BACKGROUND: The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented. RESULTS: A brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements. CONCLUSIONS: Molecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced.

Department for Nuclear Medicine University Hospital of Cologne Cologne Germany

Department of Basic Medical Sciences Division of Medical Physics Ghent University Ghent Belgium

Department of Diagnostic Physics Oslo University Hospital Oslo Norway

Department of Dosimetry and Application of Ionizing Radiation Czech Technical University Prague Prague Czech Republic

Department of Medical Physics and Radiation Protection Gurutzeta Cruces University Hospital Barakaldo Spain

Department of Medical Physics Pammakaristos Hospital Athens Greece

Department of Medical Radiation Physics Clinical Sciences Lund Lund University Lund Sweden

Department of Nuclear Medicine and PET Center University Hospital Ghent Belgium

Department of Nuclear Medicine University Hospital of Geneva Geneva Switzerland

Department of Radiology and Nuclear Medicine Erasmus MC Rotterdam The Netherlands

Joint Department of Physics Royal Marsden Hospital and Institute of Cancer Research Sutton UK

Nuclear Medicine Division Foundation IRCCS istituto nazionale Tumori Milan Italy

Nuclear Medicine Radiotherapy Physics UCL Institute of Nuclear Medicine and UCL Hospitals NHS Foundation Trust London UK

Nuclear Medicine Sant'Andrea Hospital Department of Surgical and Medical Sciences and Translational Medicine Sapienza University of Rome Rome Italy

School of Engineering Cardiff University Cardiff UK

Section of Nuclear Medicine and PET Department of Surgical Sciences Uppsala University Uppsala Sweden

The Christie NHS Foundation Trust Nuclear Medicine Manchester UK

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Sawin CT, Becker DV. Radioiodine and the treatment of hyperthyroidism: the early history. Thyroid : official J. Am. Thyroid Association. 1997;7:163–176. doi: 10.1089/thy.1997.7.163. PubMed DOI

Lawrence JH. Nuclear physics and therapy: preliminary report of a new method for the treatment of leukemia and polycythemia. Radiology. 1940;35:51–60. doi: 10.1148/35.1.51. DOI

Council directive 2013/59/EURATOM official journal of the European Union; 2014.

Gleisner et al. Variations in the practice of molecular radiotherapy and implementation of dosimetry: Results from a European survey. EJPH-D-17-00032R1. PubMed PMC

Silberstein EB, Alavi A, Balon HR, Clarke SE, Divgi C, Gelfand MJ, et al. The SNMMI practice guideline for therapy of thyroid disease with 131I 3.0. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2012;53:1633–1651. doi: 10.2967/jnumed.112.105148. PubMed DOI

Lassmann M, Hanscheid H, Chiesa C, Hindorf C, Flux G, Luster M, et al. EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging. 2008;35:1405–1412. doi: 10.1007/s00259-008-0761-x. PubMed DOI

Dewaraja YK, Ljungberg M, Green AJ, Zanzonico PB, Frey EC, Committee SM, et al. MIRD pamphlet no. 24: guidelines for quantitative 131I SPECT in dosimetry applications. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2013;54:2182–2188. doi: 10.2967/jnumed.113.122390. PubMed DOI PMC

Nagarajah J, Jentzen W, Hartung V, Rosenbaum-Krumme S, Mikat C, Heusner TA, et al. Diagnosis and dosimetry in differentiated thyroid carcinoma using 124I PET: comparison of PET/MRI vs PET/CT of the neck. Eur J Nucl Med Mol Imaging. 2011;38:1862–1868. doi: 10.1007/s00259-011-1866-1. PubMed DOI

Benua RS, Cicale NR, Sonenberg M, Rawson RW. The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer. Am J Roentgenol Radium Therapy, Nucl Med. 1962;87:171–182. PubMed

Jeong SY, Kim HW, Lee SW, Ahn BC, Lee J. Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms. Thyroid : off J. Am. Thyroid Association. 2013;23:609–616. doi: 10.1089/thy.2012.0106. PubMed DOI PMC

Liu B, Huang R, Kuang A, Zhao Z, Zeng Y, Wang J, et al. Iodine kinetics and dosimetry in the salivary glands during repeated courses of radioiodine therapy for thyroid cancer. Med Phys. 2011;38:5412–5419. doi: 10.1118/1.3602459. PubMed DOI

Sgouros G, Song H, Ladenson PW, Wahl RL. Lung toxicity in radioiodine therapy of thyroid carcinoma: development of a dose-rate method and dosimetric implications of the 80-mCi rule. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2006;47:1977–1984. PubMed PMC

Lassmann M, Luster M, Hanscheid H, Reiners C. Impact of 131I diagnostic activities on the biokinetics of thyroid remnants. J. Nucl. Med.: off Publ., Soc Nucl. Med. 45:619–25. PubMed

McDougall IR, Iagaru A. Thyroid stunning: fact or fiction? Semin Nucl Med. 2011;41:105–112. doi: 10.1053/j.semnuclmed.2010.10.004. PubMed DOI

Hanscheid H, Lassmann M, Luster M, Thomas SR, Pacini F, Ceccarelli C, et al. Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2006;47:648–654. PubMed

Buckley SE, Chittenden SJ, Saran FH, Meller ST, Flux GD. Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2009;50:1518–1524. doi: 10.2967/jnumed.109.064469. PubMed DOI

Chiesa C, Castellani R, Mira M, Lorenzoni A, Flux GD. Dosimetry in 131I-mIBG therapy: moving toward personalized medicine. The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear. Medicine. 2013;57:161–170. PubMed

Gaze MN, Chang YC, Flux GD, Mairs RJ, Saran FH, Meller ST. Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma. Cancer Biother Radiopharm. 2005;20:195–199. doi: 10.1089/cbr.2005.20.195. PubMed DOI

Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3] octreotate in patients with endocrine gastroenteropancreatic tumors. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2005;23:2754–2762. doi: 10.1200/JCO.2005.08.066. PubMed DOI

Sundlov A, Sjogreen-Gleisner K, Svensson J, Ljungberg M, Olsson T, Bernhardt P, et al. Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. Eur J Nucl Med Mol Imaging. 2017; PubMed PMC

Sandstrom M, Garske U, Granberg D, Sundin A, Lundqvist H. Individualized dosimetry in patients undergoing therapy with (177) Lu-DOTA-D-Phe (1)-Tyr (3)-octreotate. Eur J Nucl Med Mol Imaging. 2010;37:212–225. doi: 10.1007/s00259-009-1216-8. PubMed DOI

Ljungberg M, Celler A, Konijnenberg MW, Eckerman KF, Dewaraja YK, Sjogreen-Gleisner K, et al. MIRD pamphlet no. 26: joint EANM/MIRD guidelines for quantitative 177 Lu SