irst step consists in the addition to the (Rf) of 1, and radiolabelled antibody remains reaction vial of a 1.2-fold excess of sodium at the deposit with an Rf of 0. The radiochro- acetate solution compared with the yttrium matogram may be analysed in diferent ways: volume. The second step involves aseptically by cutting the ITLC into two parts and count- transferring 1,500 MBq of 90Y to the reaction ing each part in an appropriate counter, by vial and mixing the solution by inversion (or using a radiochromatograph or by using a ‘rolling’ the vial). Then 1.3 mL ibritumomab phosphorimager. Radiochemical purity is tiuxetan solution, previously brought to calculated as follows: room temperature, is transferred to the reac- EANM tion vial, and after mixing the reaction solu- % RCP = net count bottom half / total count x 100 tion is left at room temperature for 5 min. A labelling time longer than 6 min or shorter Common sources of error in quality control than 4 min or foam formation during the mix- are drop size and dead-time error during ing will result in inadequate radiolabelling. In measurement of the ITLC strips. If the aver- order to chelate free 90Y and inhibit radiolysis age radiochemical purity is less than 95%, the of the radiolabelled antibody, an appropriate preparation must not be administered. volume of formulation bufer that contains human serum albumin and DTPA is added to Method of administration the reaction vial; this results in a combined Before Zevalin® infusion, the activity in the total volume of 10 mL. 10-mL syringe must be measured using a calibrated ionisation chamber under the ap- The inal formulation after radiolabelling con- propriate geometric-, volume- and material- tains 2.08 mg ibritumomab tiuxetan in a total speciic (plastic needles, glass vials) condi- volume of 10 mL. After radiolabelling, imme- tions of calibration. diate use is recommended, but the solution may be stored at 2°-8°C (in a refrigerator). The prepared solution must be given as a At these temperatures and protected from slow intravenous infusion over a minimum , it can be used up to a maximum of 8 h. of 10 min. The infusion must not be admin- istered as an intravenous bolus. Zevalin® may Quality control be infused directly by stopping the low from The radiochemical purity of the prepared an infusion bag and administering it directly 90Y-radiolabelled Zevalin must be checked into the line. A 0.2- or 0.22-µm low-protein- before administration. Instant thin-layer binding ilter must be on line between the

107 patient and the infusion port. The line must • A representative (>2 cm long cylinder) be lushed with at least 10 mL of sodium bone marrow biopsy from the iliac crest: chloride 9 mg/mL (0.9%) solution after the The biopsy must have been performed no infusion of Zevalin®. earlier than the last point in time at which disease progression was detected or in any Administration schemes case a maximum of 3 months before the Zevalin® is administered 6-8 days after a pre- scheduled RIT. dose of 2 x 250 mg of rituximab, to improve biodistribution and tumour targeting. The • Exclusion of pregnancy and conirmation whole therapy requires only two outpatient of cessation of breast feeding. visits. No dosimetry study is required. When a dosimetry study is performed for research • Recording of current medications, espe- purposes, the irst dose of cold MAb is in- cially those afecting haematological func- jected with 185 MBq of 111In-ibritumomab tion. tiuxetan. The injected activity depends on body weight and platelet count. The thera- • Determination of blood proile, prothrom- peutic dose is 14.8 MBq/kg (11.1 MBq/kg in bin time (INR) and serum creatinine and patients with a platelet count of 100,000 to bilirubin levels within 1 week prior to RIT: 149,000/mm3) to a maximum total activity of RIT should not be performed if these val- 1,184 MBq [5]. ues are above 2.5 times the upper normal limits for the local laboratory. Pre-therapeutic evaluation Evaluation prior to RIT should be carried out • Estimation of life expectancy (life expec- as proposed in the EANM guideline (6) and tancy >3 months, Karnofsky index >70%): should include: Patients with a life expectancy of less than 3-4 weeks or rapid disease progression are • A clinical examination. unlikely to beneit from RIT.

• Careful recording of the patient’s history, including information on previous thera- pies, in particular external beam radiation therapy involving active bone marrow and stem cell transplantation.

108 Section II 5. Radioimmunotherapy in Lymphomas

Post-therapeutic assessment represents a strong treatment choice in this Safety group. Immunogenicity with human anti- Haematological toxicity is the major side-ef- mouse and human anti-chimeric antibody fect of RIT, and depends on bone marrow in- production has been observed, ranging from volvement and prior treatment [6, 7]. After a 1% to 63% between studies. dose of 14.8 MBq/kg of Zevalin®, a reduction of 30-70% in leucocyte and platelet counts Secondary myelodysplastic syndrome or from baseline levels is possible, sometimes acute myelogenous leukaemia has been re- occurring very rapidly. Grade 4 neutropenia, ported in 1-3% of cases [7]. The risk appears thrombocytopenia and anaemia have been to be increased in patients previously treated reported in 30%, 10% and 3% of patients, with several lines of chemotherapy or radio- respectively, with the nadir in counts occur- therapy. A cytological and genetic analysis of ring 7-9 weeks after Zevalin® injection, i.e. bone marrow could be proposed for heavily EANM later than after chemotherapy. Median time pre-treated patients prior to beginning RIT. to complete recovery of blood count (hae- In the long-term analysis of the International moglobin >12 g/dL, platelets >150,000/μL Radioimmunotherapy Network, the rate of and leucocytes >4,300/μL) is 99 days for FL secondary solid tumours was 0.8%, including patients [8]. After RIT, weekly blood tests from breast cancer, prostate cancer, glioblastoma the second post-RIT week are recommend- and non-small-cell [8]. ed, until baseline levels have been reached [9]. If levels drop faster than expected, short- Eicacy er-term controls should be instituted. If the In a study of 143 patients with relapsed or re- platelet count falls below 30 x 109/L, levels fractory FL or transformed B-cell NHL, Zeva- should be checked at least three times per lin® appeared more eicient than rituximab, week. Platelet transfusions and growth fac- yielding signiicantly higher overall response tors should be administered if indicated. The (OR) and complete response (CR) rates (80% patient should also be informed of the in- vs 56%, p=0.002, and 30% vs 16%, p=0.04, creased risk of infection and bleeding. respectively) [10]. Patients refractory to ritux- imab had a 74% OR and those with throm- Non-haematological toxicity is generally low, bocytopenia had an OR of 83% [11]. Mean including asthenia, anorexia, fever, nausea, time to progression (TTP) in responders was headache, chills, arthralgia and myalgia. Al- 12.6 months. OR was observed in 50% of lergic reactions have been observed dur- patients with bulky lymphoma. Chemother- ing MAb infusion, in particular after the irst apy, administered in patients treated with rituximab injection prior to Zevalin admin- RIT, was not associated with higher toxicity istration. It is important to highlight that [12]. In a meta-analysis involving relapsed RIT is well tolerated by older patients and NHL patients treated with Zevalin® in four

109 clinical trials, long-term responses (TTP >12 After RIT, response should be assessed 3 months) were seen in 37% of patients [13]. months after Zevalin® injection using the At a median follow-up time of 53.5 months, international guidelines on lymphoma re- the median TTP was 29.3 months. A third of sponse criteria. The quality of response may these patients had been treated with at least still be improved beyond 3 months after RIT. three previous therapies, and 37% of them had not responded to their last therapy. The Conclusion estimated 5-year overall survival was 53% for The anti-CD20 radiolabelled antibody 90Y- all patients treated with Zevalin and 81% for ibritumomab tiuxetan (Zevalin®) is approved long-term responders. in Europe for the treatment of patients with relapsed or refractory FL or as consolidation The FIT (First-Line Indolent Trial) randomised after induction chemotherapy in the front- phase III trial showed the beneits of Zeva- line treatment in FL patients. In relapsing lin® as consolidation in previously untreated refractory FL and transformed NHL, RIT as FL patients [14]. After completing induction monotherapy induces a CR rate of around therapy, patients were randomised to receive 30%, with a possibility of durable remissions. either a standard dose of Zevalin® (n=208) or RIT consolidation after induction therapy no further treatment (n=206). Induction ther- signiicantly improves the quality of the re- apies included CVP/COP (n=106), CHOP and sponse. Dose-limiting toxicity of RIT is hae- CHOP-like (n=183), ludarabine combina- matological, depending on bone marrow tions (n=22), chlorambucil (n=39) and ritux- involvement and prior treatment. Non-hae- imab–chemotherapy combinations (n=59). matological toxicity is generally low. A high conversion rate from partial response (PR) to CR of 77% was observed after RIT, leading to a high CR rate of 87% after RIT. The improvement in response was associated with an increase in progression-free survival of more than 2 years in the RIT consolidation as compared to the control arm.

110 7. Czuczman MS, Emmanouilides C, Darif M, CzuczmanMS,EmmanouilidesC,Darif Witzig TE, 7. Witzig TE, White CA,Gordon LI, Wiseman GA,Emma- 6. Witzig TE, White CA, Wiseman GA,Gordon LI,Emma- 5. progress RM. Recent Goldenberg DM,Sharkey in cancer 1. References References II,Chapter 5 Section 8. Hohloch K, BischofDelaloye A, HohlochK, Windemuth-Kieselbach 8. Delacroix D, Guerre JP, Leblanc P, C.Radionu- 4. Hickman Coiier B, F, Reyes Groupe d’étude deslymphomesde 3. NL,Jafe ES,DieboldJ, Harris Flandrin G,Muller-Herme- 2. patients treated tiuxetan withibritumomab radioim- plastic syndrome andacute myelogenous in Gordon S, et LI, Revell al. Treatment-related myelodys- lymphoma. JClinOncol2003;21:1263-70. low-grade, follicular, ortransformed non-Hodgkin’s tumomab tiuxetan radioimmunotherapy for relapsed JL,etal.nouilides C,Murray ibri- Safety ofyttrium-90 J ClinOncol1997;17:3793-803. CD20 or refractory Y2B8 radioimmunotherapy for treatment of relapsed A,etal. Phase ofIDEC- nouilides C,Raubitschek I/IItrial àl’EnergieCommissariat Atomique, 2002. 2nd edn. clides andradioprotection datahandbook, 15. lymphoma : aFrench perspective. Oncology2005;19:7- l’adulte, treatment Best ofaggressive non-Hodgkin’s 1999;17:3835-49. ing, House, Airlie Virginia, November 1997.JClinOncol committee meet- oftheclinicaladvisory sues: Report classiication ofthehematopoietic andlymphoidtis- link HK, Vardiman J, etal. World HealthOrganization 2011;2:675-9. Deliv therapy with radiolabeledmonoclonalantibodies. Ther Nucl Med 2011;52:1354-60. Nucl Med Network. Radioimmunotherapy by theInternational analysis registry ma patientswithacceptabletoxicity: to lympho- immunotherapy confers survival long-term J, C, Gómez-Codina Linkesch W, Jurczak W, et al. Radio- munotherapy. JClinOncol2007;25:4285–92. + B-cell non-Hodgkin’s B-cell lymphoma. J 111 12. KM,Habermann Ansell SM,Ristow TM, Wiseman GA, Witzig TE, Flinn IW, 11. Gordon LI,EmmanouilidesC,Czucz- Tennvall J, Fischer M,BischofDelaloye A,Bombardieri E, 9. 14. 14. F,Morschhauser Radford J, Van HoofA, Vitolo U, Soubey- 13. 13. Witzig A,Gordon LI,EmmanouilidesC,Schil- TE, Molina 10. Witzig TE, Gordon LI,Cabanillas F, CzuczmanMS,Em- with recurring or refractory B-cell non-Hodgkin lym- non-Hodgkin B-cell orrefractory with recurring Clin Oncol2002;20:3885-90. tiuxetanibritumomab for non-Hodgkin’s lymphoma,J tolerated radioimmunotherapy after withyttrium-90 Witzig TE. Subsequentchemotherapy regimens are well Clin Oncol2002;20:3262-9. follicular non-Hodgkin’simab-refractory lymphoma.J tiuxetan radioimmunotherapy inpatientswithritux- man MS,SalehMN,etal. Treatment withibritumomab Oncol 2002;20:2453-63. non-Hodgkin’sor transformed B-cell lymphoma. J Clin low-grade, follicular,patients withrelapsed orrefractory immunotherapy versus immunotherapy for rituximab tiuxetan ibritumomab radio- ofyttrium-90-labeled trial manouilides C,Joyce R,etal. controlled Randomized 2007;34:616-22. Imaging Mol Med tiuxetanradiolabelled ibritumomab (Zevalin). Eur J Nucl for lymphomawith90Y- for radio-immunotherapy B-cell F, L, Giammarile Bodei et al. EANMprocedure guideline follicular lymphoma.JClinOncol2008;26:5156-64. no additionaltherapy irstremission after inadvanced tiuxetan comparedwith yttrium-90-ibritumomab with ran P, Tilly H,etal. Phase ofconsolidationtherapy IIItrial Cancer 2007;109:1804-10. phoma treated tiuxetan. 90ibritumomab withyttrium der RJ, Flinn IW, etal. Long-term responses inpatients

EANM Section II 6. Radionuclide Therapy of Refractory Metastatic Bone Pain Brian A. Lowry, Ruth B. Menghis, Christopher Mayes and Sobhan Vinjamuri

Introduction Radiopharmaceuticals In recent years there has been improvement Bone metastases may involve mainly osteo- in treatment strategies in many types of can- blastic cells, leading to a sclerotic type lesion, cer and survival rates have improved. Many or mainly osteoclasts, which will result in lytic of the more common cancers metastasise to lesions. Often there is a mixture of the two. bone and a signiicant number of patients There are virtually no bone metastatic lesions may therefore experience pain from such that do not have at least an element of os- lesions. Patients are often fearful of meta- teoblastic activity, meaning that substances static bone pain, and report it as their worst involved in bone re-mineralisation, such as symptom. If it is not well controlled, it can be calcium and phosphate, will be preferentially the factor which most reduces their quality taken up there [2]. The exact mechanism of life. The majority of patients respond well of action of the radionuclides used for this to conventional analgesia using the widely type of therapy is not fully understood, but accepted World Health Organisation (WHO) it is thought to be related to the reduction of pain ladder approach, and there is a role for inlammatory processes at the interface be- bisphosphonates in many types of cancer [1]. tween neoplastic and normal bone, resulting However, some patients have pain which is in reduced mechanical pressure efects on not controlled well by conventional analge- the periosteum [3]. sia, and may have an unacceptable level of side-efects from it. The ideal radiopharmaceutical for bone me- tastases – often termed “bone seeking” – is In some cancers, disease-modifying treat- one which is preferentially taken up by the ments may also help with bone pain, and sites of metastatic bone damage and re- the efects of chemotherapy may provide tained there for a prolonged period. Beta par- pain relief in some cases. In more diicult ticle emission is preferable, but recently al- cases, external beam radiotherapy (EBRT) pha emitters have been used and are likely to can be highly efective, especially in local- be used more widely in the future. The pres- ised disease. When patients have metasta- ence of gamma emissions may be helpful in ses that are more widespread, EBRT can be enabling imaging of the distribution of the used to treat a wide ield, but toxicity may radiopharmaceutical in the body, but may begin to outweigh the beneicial efects [1]. present radiation protection problems. They As it is a systemic treatment, treatment with should deposit energy over a path length radionuclide therapy is likely to be most use- similar to that of the tumour deposit size and ful in patients with multi-site disease. Due to decay to a stable daughter product [2]. The the fact that the treatment is targeted to range of the particle in tissue may inluence tumour, the potential toxicity is relatively its suitability for a particular situation – more reduced [1]. bulky tumours may be better treated with a

112 Section II 6. Radionuclide Therapy of Refractory Metastatic Bone Pain

radionuclide with a longer range. The physi- half-life of the radiopharmaceutical [1]. The cal half-life of the radionuclide should be physical properties of the commonly used approximately the same as the biological radionuclides are shown in Table 1.

Mean Gamma Maximum Maximum Half-life energy emission energy range (MeV) (keV)

Strontium-89 50.5 d 1.4 0.583 β 7 mm None

Rhenium-186 3.7 d 1.07 0.362 β 5 mm 137

Rhenium-188 16.9 h 2.1 0.764 β 10 mm 155 EANM

Samarium-153 1.9 d 0.81 0.229 β 4 mm 103

Radium-223 11.4 d 5.78 α <10 µm 154

Table 1: Properties of radionuclides used in bone pain palliation [2].

There are three main ways in which a radio- (99mTc-MDP) is used in bone imaging). The pharmaceutical may be taken up in a bone rhenium isotopes rhenium-186 and rhe- metastasis [2]. The irst is to use the normal nium-188 can be combined into a complex physiology of bone remineralisation, where molecule called 1-1-hydroxyethylidene di- a substance with chemical properties similar phosphonate (HEDP), which, in contrast to to calcium will be taken up by the osteoblasts most bone-seeking radiopharmaceuticals, is and incorporated into the bone structure. thought to be taken up by the osteoclasts. Examples of these are strontium-89 and ra- The third way is to use a tumour-speciic dium-223. A second way is to incorporate the radiopharmaceutical, such as iodine-131, radionuclide into a molecule which will be which is taken up by functioning thyroid tis- taken up at sites of increased bone turnover. sue and therefore by metastases from thyroid Samarium-153 is used as part of an ethylene cancer; this is considered in Chapter 4. diamine tetramethylene phosphonic acid (EDTMP) complex which is taken up by the Strontium-89 osteoblasts and incorporated into hydroxy- Strontium-89 (89Sr) is a beta-emitter with apatite (similar to the way that - a long half-life. The beta particles have 99m labelled methylene diphosphonate a relatively long range. It is used in the

113 radiopharmaceutical form 89Sr chloride. The Samarium-153 maximum range of the beta particles in tis- Samarium-153 (153Sm) emits lower energy sue is relatively long, at 7 mm. It is handled by beta particles with a range of only 4 mm. A the body in a manner similar to calcium and high proportion of the radiopharmaceutical is therefore taken up by bone which is more is quickly taken up by bone – preferentially metabolically active. It is renally excreted and at sites with increased osteoblastic activ- the glomerular iltration rate of the patient ity. The gamma emissions have potential for should be considered. It has mainly been used imaging. There is typically a quick pain relief to treat metastatic bone pain from hormone- response in most patients – within about resistant prostate cancer and has been found one week – with the duration being in the to give pain relief in 60-70% of patients. The order of 8 weeks. Myelosuppression may oc- onset of pain relief is typically around 10-14 cur, with a nadir in blood counts at around days and the duration of pain relief may be 6 weeks [1]. prolonged, at up to 15 months. Its toxicity is usually in the form of myelosuppression, which Radium-223 typically occurs in the irst 6 weeks post treat- Radium-223 (223Ra) has been the subject of ment and reverses over the next 6 weeks [2]. considerable interest recently. It is an emitter and the energy will therefore Rhenium-186 be deposited over a short range: less than a Rhenium-186 (186Re) is a beta emitter with tenth of a millimetre. It is a calcium mimetic a half-life of 3.7 days and also has gamma and will therefore be taken up by the osteo- emissions which permit imaging. The range blasts and incorporated into hydroxyapatite of the beta particles is 5 mm. It has been used at sites of increased bone turnover [4]. A rela- in prostate cancer and breast cancer and tively low number of “hits” to a cell by alpha most patients report pain relief within about particles will result in cell death, so there is 2 days of administration. It causes temporary potential for an alpha-emitting radiopharma- myelosuppression with a nadir in counts at ceutical to eiciently kill tumour cells with- around 4 weeks and recovery in 8 weeks [1]. out having a signiicant impact on the bone marrow. Rhenium-188 Rhenium-188 (188Re) is also a beta emitter. Clinical applications It has a shorter half-life of 16.9 h and may The most established indication for radionu- produce more rapid pain relief than other ra- clide therapy for bone pain is in prostate can- diopharmaceuticals. Its beta particles have a cer, and 89Sr has been found to be efective relatively long range, 10 mm, which may be in achieving pain relief in 65-75% of patients. useful for some clinical applications. It also A sub-group of patients may even report causes myelosuppression [1]. complete pain relief [5,6]. 89Sr has also been

114 Section II 6. Radionuclide Therapy of Refractory Metastatic Bone Pain

used both instead of EBRT and as an adjuvant and recovery occurs at around 8 weeks post to it, showing pain relief in most cases [2]. treatment [2]. Patients with signiicant bone 153Sm has also been used with good efect in marrow involvement will be at higher risk of metastatic prostate cancer [2]. 223Ra, with the haematological toxicity and this should be trade name Alpharadin®, has been used with considered before treatment. Toxicity may very promising results in hormone-resistant be increased in patients with subclinical dis- prostate cancer and, at the time of writing, a seminated intravascular coagulation (DIC), trial called Alpharadin in Symptomatic Pros- which is often present in advanced stage tate Cancer (ALYSMPCA) is soon going to cancer patients, particularly those with pros- be formally published. The initial data show tate cancer [1]. signiicant reductions in the pain reported by patients and their use of opioid analgesia. A signiicant number of patients may expe-

A signiicant survival beneit has also been rience a short-term increase in pain, a phe- EANM found [7]. The radiopharmaceutical is now nomenon known as “pain lare”. This is more going through licensing procedures and is common with rhenium treatments. There do likely to be brought into widespread clinical not appear to be any clinical features that use over the next few years. identify patients likely to experience pain lare [2]. In breast cancer, 89Sr, 186Re and 188Re have all been used and found to be efective in Contra-indications and situations requiring achieving pain relief in most patients [6]. caution Signiicant reduction in pain was found in As with many medical radiation exposures, a small study using 186Re-(Sn)-HEDP. A trial pregnancy is an absolute contra-indication which included breast cancer patients found and should be excluded according to local that 153Sm-EDTMP yielded a signiicant re- protocol. duction in pain and opioid use [8]. Patients with bone metastases are at risk of Toxicity and limitations developing spinal cord compression, where a The most important consideration for patient metastatic deposit in the spine enlarges suf- safety with bone-seeking radionuclide thera- iciently to exert mechanical pressure on the py is the efect on the bone marrow. Almost nervous tissue. Treatment with bone-seeking all patients will have some myelosuppression radiopharmaceuticals can potentially worsen [1], which in most cases will be relatively mild this and it is therefore a contra-indication. and transient. The timing of myelosuppres- Any health professionals dealing with such sive efects varies with the radiopharmaceu- patients should be alert to the symptoms tical used, as mentioned above, but typically of this condition, which include worsen- the nadir in blood counts is around 4 weeks ing back pain (particularly pain outside the

115 lumbar region), limb weakness, sensory loss earlier stages of the development of bone in a dermatomal distribution and bowel and/ metastases, with relatively limited and lo- or bladder dysfunction. A patient with symp- calised disease, may gain more beneit from toms or signs suspicious of spinal cord com- radionuclide treatment [3]. Bearing in mind pression will require urgent medical review. the time frames for onset of pain relief and its duration, consideration should be given As the radiopharmaceuticals are predomi- to which radionuclide is most suitable. A ra- nantly renally cleared it is important to con- dionuclide with a shorter half-life may give a sider the patient’s renal function. A patient quicker response, but with a shorter duration with poor renal function will receive a higher in a patient with relatively rapidly progress- efective dose due to more radiopharma- ing disease. A radionuclide with a longer half- ceutical remaining present in the body for life may be appropriate to achieve a longer longer. Acute kidney injury will be a contra- duration of efect in other patients. Patients indication to bone-seeking radionuclide with a short life expectancy may not be suit- therapy and the patient will require stabilisa- able for therapy with some of the longer- tion before it can be considered. The pres- lived radionuclides, particularly 89Sr. ence of vesico-ureteric low obstruction and/ or bladder outlow obstruction, of particular A suitably qualiied medical practitioner concern in prostate cancer, may cause an in- should obtain suicient medical history and creased dose to those organs and surround- perform an appropriate examination prior ing structures; this may need assessment and to therapy. Enquiries should be made about possibly intervention before treatment [1]. symptoms suggestive of conditions which Urinary incontinence, again a common sce- would contra-indicate radionuclide therapy. nario in prostate cancer, may cause problems Medication history should be looked at to with radioactive contamination. see whether there are any medicines which may afect radiopharmaceutical uptake or Pre-therapeutic evaluation cause interactions. It should be borne in The indication for treatment with bone- mind that many patients will take “over the seeking radionuclides is therefore metastatic counter” medicines which do not require bone pain that is not controlled with con- prescriptions. Many may also be taking ventional analgesia and is limiting activities “complementary therapies” such as herbal of daily living. The patient group presenting substances and food supplements. for nuclear medicine therapy is likely to in- clude those in whom other treatments, such as bisphosphonates, hormonal treatment and EBRT, have failed. It should be noted that evidence shows that patients in somewhat

116 Section II 6. Radionuclide Therapy of Refractory Metastatic Bone Pain

Test Reason for test Results raising concern

Full blood count (FBC) To assess risk of Pancytopenia myelosuppression Neutropenia Anaemia Thrombocytopenia

Urea and electrolytes Renal function Dehydration (U&E) glomerular iltration rate Reduced glomerular iltration rate (GFR) Acute kidney injury

Biochemical proile Calcium status Hyper- or hypocalcaemia

Coagulation screen Risk of DIC Signs of DIC EANM Table 2: Pre-therapeutic blood tests [1].

Bearing in mind the myelosuppressive side- bone scan with 99mTc-MDP should be per- efects which are likely, and the importance formed prior to therapy and a history of the of renal function, it is necessary to obtain the sites of pain taken. An example of a bone results of suitable blood tests before radio- scan with metastases is shown in Fig. 1; if the nuclide therapy, as summarised in Table 2. patient concerned describes pain in the back Patients with pre-existing problems in their and ribs, the therapy will have a good chance haematological status will be at increased of success. These pain sites can then be risk of more serious adverse events after “mapped” to areas of increased uptake on the therapy. Results outside the normal ranges bone scan. Treatment success is likely when may mean the treatment is contra-indicated. areas giving pain are well matched to regions A centre performing radionuclide therapy of increased osteoblastic activity. When a pa- should draw up a protocol based on exist- tient indicates pain from a site which does ing guidelines and evidence and patients not show increased uptake on a bone scan, will need medical assessment of their results it should be considered that the pain may be before treatment. due to a cause other than metastatic disease. Possibilities include osteoporotic collapse, Consideration of the mode of action of radio- degenerative arthropathy such as osteoar- nuclide therapy tells us that it will be success- thritis and pain from internal organs, e.g. due ful where pain is being caused by metastatic to obstruction in the urinary system [1]. It is deposits with osteoblastic activity – although important for imaging of all modalities to be it can also help where there is predominantly reviewed before therapy. osteoclastic activity. A standard radionuclide

117 of the therapy should be emphasised as many patients have unrealistic expectations of cancer treatment. Radiation protection regulations and requirements and arrange- ments, as discussed in Chapter 3, will need to be gone through in detail. Individual in- formation should be given regarding the po- tential time required for pain reduction to be noticed and the possible duration of pain re- duction, according to the radionuclide used [3]. The possibility of a pain lare should be mentioned. Informed consent should be ob- tained and the authors would recommend a speciic consent form to be signed by the patient.

Therapy should be carried out in a depart- ment with suitable facilities which meet the local regulations as discussed in Chapter 3. The therapy should be supervised by a physi- cian who has suicient knowledge and expe- rience and administered by a suitably quali-

From archives of the Nuclear Medicine Department, Royal Liverpool and Broadgreen University Hospitals NHS Trust of the Nuclear Medicine Department, University Hospitals NHS archives Liverpool Royal and Broadgreen From ied practitioner. support is invaluable. Radiopharmaceuticals should Figure 1: 99mTc-MDP bone scan showing bone be administered according to the manufac- metastases due to prostate cancer. turer’s instructions. An intravenous cannula Therapeutic procedure or butterly should be used and great care The therapy should be explained to the pa- should be taken to avoid extravasation [3]. tient, and provision of written information is highly recommended. There may be mis- Post-therapeutic assessment conceptions in the patient population about Considering the possibilities of toxicity post the use of radionuclides, and considerable therapy, clear arrangements are required for explanation may be required regarding the patient follow-up and it must be agreed in mode of action of the therapy and its pos- advance who will be taking responsibility sible beneits and risks. The palliative nature for this. Information regarding the therapy

118 Section II 6. Radionuclide Therapy of Refractory Metastatic Bone Pain

and follow-up plans should be conveyed In patients who respond to therapy, par- immediately after its administration to the ticularly with shorter-acting radionuclides, patient’s supervising physician, e.g. an on- re-treatment may be suitable. The period be- cologist or urologist, and to the general prac- tween therapy should be consistent with the titioner. radionuclide, e.g. around 8 weeks for 153Sm and 12 weeks for 186Re [3]. It will be important to monitor the patient for haematological toxicity and this will again depend on the radionuclide used. Such monitoring will involve periodic blood tests – typically every 1-2 weeks – for up to 6 weeks in the case of 186Re and 153Sm, and up to 16 weeks for 89Sr [3]. The patient should be told EANM to be alert to potential symptoms suggesting more serious toxicity, such as lethargy and pyrexia. A pain lare may require temporarily increased analgesia.

119 References Section II, Chapter 6

References 1. Lewington VJ. Bone seeking radionuclides for therapy. 6. Liepe K, Kotzerke J. A comparative study of rhenium- J Nucl Med. 2005;46 Suppl 1:38S-47S. 188-HEDP, rhenium-186-HEDP, samarium-153-EDTMP and strontium-89 in the treatment of painful skeletal 2. Hoskin P. Radioisotope therapy for metastatic bone dis- metastases. Nucl Med Commun 2007;28:623-30. ease. In: Hoskin P, ed. Radiotherapy in practice - radio- isotope therapy. Oxford: Oxford University Press, 2007. 7. Nilsson S, Sartor AO, Bruland ØS, Fang F, Aksnes A-K, Parker C. Pain analysis from the phase III randomized 3. Bodei L, Lam M, Chiesa C, Flux G, Brans B, Chiti A, Giam- ALSYMPCA study with radium-223 dichloride (Ra-223) in marile F; European Association of Nuclear Medicine patients with castration-resistant prostate cancer (CRPC) (EANM). EANM procedure guideline for the treatment with bone metastases. 2013 Genitourinary Cancers of refractory metastatic bone pain. Eur J Nucl Med Mol Symposium. J Clin Oncol. 13 Suppl 6. Imaging. 2008;35:1934-40. 8. Seraini AN, Houston SJ, Resche I, Quick DP, Grund FM, 4. Brady D, Parker C C, O’Sullivan JM. Bone targeting ra- Ell PJ, et al. Palliation of pain associated with meta- diopharmaceuticals including radium-223. Cancer J. static bone cancer using samarium-153 lexidronam: 2013;19:71-8. A double blind placebo controlled trial. J Clin Oncol 5. Lewington VJ, McEwan AJ, Ackery DM, Bayly RJ, Keel- 1998;16:1574-81. ing DH, Macleod PM, et al. A prospective, randomised double blind crossover study to examine the eicacy of strontium-89 in pain palliation in patients with ad- vanced prostate cancer metastatic to bone. Eur J Cancer. 1991;27:954-8.

120 7. Radiosynovectomy II Section taken into thistherapy. accountaswetaken practise thatneedto be challenges andopportunities the ieldofnuclearmedicineprovide new the advancesinmedicaltechnology outside technique itself has not changed massively, long time ago in medicine, and although the published in2003[2].However, even 2003isa ofEANMguidelines 1952 [1]andisthesubject follows. by Fellinger wasirstdescribed It in diseasethat the damageandchronic arthritic cesses inindividualjointsandsominimises protherapy to combatsynovial inlammatory therapeutic technique thatprovides targeted isan established, powerful synoviorthesis) radiosynovectomy Table thatare indications for 1:Arthropathies indicated are shown in Table 1. forArthropathies whichradiosynovectomy is forIndications radiosynovectomy Radiosynovectomy Introduction Mayes,Christopher A.Lowry, andSobhan Brian Menghis RuthBerhane Vinjamuri arthritis Calcium pyrophosphate dihydrate (CPPD) orefusion synovial thickening withsynovitis,Undiferentiated arthritis (e.g. Lyme disease, Behçet’s disease) jointdisease inlammatory Other Persistent efusionfollowing prosthesis Persistent synovial efusion arthritis psoriatic Spondyloarthropathy, e.g. reactive or Haemophilic arthritis arthritis Rheumatoid (also known asradio (alsoknown - - 121 in Western [3]. countries surgical and radiosynovectomy interventions years and this is reducing RA referrals for both management has improved in thelast 20 of referrals for radiosynovectomy, butdrug Traditionally RAhasbeenamajorsource is alsoacommondevelopment inthedisease. anddeformation. Baker’sjoint destruction cyst sible. Later stage disease involves progressive and swelling, andreduced movement ispos stages, theearly painincreases withstifness In lins, factor. suchasrheumatoid and mature B cells produce immunoglobu- suchastumournecrosislymphokines, factor, and plasma cells. phocyctes T cells produce Synovial liningcellsare colonised by lym- bone, the capsuleandligaments. subchondral (pannus) thaterodes cartilage, leads to hyperplastic synovial tissuegrowth growth andintensive vascularisation. This lining cellswithcolonisationby ibroblast ulation. RA increases the numbers of synovial lence ofapproximately 1%inthewholepop- more women than menandhasapreva- afects diseases.common auto-immune It (RA)isoneof themost arthritis Rheumatoid arthritis Rheumatoid thejoint. bricates um secretes thethicksynovial luidthatlu- the jointcapsule, thesynovium. The synovi- up tive tissueliningtheligamentsthatmake Synovitis istheinlammationofconnec- Synovitis Overview ofsynovitis andarthritis Overview - EANM Drug therapies for RA. New drug regimens especially skin cancers [4-6], so targeted ther- have improved the management of the apies may continue to have an important disease in recent years. Non-steroidal anti- role for some patients. inlammatory drugs are used to relieve pain and stifness in early disease by inhibiting Reactive arthritis cyclo-oxygenase (COX) but do not inluence Reactive arthritis is another autoimmune dis- the radiographic progression of the disease. ease that is triggered by an infection in an- other part of the body, e.g. by food poisoning Systemic corticosteroids improve symptoms or chlamydial infection. and do reduce damage. Intra-articular corti- costeroid injections are widely used and can Psoriatic arthritis produce rapid and sometimes sustained re- Psoriatic arthritis, which causes destruction lief in target joints. of joints, can be as severe as RA but will at- tack fewer joints and thus is suitable for tar- Disease-modifying anti-rheumatic drugs geted radiosynovectomy. (DMARDS) are a group of systemic drugs that require sustained use, but do slow the progres- Osteoarthritis sion of RA. Methotrexate and sulfasalazine are Erosion of the normal covering of the carti- of this type and they can be used efectively lage allows the breaking of of tissue, irrita- in combination therapies with other DMARDs tion of the synovium and osteophyte forma- and biological response modiiers (BRMs). tion. Synovitis can be treated with radiosyno- BRMs include tumour necrosis factor (TNF) vectomy but the underlying cartilage disease blockers and monoclonal antibodies which act cannot. Radiosynovectomy has been shown on the immune system, e.g. rituximab. to be useful in osteoarthritis, especially in younger patients with early disease, whose This improved management of RA means joints show little radiographic damage [7]. the injury to many patients’ joints has been successfully reduced or at least postponed. Haemophilic arthritis There are new products and combinations Haemophilia is an X chromosome-linked dis- that are fortunately reducing the need for order caused by a deiciency of factor VIII or patient referral for radiosynovectomy. This factor IX due to mutation of the respective reduction in demand does not mean that ra- clotting factor genes. This is a rare disease with diosynovectomy has been replaced, howev- an estimated frequency of 1 in 10,000 births. er. Furthermore, the new drug regimens are It generally afects males on the maternal side systemic and have signiicant side-efects. and, although this can usually be traced down There are concerns about anti-TNF therapy family lines, as many as one-third of all cases regarding a possible dose-dependent in- are the result of spontaneous mutation where crease in serious infection and malignancies, there is no prior family history.

122 Section II 7. Radiosynovectomy

In haemophilia, between 70% and 80% of that bleeding episodes are signiicantly re- bleeding occurs internally into joints, especial- duced following radiosynovectomy. In a ly the hinged joints: ankles, knees and elbows. 2012 review [9], 75% of patients were said to Best medical practice in caring for patients is beneit from a reduction in articular bleeding. detailed in the World Federation of Hemophil- Furthermore, reduction in bleeding is not the ia (WFH) Guidelines for the Management of only beneit, with pain, range of motion, clin- Hemophilia [8], published in 2013, which rec- ical synovitis and the size of the synovium all ommend prophylactic clotting factor replace- showing great improvement [10]. ment: “Prophylaxis prevents bleeding and joint destruction and it should be the goal of Contra-indications to radiosynovectomy therapy to preserve normal musculoskeletal Pregnancy, breast-feeding, ruptured Baker’s function.” The importance of the musculoskel- cyst of the knee, local skin infection and etal system is highlighted in the guidance. Tar- massive haemarthrosis are absolute contra- EANM get joints are deined as joints in which three indications to radiosynovectomy. Relative or more spontaneous bleeds have occurred contra-indications include age less than within a 6-month period and “with repeated 20 years, evidence of signiicant cartilage loss bleeding, the synovium becomes chronically and extensive joint instability. inlamed and hypertrophied”. Synovectomy is the recommended action to deactivate the Radiopharmaceuticals for synovium as quickly as possible and preserve radiosynovectomy joint function. Non-surgical radiosynovecto- EANM guidelines [2] propose three radionu- my is the treatment of choice. clides that are available in Europe for use in radiosynovectomy; their physical properties These guidelines support radiosynovectomy are summarised in Table 2. because research has consistently shown

Yttrium-90 (90Y) Rhenium-186 (186Re) Erbium-169 (169Er)

Use Large Medium Small

Half-life (days) 2.7 3.7 9.4

Max. beta energy (MeV) 2.27 1.07 0.34 Max. beta particle 11 3.7 1.0 range (soft tissue) (mm) Mean beta particle 3.6 1.1 0.3 range (soft tissue) (mm) Gamma ray energy None 137 keV None

Table 2: Radionuclides available for radiosynovectomy

123 The radiopharmaceuticals used in radio- beta particles emitted create free radicals synovectomy are in the form of colloidal that cause apoptosis and thus ablation of the particulates that are small enough to be inlamed synovial membrane. phagocytised and trapped in the inlamed synovial membrane. The particles must be The colloids available are: 90Y as yttrium ci- large enough to resist escape from the joint trate, 186Re as rhenium sulphide and 169Er as by absorption into the be- erbium citrate. The activities and recom- fore they have been phagocytised. Particle mended volumes injected for each joint are sizes are thus in the range of 2-10 µm. The detailed in Table 3.

Joint Radiopharmaceutical Activity (MBq) Volume (ml)

Knee 90Y citrate 185-222 1

Hip 186Re sulphide 74-185 3

Shoulder 186Re sulphide 74-185 3

Elbow 186Re sulphide 74-111 1-2

Wrist 186Re sulphide 34-74 1-1.5

Ankle 186Re sulphide 74 1-1.5

Subtalar 186Re sulphide 37-74 1-1.5

Metacarpophalangeal 169Er citrate 20-40 1

Metatarsophalangeal 169Er citrate 30-40 1

Proximal interphalangeal 169Er citrate 10-20 0.5

Table 3: Joint activities and injection volumes.

124 Section II 7. Radiosynovectomy

The radiosynovectomy procedure referred for radiosynovectomy. Recent ra- National legislation requirements vary be- diographs of joints to be treated will be re- tween countries for administration of radio- viewed prior to the procedure. Other imag- active agents. In-patient treatment may be ing techniques may be useful: Scintigraphic required and although this may not be legal- assessment of soft tissue and active inlam- ly demanded, because immobilisation must mation is often carried out using 99mTc-MDP/ follow radiosynovectomy, procedures may HDP/HEDP. Ultrasound is useful to evaluate require that less able patients stay in hospital. synovial structure and thickness and exclude Appropriately shielded accommodation and ruptured Baker’s cyst. Magnetic resonance toilet facilities may therefore be necessary. imaging may also be useful.

Radiosynovectomy demands an aseptic in- Knees with Baker’s cysts can be treated by jection so appropriate clean areas and sterile skilled practitioners [11]. The cyst may be EANM protocols are needed during administration. reduced using external pressure or synovial puncture and aspiration of the main joint. Knees are the joints most often treated and The danger of rupture and escape of the ra- these are the only joints that can be injected diopharmaceutical must be assessed by the without imaging. Conirmation of the correct clinician. intra-articular placement of the needle is pos- sible by aspiration of synovial luid. For other Arthroscopy or surgery must not have been joints, imaging, e.g. by mobile image intensi- performed during the 2–6 weeks preceding ier or ultrasound, is necessary to ensure safe radiosynovectomy. positioning of the needle for injection. The minimum interval between repeat radio- Staing requirements synovectomy is 6 months. Radiosynovectomy requires a multi-disciplin- Consent ary team to be run eiciently. In addition to Informed written consent must be obtained the nuclear medicine medical, technological, prior to radiosynovectomy. Written and ver- nursing and physics staf, a rheumatologist or bal information must be given to the patient orthopaedic surgeon will probably supply the and this should include: expertise in synovial puncture. In the case of haemophilic patients, haematologists will have 1. Between 60% and 80% of patients beneit ensured prophylactic clotting factor cover. from the therapy.

Patient preparation 2. Response is unlikely within 14 days of Previous intra-articular glucocorticoid injec- injection and may not be noticeable for tion will have been unsuccessful in patients 1 month.

125 3. There is a risk of a temporary increase in Once the needle has been advanced into the synovitis. joint, aspiration of synovial luid will conirm the correct position of the needle. Radio- 4. Potential complications of treatment are: pharmaceutical must not be injected unless a) Due to joint puncture: local haemor- intra-articular placement has been ensured rhage, bruising, infection (very rare) and by aspiration. As already mentioned, joints future malignancy. other than the knee must have imaging con- b) Theoretical risk of exposure to beta- irmation of position, e.g. by mobile image emitting radiation, including radiation intensiier; this is particularly important as necrosis (rare) and future malignancy. the joint may be misshapen by the disease c) Risk of post-injection pyrexia or radio- process and small joints with little luid make pharmaceutical (very rare). the aspiration test impracticable.

Administration In a joint with efusion, aspiration of excess Radiosynovectomy is an aseptic technique. luid is useful so long as enough luid is left It must therefore be performed under full to distribute the radiopharmaceutical in the aseptic conditions by suitably qualiied med- joint space. If no efusion is present, 10 ml ical, nursing and technical staf. Skin prepa- or more of saline may be useful to achieve ration may have included the removal of ex- good dispersion. The radiopharmaceutical cess hair. After clinical examination a sterile is then injected and it is recommended that ield is created around the joint to be treated this be followed by use of long-acting gluco- using towels. corticoids to reduce any acute synovitis and improve treatment response. There follows a brief description of the pro- cedure using the example of the knee as the The needle is inally lushed with saline, be- target joint: The exposed skin of the injection fore and during withdrawal, to reduce the site is disinfected. Local anaesthesia is advis- chance of leakage of radioactivity down the able before the joint puncture. Intra-articular needle track. puncture of the knee may be achieved using a 20-gauge 7.6-cm needle on a slightly lexed Once the needle has been removed, a skin knee proximal and lateral to the superolateral is applied to the puncture site angle of the patella. Local anaesthetic can be and this is followed by joint immobilisa- injected irst subcutaneously through this tion (splinting) for 48 h. For a knee this may needle (this also ensures that skin-punch cyl- consist of a thigh-leg plaster/ resin cast. Im- inders are not carried into the joint). mobilisation reduces the transport of par- ticles through the lymphatics to the regional lymph nodes.

126 Section II 7. Radiosynovectomy

Many centres will carry out scintigraphy of Radioactive urinary excretion is greatest the treated joint to demonstrate that accu- during the irst 2 days after the procedure. rate intra-articular dispersion of the radio- Rigorous hygiene will avoid contamination. pharmaceutical has been achieved (Fig. 1). Incontinent patients should be catheterised For 90Y bremsstrahlung radiation is imaged; prior to radiopharmaceutical administration the gamma rays from 186 Re can be imaged and the catheter should remain in place for directly. 3-4 days and the collection bag emptied frequently. The risk and beneits of the pro- cedure must be assessed in these diicult cases.

Women should avoid pregnancy for

4 months after treatment. EANM

Image courtesy of Department of Liverpool Royal Nuclear Medicine, University and Broadgreen UK. Trust. Hospitals NHS At 6-8 weeks after radiosynovectomy, pa- Figure 1: Post-radiosynovectomy imaging tients should be reviewed for treatment following successful administration of response, assessment of synovial inlam- 90Y into the knee joint, demonstrating mation and possible radionecrosis. Assess- an even distribution and no leakage of ment should be repeated at 3-4 months and radiopharmaceutical [12]. 12 months.

Post-radiosynovectomy care Pain reduction typically occurs within Patients must understand the importance of 3 weeks of injection and the treatment has immobilisation. Radiation protection advice, probably failed if no response has been de- which may need to be in writing for legal rea- tected after 6 months. Patients who fail to sons, must be given to the patient to reduce respond to the irst injection may respond to unnecessary radiation exposure to family a second attempt after a delay of 6 months. If members and the public. If the patient is a two procedures fail to achieve any response, hospital in-patient, staf must be instructed further radiosynovectomy should not be at- in radiation safety. tempted.

127 References Section II, Chapter 7

References 1. Fellinger K, Schmid L. Die locale Behandlung der rheu- 7. Markou P, Chatzopoulos D. Yttrium-90 silicate radio- matischen Errkrankung (local therapy of RA). Wien Ztsch synovectomy treatment of painful synovitis in knee Inn Med. 1952;33:351. osteoarthritis. Results after 6 months. Hell J Nucl Med. 2009;12:33-6. 2. Clunie G, Fischer M; European Association of Nuclear Medicine. EANM procedure guidelines for radiosyno- 8. Srivasta A, Brewer AK, Mauser-Bunschoten EP, Key NS, vectomy. Eur J Nucl Med Mol Imaging. 2003;30:BP12-6. Kitchen S, Llinas A, et al. WFH guidelines for the manage- ment of hemophilia. Haemophilia. 2013;19:e1-47. 3. Momohara S, Tanaka S, Nakamura H, Mibe J, Iwamoto T, Ikari K, et al. Recent trends in orthopedic surgery per- 9. Peyvandi F, Klamroth R, Carcao M, Federici AB, Di Minno formed in Japan for rheumatoid arthritis. Mod Rheuma- G, Jimenez-Yiste V, Rodriguez Merchan EC. Management tol. 2011;21:337-42. of bleeding disorders in adults. Haemophilia. 2012;18 (Suppl 2):24-36. 4. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matte- son EL, Montori V. Anti-TNF antibody therapy in rheu- 10. De La Corte-Rodriguez H, Rodriguez-Merchan EC, matoid arthritis and the risk of serious and Jimenez-Yuste V. Radiosynovectomy in hemophilia: malignancies: systematic review and analysis of rare quantiication of its efectiveness through the assess- harmful efects in randomized controlled trials. JAMA. ment of 10 articular parameters. J Thromb Haemost. 2006;295:2275-85. 2011;9:928-35.

5. Ding T, Ledingham J, Luqmani R, Westlake S, Hyrich K, 11. Modder G. Radiosynoviorthesis: involvement of nuclear Lunt M, et al.; Standards, Audit and Guidelines Work- medicine in rheumatology and orthopaedics. Mecken- ing Group of BSR Clinical Afairs Committee and BHPR. heim: Warlich, 1995. ISBN 3-930376-04-0. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. Rheumatology (Oxford). 2010;49:2217-9.

6. Raaschou P, Simard J, Holmqvist M, Askling J. Rheuma- toid arthritis, anti-tumour necrosis factor therapy, and risk of malignant : nationwide population based cohort study from Sweden. BMJ. 2013;346:f1939.

128 to preserve the health of the population toin preserve development ofspeciicpolicies designed at recovering theindividual’s health,to the aimed range from individualinterventions a response to againstdisease, thereactions or acommunity. as Nursing interventions, or potential health problems ofindividuals the disease. They needto respond to thereal individual, familialorgroup against reactions atany age.and disability Nursesfocus on for of disease (physical all types or mental) tance, diseaseprevention andhealthcare assistance system, includeshealthassis- Nursing, ofthesocial asanintegrated part grounded are into consideration. taken inwhichtheirhealthandwell-beingtext are that all the needs of patients and the con- ofaholistic approachnecessity to ensure conceptsandmodelsemphasisethe Most recovering thestate ofhealth[2]. in maintaining and/or and the community role oftheindividual, theindividual’s family Central to nursingconceptual models is the ronment withthepatient[1]. whichinteracts state ofhealthandthedeinitionenvi- the deinition of the patient, the deinition of to thedeinitionofnursinganditspurpose, ing, the diferences them relating between There are many conceptualmodelsofnurs- orpotentialto healthproblems actual [1]. diagnosis andtreatment ofhumanreactions appropriately beconsidered the to comprise Nursing hasmany deinitions, Concepts andmodels ofnursing General aspects LupuAna Gorgan, Nicoleta andClaudiuPeștean for8. NursingImplications Patients Metabolic Undergoing Radionuclide Therapy II Section butmay most 129 sions: bio-physiological, psychological, listically, including the following dimen- The individualshouldbeconsidered ho- tal needs. that individualto satisfy his orherfundamen- level ofindependence, allows least acertain nance oftheindividual’s independence, orat tient needs. According to thismodel, mainte- ia Henderson is basedon14fundamental pa- ceptual nursing model established by Virgin- to dothis[4]. and theknowledge The con- individual shouldhave thestrength, thewill recovery, into considerationthatthe taking individual to indhisorherroute to healthor nursing,modern nursingmeanshelpingthe igure inlayingneeds andakey thebasisfor abouthealth care the irst scientiic theory According to Virginia Henderson,authorof oreven death. of disability andassistance in the event health recovery health maintenance, disease prevention, areactivities aimed in four main directions: personnel. Nursing by skilled with ability about healthcare, appliedindailypractice itrequires theoreticaland art: knowledge patient’s hand. Nursingisamixofscience or simple, such as the gesture of holding a tivities thatcanbecomplexandspecialised Nursing, as aprofession, involves ac- various system [3]. ofthehealth Nurses deinenursingaspart Council of Organisation andtheInternational national Council ofNurses. The World Health aspointedthe longterm, outby theInter-

EANM sociocultural and spiritual. Environment fac- • The identiication of the patient’s needs tors should also be taken into consideration improves communication between the because they may produce imbalances and members of the health care team. consequently adversely afect the indepen- dence of the individual. • The nursing process uses consistent and orderly records relating to all aspects of The state of disease represents a disruption nursing. These records allows quantiica- of the equilibrium between the organism tion of all health care activities and, in this and the environment, which is an alarm sig- way, evaluation of the quality of health nal expressed as physical and/or psychologi- care provided. cal distress, a diiculty or maladjustment to a new situation, temporary or permanent. This The nursing process imbalance represents a negative event or ex- The nursing process has ive phases: perience for the individual. The analysis. This entails the gathering of all necessary information to identify the ac- The conceptual nursing model, through its tual or potential health problems, and for perspective, ofers a systematised meth- this purpose, an objective and impartial odology to identify the health problems of attitude is required. The information ob- the patient and to elaborate a nursing plan tained can be subjective (when collected which will reduce the patient’s dependency. from the patient or his family) or objective It also ofers modalities for the implementa- (when it derives from measurable condi- tion of this plan and for the evaluation of its tions). eicacy upon completion. Nursing diagnostics (the analysis from a clinical point of view of the individual’s The conceptual nursing model ofers several response to actual or potential health advantages: problems). This consists in identifying the patient’s health problem and formulat- • It identiies the speciic problems of the ing and validating a nursing diagnosis. patient. In this way it is possible to estab- Formulation of a diagnosis consists in cor- lish general and speciic objectives that relating the health problem to its cause or will enable recovery from these problems. aetiology. One example concerns the im- To accomplish these objectives, speciic in- pact of restrictions on contact with other terventions are applied according to nurs- persons on positive relations with others; ing skills and knowledge. The patient and this is a potential nursing diagnosis for a his or her family are included in the health patient undergoing radioiodine therapy care team. for diferentiated thyroid carcinoma,

130 Section II 8. Nursing Implications for Patients Undergoing Radionuclide Metabolic Therapy

which for radiation protection reasons this purpose reference may be made to requires certain restrictions on contact the so-called Maslow hierarchy, a struc- with family or visitors. As multiple nursing tural model of need categories based on diagnoses may be identiied in the same priorities (Fig. 1). patient, their prioritisation is essential; for

SELF morality, creativity, spaonteity, ACTUALISATION recognition of facts EANM Conidence, respect of others, SELF ESTEEM respect from others, recognition Friendship, family, sexual LOVE AND BELONGING intimacy

SAFETY physical and mental safety

Breathing, homeostasis, food phYSIOLOGICAL NEEDS water, sex, sleep Buxbaum BS, Mauro E, Norris CG, eds. Illustrated manual of nursing eds. E, NorrisBuxbaum BS, Mauro CG, practice, 2nd edn. Springhouse: Springhouse Corporation; 1994.

Figure 1: Maslow’s hierarchy, adapted after Illustrated manual of nursing practice, 2nd edn. [1]

The nursing plan. The nursing plan consists Implementation of the nursing plan. This in the elaboration of all objectives to be consists in enactment of the sum of the accomplished and also all the nursing planned interventions. interventions necessary to achieve these objectives. For a nursing plan to be ob- Evaluation of the nursing plan. The results are jective, it has to be realistic: objectives analysed and compared with the estab- too diicult to accomplish should be lished objectives. Correction of the nurs- avoided since they can discourage pa- ing plan is done if necessary. tients. The nursing plan must be individu- ally adapted, as every patient is diferent, and should be designed without unclear terms.

131 The nursing applied to patients medications and evaluation of their efects, undergoing radionuclide metabolic preparing and using instruments for oxygen therapy therapy, preparing the patient (physically Radionuclide metabolic therapy is a speciic and psychologically) and the materials for and complex therapeutic alternative. The investigations (e.g. pleural puncture, bron- approach is multidisciplinary and nursing choscopy, tomography), helping in mobilisa- care plays a well-deined role in the process tion and transport and teaching the patient of healing. Besides carrying out the speciic how to cough. duties associated with health care, the nurse has the role of teaching the patient about dif- Inadequate circulation/alteration of ferent aspects relating to his or her sufering, cardiovascular function thereby assisting the patient in accepting Example: some cases of hyperthyroidism or and defeating the illness. neroendocrine tumours secreting adrena- line/noradrenaline. Potential nursing in- The pathologies in which radionuclide meta- terventions include monitoring of blood bolic therapy can be applied are diverse, but pressure and heart rate, consciousness most are oncological diseases. The disease, surveillance, prevention of complications, its symptomatology and also its therapy may maintenance of appropriate climate and en- afect the patient’s needs, from the vital ones vironmental conditions, teaching the patient to those with low priority. Nursing interven- to ensure appropriate hydration, administra- tions are extremely important in recovering tion of medications and evaluation of their or improving the patient’s state of health. efects, preparing the patient (physically and psychologically) and the materials for inves- In the following we will approach radionu- tigations (e.g. ECG, SPECT-CT, PET-CT), and clide metabolic therapy not from the per- helping in mobilisation and transport. spective of pathology, but from the perspec- tive of the altered patient’s needs and the Inadequate nutrition nursing care to be applied. Example: some gastrointestinal tumours or advanced stages of disease. Potential nursing Alteration of respiratory function interventions include help/support in feed- Example: patients with primary or secondary ing, assuring balanced nutrition, improve- lung tumours. Potential nursing interventions ment of nutritional status, maintenance of include monitoring of breathing, conscious- an appropriate nutritional status, hydro- ness surveillance, prevention of complica- electrolytic equilibrium, administration of tions, maintenance of an appropriate climate medications and evaluation of their efects, and environmental conditions, maintenance dietary assessment, and patient training in of an adequate position, administration of relation to diet, encompassing the purpose

132 Section II 8. Nursing Implications for Patients Undergoing Radionuclide Metabolic Therapy

of the diet, the type and quantity of food, Alteration of physical and psychological food to be avoided, how to replace forbid- comfort den nutriments and what substances to use Potential nursing interventions include pro- to improve taste [5]. viding psychological support for the patient and his/her family, maintaining a support- Inadequate intestinal evacuation ive attitude in all phases through which the Example: serotonin-induced diarrhoea in patient passes in relation to the illness (de- patients with secreting neuroendocrine nial, confusion, resignation and acceptance), tumours. Potential nursing interventions helping the patient to accept the illness include monitoring of vital and vegetative according to his/her beliefs and traditions, signs, evaluation of hydro-electrolytic equi- improving self-esteem, maintaining a safe librium, hydro-electrolytic equilibration via environment, and maintaining psychologi- intravenous infusion of solutions, assess- cal comfort. In addition, the patient must be EANM ment of signs of dehydration, maintenance informed about the radionuclide metabolic of hygiene, administration of medications therapeutic procedure and its potential side- and evaluation of their efects, prevention of efects [8]. complications, maintenance of an appropri- ate climate and environmental conditions, Alteration of health status related to anxiety prevention of infection, and helping in mo- Examples: the anxiety due to lack of knowl- bilisation and transport [6]. edge regarding disease prognosis or the treatment, and anxiety due to alteration of Alteration of body temperature; fever with or self-image. Potential nursing interventions without rigors include eicient communication with the Example: radionuclide metabolic therapy patient and his/her family and training relat- of lymphomas [7]. Potential nursing in- ing to the prescribed treatment, e.g. names terventions include monitoring of body of medicines, doses, schedule of administra- temperature, prevention of complications, tion and path of administration. The patient maintenance of an appropriate position, should be encouraged to communicate feel- maintenance of an appropriate climate and ings and thoughts, which will assist in accep- environmental conditions, maintenance of tance of the disease [9]. hygiene, and preparation of the patient for investigations or speciic procedures.

133 Alteration of the need for movement Potential nursing interventions include help- Example: due to increasing bone pain in the ing patients to stimulate and exploit their irst days after bone pain palliation therapy or personal psychological resources, teaching due to the restrictions on movement after ra- patients how to gain conidence, teaching diosynovectomy). Potential nursing interven- patients to express their feelings and con- tions include maintenance of an appropriate cerns about their condition, helping patients climate and environmental conditions, help- to accept their situation and educating pa- ing the patient to adopt an adequate posi- tients to respect the restrictions. tion, and helping in mobilisation [10]. These are the patient’s needs that are most Alteration of self-image/self-esteem frequently altered in the pathologies in Example: due to degradation of life, the main which radionuclide therapy may be applied. causes being the symptoms speciic to each Almost all nursing care needs arise due to disease, especially in advanced stages. Po- the pathology itself, but some also appear tential nursing interventions include teach- as a consequence of therapy, as collateral ef- ing the patient to accept his or her condition, fects. The nurse has an extremely important helping the patient to improve self-percep- role in the multidisciplinary team, being di- tion and helping the patient to accept the rectly responsible for identifying the nursing conditions associated with being ill. care required, establishing the nursing plan and applying the plan in accordance with Alteration of the need for communication established nursing principles, thereby con- Example: due to the restrictions required by tributing to recovery or improvement of the radionuclide therapy regarding contact with patient’s health status. others, such as in the case of radioiodine therapy for diferentiated thyroid carcinoma.

134 1. References References II,Chapter 8 Section 5. 4. 3. 2. Medicală Românească; 2008. Românească; Medicală corespunzãtoare fundamentale. nevoilor liams & 2011. Wilkins; Philadelphia: Wolters Health/Lippincott Kluwer Wil- of nursing. andscienceofnursingcare, 7thedn. The art 1994. Corporation; Springhouse 2ndedn.Springhouse: of nursingpractice, CG,Buxbaum BS, Mauro E, Norris eds. manual Illustrated Titirca L.Ghiddenursing Press;sity 2009. nostic înnursing, 2ndedn.Arad: Goldiş”“Vasile Univer- Teodorescu M. DL,Iorga A,Rista Teorii, concepte, diag- Napoca: Dacia;2000. universalăButa MG,L.Oistorie anursingului.Cluj- Taylor CR,LillisC,LeMone P, Lynn P, eds. Fundamentals cu tehnici deevaluare siîngrijiri Bucharest: Viaţa 135 6. 9. 8. 7. 10. agnosis, 11thedn.Philadelphia: J.B. Lippincott;2005. Juall Carpenito L,Moyet L.Handbookofnursingdi- Walton Spradley B 2005. & Wilkins; step guide, 6thedn.Philadelphia: Lippincott Williams Alfaro-Lefevre R.Applyingnursingprocess: a step by York: Healthcare; Informa 2007. JF,Eary Brenner W, eds. Nuclearmedicine therapy. New 2008. Românească; Medicală jiri acordate deasistentii medicali, vol II. Titirca L.Ghiddenursing pincott Williams & Wilkins; 1995. & Wilkins; pincott Williams 4thedn.Philadelphia:ing: conceptsandpractice, Lip- , AllenderJA. : tehnici deevaluare siîngri- Community healthnurs- Community Bucharest: Viaţa EANM Section III 1. Future Perspectives in Radionuclide Therapy Cathy S. Cutler

Introduction exact patient assessment and dosage, there Radiotherapy has progressed signiicantly are signiicant savings of time and other re- since the days in which X-rays or radioac- sources when developing one drug that can tive sources were used to ablate cells. Today serve two purposes rather than two separate technology has advanced to methods that drugs. Theranostics for [dual] imaging and selectively deliver radiation to the tumour, therapy hold out promise for accelerated thereby sparing normal tissue, leading to drug development and translation into the efective ablative doses. Advances in imag- clinic. The aim of this chapter is to review ing and therapy have led to more efective some recent advances in the development approaches to treatment with fewer side- of radiotherapeutic agents. efects. This chapter presents methods still in the early stages of development that have The fundamental challenge for therapy is to the potential to change the way clinical prac- deliver toxic doses selectively to cancer cells tice in radiotherapy is performed. while sparing all normal tissues. A variety of platforms have been used to design radio- Molecular imaging has shown its potential to therapy agents, from radiolabelling small non-invasively image both normal and ab- molecules, tracers that mimic the in vivo be- normal biochemical pathways in individual haviour of the natural substance, to the use patients. Molecular targets such as hypoxia, of much more complex molecules such as angiogenesis, receptor expression and me- antibodies and nanoparticles. Conventional tabolism are just a few of the biochemi- agents have had low therapeutic indices cal pathways of interest to evaluate as end due to suboptimal biodistribution — large points in clinical trials. Preclinical imaging is doses are delivered to normal tissues while becoming a key translational tool for proof only a minute portion of the intravenously of mechanism and concept studies. Agents administered drug actually reaches the tar- currently being designed utilise radionu- get. Targeted delivery techniques are being clides that emit photons that can be imaged developed to circumvent such problems by as well as particles that can be used for treat- resulting in selective localisation of drugs to ment. Besides the obvious advantages, more cancer cells [1–6].

136 Section III 1. Future Perspectives in Radionuclide Therapy

Gamma Mean E b- Radionuclide Half-life (h) Decay mode max energy in keV tissue In, MeV (%) (%) range (mm)

198Au 64.7 β-, γ 0.96 (99%) 412 (95.6) 0.38

0.45 208 (9.1) 199Au 75.4 β-, γ 0.14 158 (40) 208 (11) 177Lu 161.0 β-, γ 0.50 0.16 113 (6.6)

153Sm 46.3 β-, γ 0.81 103 (28.3) 0.30

186Re 89.2 β-, γ 1.10 137 (9) 0.43 EANM 212Pb 10.6 β-, γ 0.57 238.6 (43.1) 0.19

212Bi 1.0 α, β- 2.25 (55.5) 727 (11.8)

225Ac 240 α 5.94 99 (5.8)

Table 1: Properties of selected radioisotopes for radiotherapy [34,35]

Palliative treatment palliation of bone pain in some countries. It has been estimated that 60-75% of patients Radionuclides chosen for bone pain pallia- diagnosed with breast and prostate cancer tion need to have particle emissions that are will eventually develop bone metastases. relatively low to minimise bone marrow ab- Among patients with metastatic, castrate-re- lation. Lutetium-177 (177Lu) is a promising ra- sistant prostate cancer, 90% have radiograph- dionuclide for bone pain palliation due to its ic evidence of bone metastases [7]. These low-energy beta emission, long half-life and metastases are extremely painful and result ability to be produced in large quantities at in low quality of life. Radionuclides that mim- most medium lux reactors. 177Lu complexed ic calcium/calcium metabolism or those that to both ethylene diamine tetramethylene are bound to bone-seeking phosphorous phosphonate (EDTMP) and 1,4,7,10-tetra- chelators have been developed and used to azacyclododecane-1,4,7,10-tetramethylene- palliate the pain associated with metastatic phosphonate (DOTMP) is being evaluated bone disease. Several radioisotopes such as for bone pain palliation [8]. A study compar- samarium-153 (153Sm)-EDTMP (Quadramet®) ing 177Lu-DOTMP with 153Sm-EDTMP showed and strontium-89 chloride are approved for that little to no toxicity was observed for

137 the 177Lu agent when administered to give International Atomic Energy Authority (IAEA) the same skeletal dose as the 153Sm agent, coordination evaluating 177Lu-EDTMP. A scan indicating larger 177Lu doses could be given showing the bone uptake observed for 177Lu- that may result in longer remission times EDTMP giving a dose of 37 MBq/kg and im- [8]. Clinical trials are ongoing through the aged at 7 days is shown in Figure 1.

Figure 1: Planar image of a patient 7 days after receiving 37 MBq/kg of 177Lu-EDTMP for palliation of pain due to metastatic bone cancer [35,37,38]

223 Radium-223 ( Ra; RaCl2) is an alpha-emit- like the agents described above, which are ting radioisotope that has been shown to excreted very quickly (normally within 4 h) target areas of osteoblastic metastases. Un- via the kidneys, 223Ra is cleared primarily via

138 Section III 1. Future Perspectives in Radionuclide Therapy

the intestines [9]. This may be advantageous tumour penetration, dose-limiting toxicity to in patients who have genitourinary cancers the liver and bone and, in some patients, ad- or reduced kidney function. 223Ra, as an al- verse haematological efects and resistance. pha emitter, delivers a very high dose to a It can take up to 7 days for these large pro- very small area. This may lead to a reduction teins to reach maximum uptake at the target in some of the toxic side-efects observed site, limiting the radionuclides that can be with the beta-minus emitters such as leuko- used. A concerted focus has turned to evalu- penia, thrombocytopenia and bone marrow ating peptides for their smaller size and rapid suppression. In a large randomised phase III receptor targeting and blood clearance, abil- trial, 223Ra has demonstrated improvements ity to be easily synthesised and rapidly modi- in overall survival, a delay of skeletal-related ied through solid phase and solution phase events (pathological fractures, spine cord peptide synthesis, and increased tumour compression and requirements for surgery or penetration and distribution; in addition, EANM radiation to the bone) and biochemical pa- they do not elicit immune responses. Thus rameters, with a remarkably tolerant adverse peptides are being developed as diagnostic event proile in men with castration-resistant tools and biomarkers for cancer prognosis prostate cancer [9]. This has been the irst and tumour targeting agents carrying ra- agent to demonstrate improvement in over- dionuclides to cancer cells. Many are being all survival, although it should be pointed out used for theranostic applications in which this was never evaluated for the other agents. they can be used both as an imaging char- Expanded trials are planned with this agent. acterisation tool and as a delivery device for radiotherapy radionuclides. Peptides The use of peptides and proteins such as Peptide receptor radionuclide therapy (PRRT) monoclonal antibodies to deliver cytotoxic combines peptides with radionuclides to tar- drugs has resulted in more selective treat- get receptors overexpressed on cancer cells. ments and in huge advancements in treating Somatostatin analogues, the irst developed, metastatic disease. CD20-targeted Bexxar® have been the most widely investigated. labelled with iodine-131 (131I) and Zevalin® Octreoscan was the irst radiolabelled pep- labelled with yttrium-90 (90Y), routinely used tide approved for imaging neuroendocrine to treat follicular non-Hodgkin’s lymphoma, tumours and is considered the gold stan- have demonstrated the efectiveness of the dard for diagnosis of somatostatin receptor targeted approach. Large proteins such as positive tumours [10, 11]. Upon injection, the monoclonal antibodies demonstrate high radiolabelled octreotide attaches to soma- ainity, but due to their large sizes, sufer tostatin receptors overexpressed on cancer from long residence times in the blood, slow cells, thereby allowing an external SPECT

139 camera to image the location of the tumours is removed, enabling a bond between the in the body. A number of somatostatin ana- Phe and Cys of the cyclic hexapeptide tar- logues have been developed for imaging geting vector. Hydrophobicity was added and have been expanded to bind radionu- by substituting a Tyr for a Val and linking to clides for PRRT. These agents are composed a linear tetrapeptide chelator motif, which of a peptide conjugated to a bifunctional serves to coordinate the Tc at the Dap-Lys- chelator through a linker. The peptide acts as Cys sequence (Dap= β-diaminopropionic the guiding system for selective delivery, the acid) shown in Fig. 2 [12, 13]. The chelation bifunctional chelator serves to stably com- involves three (two amide plex the radioisotope, normally a metal, and atoms of Lys and Cys and one amine nitro- the linker serves not only for stable conjuga- gen of Dap) and one sulphur of Cys. 99mTc of- tion but also as a pharmacodynamic modii- fers better imaging quality than indium-111 er. Changes to the linker can be made to ine (111In) and is more widely available. NeoTect® tune the uptake and clearance of the agent, itself has demonstrated higher ainity than such as increasing the hydrophobicity if the Octreoscan® for receptor subtypes 2 and 5 overall molecule proves to be too hydrophilic and slower clearance from normal tissues via and clears too quickly. The most commonly the kidneys, where it is excreted intact. used chelator has been DOTA (1,4,7,10-tetra- azacyclotetradecane-N,N’,N”,N”’-tetra-acetic acid) which forms kinetically and thermody- namically stable complexes with a variety of metals but sufers from having to be heated at high temperatures for long periods of time and promiscuous binding with all metals, which can result in lowered speciic activ- ity. Other chelators have been developed that are more metal speciic and that can be labelled at room temperature in high yields and often negate the need for a terminal puriication. The technetium-99m (99mTc) so- matostatin analogue, NeoTect®, approved in the United States, is used for the diferen- tiation of malignant versus benign masses in the lungs, often after initial disclosure with CT or MRI. It difers from octreotide in that the disulphide bond between the two Cys

140 Section III 1. Future Perspectives in Radionuclide Therapy EANM Cutler CS. University of MO Cutler

Figure 2: Structure of the somatotastatin analogue for the drug NeoTect®

Signiicant work has gone into developing als in the United States within the next year. analogues that could deliver therapeutic Further studies have shown that using the doses. It was determined that replacement of two radionuclides in combination results in a tyrosine with phenylalanine enhanced aini- more eicacious treatment than using either ty for the subtype 2 receptor, and that chang- alone. A small study in 50 patients in which ing the chelate from DTPA to DOTA resulted combined 90Y/177Lu-DOTATATE therapy was in a more stable complex that could be used evaluated in comparison to 90Y-DOTATATE with 90Y, i.e. 90Y-DOTA-Tyr3-octreotide [14]. The alone, applying 90Y/177Lu-DOTATATE in a ratio DOTA chelator is able to coordinate most +2 of 1:1, demonstrated higher progression- and +3 radiometals and remain stable in vivo. free survival in the tandem therapy group: This version is termed DOTATOC and, labelled 29.4 months vs 21.4 months [15]. Treatment with 90Y, it has been used to treat hundreds has also been enhanced by the use of PET of patients. Toxicity in the kidneys led to the imaging with -68 (68Ga) labelled to development of DOTATATE, which has been DOTATOC, DOTATATE or the new analogues predominantly used with 177Lu. 177Lu has low- NODAGATOC (DOTA has been replaced with er b- than 90Y and an imageable gamma emis- the NOTA chelator) and DOTANOC (NOC = sion at 208 keV that can be utilised to assess NaI3-octreotide, an sst2, sst3 and sst5 bind- post-therapy uptake and dosimetry. 177Lu has ing peptide), in which the peptide has been also been used in a large number of patients further modiied. PET imaging with 68Ga al- in Europe and is expected to enter clinical tri- lows for the determination of the receptor

141 density through the standardised uptake therefore involve selection of a compatible value (SUV). Novel derivatives such as NODA- combination of a targeting molecule, to de- GATOC made with the NOTA chelator have liver the radiolabelled compound with high allowed for room temperature synthesis in selectivity to site(s) of disease, and a radioiso- high yields that have been converted to easy tope, to cause damage/destruction to its lo- kit formulations similar to those routinely cal environment through its energetic decay used for 99mTc. properties. Radioimmunotherapy treatment of cancer uses a class of compounds that PRRT and imaging have been extended to combine monoclonal antibodies (mAbs) looking at other peptides, such as bombesin, and particle-emitting radioisotopes. mAbs that target the gastrin-releasing peptide re- target receptors either uniquely expressed ceptor known to be over-expressed in breast, on cancer cells or expressed in signiicantly prostate and lung tissues [16, 17]. A phase 1 higher numbers on cancer cells than on cells clinical trial of 177Lu-DOTA- [4-aminobenzyl]- of healthy tissue; this diference in receptor BB (6–14) was undertaken [18]. Newer expression allows for selective targeting of bombesin versions have been developed, diseased cells. Particle-emitting radioiso- such as the antagonists that demonstrate topes (i.e. Auger electron, beta and alpha less non-speciic uptake and higher receptor emitters) deposit their energy over short dis- ainity [19, 20]. Other peptides being evalu- tances, thereby localising tissue damage. For ated include those that target cholecystoki- example, lymphomas have been successfully nin (CCK) receptors [21]. In addition to new treated with the RIT compounds Zevalin® analogues, new radiometals have been eval- and Bexxar®, CD20 receptor-targeting mAbs uated, including -44 (44Sc) for imag- radiolabelled with beta-emitting radioiso- ing and -213 (213Bi) for therapy. The topes. 90Y and 131I, respectively. Zevalin® and longer half-life of 44Sc (4.4 h) allows for imag- Bexxar® exploit the long blood circulation ing at later time points. 213Bi-DOTATOC was time of mAbs (large proteins) for targeting of evaluated and demonstrated higher thera- these blood-based cancers; however, the res- peutic eicacy when compared to 177Lu- idence time in blood (~7 days after injection) DOTATOC in human adenocarcinoma cells. limits the eicacy of RIT using mAbs for solid tumour treatment. Prior to selective binding Monoclonal antibodies of their receptor targets, the blood circula- Targeted radioisotope therapy involves the tion of conventional RIT compounds contrib- administration of radiolabelled compounds utes to whole-body irradiation and results in to selectively damage and/or destroy dis- substantial radiation dose to the radiosensi- eased tissue (e.g. cancer). The design of a tive bone marrow. Protecting the bone mar- successful radiotherapeutic agent must row from excessive radiation exposure limits

142 Section III 1. Future Perspectives in Radionuclide Therapy

the amount of radioactivity that can be safely defence system. Such an immune response injected into a patient, consequently lower- precludes repeat or dose fractionation treat- ing tumour doses and reducing therapeutic ments of solid tumours, which have demon- eicacy. strated maximum eicacy for some cancer treatments, such as external beam therapy To administer the highest possible radiation and chemotherapy. A new pretargeting dose to target tissue and the lowest possible method has been proposed that uses an dose to non-target tissue, most of the decay unusually rapid organic chemical reaction, process should occur after the radiolabelled instead of biological components, to bind compound has been delivered to the target the small radiolabelled probe to the tumour- site and cleared from the blood and normal bound mAb with high ainity. Bertozzi and tissues. Thus, RIT pretargeting methods have others have developed biorthogonal reac- been developed which decouple delivery tions using ring-strained cyclo-octene deriv- EANM of the radioactivity from that of the mAb. atives for biological labelling. The approach is In brief, the mAb is conjugated with a tag based on the inverse electron demand Diels- or artiicial receptor designed to bind with Alder reaction between a DOTA-tetrazine high ainity to a small molecular probe. The analogue (Fig. 3), which demonstrates high tagged mAb is injected and allowed sui- thermodynamic and chemical stability with cient time to reach maximum uptake at the most metals, and a trans-cyclo-octene (TCO) tumour and clearance from the blood. Then, (Fig. 3) conjugated to the murine mAb CC49 a small radiolabelled probe is injected that [22]. This reaction was chosen based on its ex- binds rapidly and with high ainity to the ceptionally high second-order rate constant “receptor” on the pre-localised mAb, with the of 13,090 ± 80 M1s-1 at 37°C in phosphate- remaining unbound fraction excreted rapidly bufered saline [22]. CC49 has high ainity to via the kidneys. The outcomes of pretarget- TAG-72, an antigen with limited internalisa- ing methods are higher radiation dose deliv- tion and shedding that is over-expressed in ery to the tumour (typically tenfold improve- a wide range of solid tumours, such as colon ment), increased therapeutic eicacy and cancer [23, 24]. It is hypothesised that, by minimal dose and toxicity to normal tissues, moving away from biological pretargeting such as the bone marrow. components and instead using an orthogo- nal chemical reaction, it may be possible to Most pretargeting strategies are based on avoid an immune response to allow repeat high-ainity biological recognition systems and/or fractionated treatments and thereby (e.g. mAb/hapten and biotin/avidin), which improve therapeutic eicacy. sufer from immunogenicity-inducing re- sponses as they are recognised by the body’s

143 2: R=NHS

Cutler CS. University of MO Cutler 1

Figure 3: Structures of bio-orthogonal pretargeting molecules tetrazine DOTA (1) and trans- cyclo-octene TCONHS (2) 36

Initial in vivo proof-of-principle imaging stud- 111In-DOTA-tetrazine. Following such prom- ies were performed in mice bearing colon ising results, the TCO-CC49/DOTA-tetrazine cancer xenografts that were administered pretargeting method was further improved 100 µg of TCO-CC49 followed one day later (e.g. for dosing and timing of radiolabelled with 3.4 equivalents of 111In-DOTA-tetrazine probe) and evaluated against conventionally (40.7 MBq) [22] . The animals were imaged labelled DOTA-CC49 with the therapeutic 3 h later, and the tumour was shown to have radioisotope 177Lu [25]. Using the biodistribu- a 4.2% ID/gram uptake and a 13:1 tumour to tion data obtained, the estimated maximum muscle ratio. Besides the tumour, the bulk of deliverable dose to the tumour without be- the activity was found in the bladder, a small ing lethal to bone marrow was nearly ive amount in the kidneys and some residual in times higher with the pretargeting method the liver and blood that was attributed to at 80 Gy than the sub-therapeutic dose of circulating TCO-CC49. Control studies with 17 Gy for the conventional labelling meth- unmodiied CC49 and TCO-modiied ritux- od. If such an approach works out, it could imab, a mAb with no TAG-72 ainity, showed change the way we currently use antibodies no tumour uptake and supported the an- and also give greater eicacy. tigen-speciic binding of TCO-CC49 with

144 Section III 1. Future Perspectives in Radionuclide Therapy

Nanoparticles Liposomes have been radiolabelled either A disadvantage of the conventional bi- by incubating the liposome with the radio- functional chelating system is that, at nuclide of interest, allowing it to incorporate most, only one radioactive molecule per into the lipid bilayer, or by attachment of targeting moiety is delivered. This is highly chelators to the surface, such as DTPA ana- dependent on the of the logues and other familiar chelators. Both of radioisotope and on any metal contami- these methods sufer from signiicant loss nants, as many chelators are not selective of the radionuclides and modiication to the but will bind to a number of common met- surface, adversely impacting targeting vec- als. A low specific activity and/or high pres- tors. To overcome this, another method has ence of unwanted metal impurities can been developed in which the radiometal is result in low labelling yields for the desired irst chelated to a lipophilic chelator, which radioisotope and saturation of the receptor then crosses the bilayer, resulting in entrap- EANM sites if they are present in low quantities. ment of the radiometal in the aqueous core. This has been recently demonstrated by Examples include the use of oxime to label Asti et al. [26], who performed a system- 111In and hexamethylpropylene oxime to atic study evaluating the effect of specific incorporate 99mTc. Rhenium-186 (186Re) has activity and incorporation of a variety of been incorporated using the chelator N,N- metals on a typical DOTATOC clinical for- bis(2-mercaptoethyl-N,N-diethylenediamine, mulation. Furthermore, it is often not pos- which reacts with encapsulated cysteine sible to design a chelator that can stably to secure the 186Re within the core [28]. complex a metal such as an alpha emitter Fullerenes have been evaluated both in the and its daughters upon decay. The release spherical coniguration commonly referred of the daughter can result in unwanted ra- to as Bucky balls and as carbon nanotubes. diation dose to normal tissues and further Their surface allows for the conjugation of decrease the effectiveness of the adminis- targeting vectors, while the inside serves to tered dose. For example, DOTA is known to safeguard the radioisotope from interact- form strong complexes with 213Bi and lead- ing with the biological milieu, thus ofering 212 (212Pb); however, decay of 212Pb results the potential of stably retaining and deliv- in more than a 35% release of 213Bi. Rose- ering the radionuclide, something that has now was the first to investigate using lipo- not been possible through standard chela- somes to stably encapsulate 212Pb and its tion. Ultra-short single-walled carbon nano- daughters [26]. It has been demonstrated tubes (SWNT) were irst tested illed with that 10-nm liposomes result in the reten- iodine-125 (125I). The 125I was loaded and then 213 212 125 tion of Bi after the decay of Pb [27]. oxidised to I2, which demonstrated long re- tention. The carbon nanotubes were directed

145 to the lung and no uptake was observed in chloramine-T or N-chlorosuccinimide, the the thyroid, which is where free iodine in the AtCl molecules were more highly retained, body is known to collect. This method was showing labelling yields of 78–93%; these also shown to deliver a 10 times higher dose yields are much higher than those previously per gram of tissue than is obtainable with reported for corborane derivatives, which other methods. have demonstrated the highest incorpora- tion, 40–60%. Incubation in water showed There is considerable interest in using al- retention of 72–85% of the At in the SWNT pha emitters for treating micrometastases and 85–93% retention in serum, indicating or single cell leukaemias because the path that these may well serve as stable delivery length of the typically used beta-minus par- systems for At. ticle emitters is hundreds of cell diameters, resulting in damage to healthy normal tissue. The alpha emitter -225 (225Ac) holds With their high LET, alpha emitters are more much promise for targeted alpha therapies lethal over a shorter range — it is estimated as an in vivo generator. The nuclear decay of that only one to three alpha emissions are re- 225Ac (10-day half-life with the emission of quired to kill a cell versus thousands for beta four alpha particles) holds the potential to emitters. -211 (211At) is a prospective become an ideal radiotherapy system. The radionuclide for therapy owing to its 7.2-h 10-day half-life provides suicient time for half-life and its ability to be imaged by SPECT complex syntheses and attachment to tar- for post-therapy distribution and dosimetry; geting biomolecules, while the rapid decay furthermore, it can be produced on a cyclo- and high LET of the daughters’ alpha emis- tron. Astatine, however, has proven to be dif- sions ensure that the therapeutic payload is icult to complex as carbon–astatine bonds delivered in the vicinity of the target tissue. are weak and result in dehalogenation in vivo. Despite the clear beneits of delivering mul- Consequently, carboranes and nanoparticles tiple alpha particles from the decay of 225Ac have been evaluated [9,10]. Two diferent directly to tumour sites, the diiculty of se- types of nanoparticle have been assessed: questering the alpha-emitting daughters in nanoparticles covalently coated with traditional bifunctional-conjugated targeting poly(ethylene oxide) and SWNT. Reducing modalities leads to release of the daughters conditions with silver nanoparticles resulted and non-speciic uptake in non-target or- in high labelling yields. SWNT nanoparticles gans. This non-target dose negates the ad- were labelled with 211At- in the same man- vantages of targeted alpha therapy, namely ner as the 125I-; initially the anion was loaded high tumour dose with minimal collateral and, as with the I, signiicant leakage was damage to healthy tissue. In order to harness reported; however, upon oxidation with the potential of multiple alpha particles from

146 Section III 1. Future Perspectives in Radionuclide Therapy

225Ac, nanoparticles are being studied as a endothelium showed that the nanoparticles way to retain the decay products for delivery exhibited high lung uptake (151%ID/g) [30]. to the target site. Initially a multivesicular li- Additionally, the uptake could be blocked by posomal carrier was evaluated. The nanopar- administering cold unlabelled antibody: up- ticles were further tagged with a vector for take dropped to 16.8%ID/g. After 24 h the ac- anti-HER2/neu and evaluated in an ovarian tivity was transferred to the liver and spleen cell line. While internalisation was at a high due to the reticuloendothelium system. This rate, however, retention of the 225Ac was not can be overcome by using clodronate lipo- as high as needed. A lanthanum phosphate somes to reduce reticuloendothelial func- nanoparticle (LaPO4 NP) evaluated in vivo tioning. The properties of low toxicity and showed higher retention, and upon complex- favourable biodistributions make the LaGd- ation with an antibody to lung endothelium, PO4-AuNP system a promising platform for high retention in mouse lung tissue [29]. This targeted alpha therapy with 225Ac. EANM design has been further modiied to include a gold coating and incorporation of gado- A major challenge in cancer therapy has been linium into the lanthanum gadolinium phos- delivery and retention. Due to their size and phate nanoparticles (NPs) for the purpose of ability to circumvent some of the hurdles en- retaining both 225Ac and its daughters in an countered with traditional agents, nanopar- attempt to increase retention. The magnetic ticles are promising alternatives. They have gadolinium simpliied the separation and unique properties that can be optimised to puriication chemistry. Transmission electron allow for higher penetration and retention microscopy analysis of LaGdPO4-AuNPs par- in tumour cells. Unlike traditional medicine, ticles showed monodisperse particles with the ield of nanomedicine utilises particulate average diameters of 4–5 nm. Radiochemical matter with sizes that are the same or smaller analysis indicated that LaGdPO4-AuNPs with- than those of cellular components, allowing out additional layers sequestered 60.2±3.0% nanoparticles to cross multiple biological of the irst decay daughter of 225Ac, fran- barriers to enhance delivery and retention cium-221 (221Fr). The addition of two shells for optimal treatment. The size similarity to of LaGdPO4 and one shell of Au increased cellular components makes nanoparticles at- 221Fr retention to 69.2±1.7%, while the addi- tractive candidates for curing functional ab- tion of four shells of GdPO4 and one shell of normalities that instigate disease at the cellu- Au increased retention to 92±1.0%. Reten- lar level. Current approaches result in serious tion of the irst decay daughter is essential adverse side-efects that signiicantly limit to minimising normal tissue toxicity. In vivo the number of therapeutic molecules that distribution of the nanoparticles conjugated can be delivered to the tumour site, resulting to a that targets lung in low eicacy. Efective tumour treatment

147 requires a high-impact therapeutic payload surface to aid in localisation and recognition, to destroy cancer cells. Due to the enhanced as well as ligands for complexing diagnostic permeability of tumour cells, nanoparticles radionuclides. can be sized such that they are selectively taken up and retained in cancer cells, this Radioisotopes of gold and other coinage being called the enhanced permeability and metals have nuclear properties that make retention (EPR) efect [31]. Control over the them ideal for use in imaging and therapeu- supply of therapeutic payload enables on- tic applications. However, their biologically cologists to deliver an optimised efective active redox chemistry and lack of stable treatment for cancer patients. In this regard, chelating agents have to date limited their it is important to note that nanoparticulates utilisation in vivo. They have had application containing radioactive isotopes provide an in the area of brachytherapy with the bare opportunity to tune the radioactive thera- metal being encapsulated, but otherwise peutic dose delivered to tumour cells. have been used sparingly, the major concern being the inherent toxicities observed for the The conventional method for delivering free metals in vivo. A novel approach is the radioisotopes has been either to complex development of metal nanoparticles that them to a targeting molecule for selective can be derivatised on their surface, allowing delivery, or to form a chemical complex with for optimisation of biodistribution in vivo. in vivo properties that will efect uptake at the tumour site. Although the conventional Once a metal nanoparticle is fabricated, its method has produced successful treatments, in vivo properties can be evaluated and al- not all metals can be stably complexed by tered by varying such properties as its size, simple ligands. Some, such as gold and sil- charge, hydrodynamic size, organic surface ver, have no stable chelation methods; in vivo layer and shape. These can be optimised to injection results in their release. Others, such enable more favourable uptake and clear- as many of the alpha emitters, are released ance in vivo. Furthermore, owing to their from the compound upon decay and there- high surface area, they can be conjugated fore cause signiicant toxicity, limiting their with a plethora of agents that can be used usefulness. The irst nanoparticles developed for selective targeting, such as peptides and and translated to the clinic were liposomes. small molecules, to enhance retention in Comprising various platforms, they basi- the bloodstream or to enhance clearance. cally consist of a lipid outer sphere and an These properties can be optimised through aqueous core, which allows the trapping of in vivo studies to develop lead compounds hydrophobic drugs in the lipid layer and of for imaging and therapy. A major advan- hydrophilic drugs in the aqueous inner core. tage of nanoparticles over the commonly Targeting vectors can be attached to the used bifunctional chelator approach is that

148 Section III 1. Future Perspectives in Radionuclide Therapy

the nanoparticle platform allows for a much diameter of 60–85 nm [32]. These methods higher payload delivery, as more than one have been shown to be robust and non-toxic radioisotope can be incorporated into the in the non-radioactive form. The methods nanoparticle, producing a much higher dose have been altered to allow for formation of delivery even with a low speciic activity ra- both 198Au and 199Au nanoparticles and also dionuclide. have been shown to permit formation of nanoparticles of other coin metals such as Radioisotopes of gold (Au) as shown in and silver. Table 1 have attractive nuclear proper- ties that make them ideal for imaging and Gum arabic-coated gold nanoparticles (GA- therapy. Two radioisotopes of gold stand 198AuNPs) have been the most studied to out. 198Au has a moderate enegry beta par- date [33]. This formulation was initially evalu- ticle (0.96 keV β- max), making it a good ated for therapeutic eicacy in SCID mice EANM candidate for therapy, and more than 90% bearing induced human prostate tumours. emission of a 412-keV gamma emission that Diferent modes of injection were tried, allows for in vivo tracking and dosimetry cal- with the intratumoral injection resulting in culation. These properties prompted its use the highest uptake and retention. The par- as a brachytherapy agent for prostate cancer. ticles were then evaluated for their eicacy 199Au has a low-energy beta max (0.46 MeV) in tumour stabilisation in the same tumour and emits a 158-keV gamma in 36% yield models. Tumours received a 70 Gy dose by that is easily detected by SPECT cameras. administering 15 MBq. An overall 82% reduc- Additionally, 199Au can be produced carrier- tion in tumour volume was noted between free by neutron irradiation of -198, the mice receiving the GA-198AuNP com- which produces platinum-199, which decays pared to controls receiving saline injections. in 3.2 min to 199Au. Biodistributions at the end showed a reduc- tion of gold nanoparticles in the tumour, FGold nanoparticles (AuNPs) have been from 70% at 24 h to 19.9%±4.2% ID at 30 days around for quite some time, but their harsh post injection. Clearance was predominantly production methods with toxic chemicals through the urinary tract and minimum up- have prevented them from being attached take was observed in other organs. Based on easily to biomolecules for evaluation in vivo. these results, these nanoparticles are now An improved synthesis has been developed being evaluated for their therapeutic eicacy that uses THPAL, a trimeric phosphino ala- in dogs with spontaneous prostate cancer. nine, to reduce gold salts in water-containing Prostate cancer in dogs has been shown to organics, which coat the surface of the gold mimic that observed in humans on the func- nanoparticles and form 12- to 15-nm-sized tional level as well as in metastatic rate and gold nanoaprticles with a hydrodynamic occurrence. A phase 1 study in dogs starting

149 at 50 Gy and increasing to 105 Gy has shown no toxicity issues in the dogs and up to a 60% reduction in tumour volume. Based on these results, these nanoparticles are being evalu- ated in other solid tumours and are being considered for a phase 1 human study.

Conclusion An expanding role for radiotherapy is unfold- ing through the recent advances presented here. These novel delivery methods are giv- ing rise to even higher doses to cancer cells while vastly minimising the dose to sur- rounding normal tissues. These methods are providing more lexibility in the use of radio- on the one hand and increasingly personalised treatments regimens on the other. These novel delivery systems are going to make radiotherapy a more exciting option for patients and their physicians.

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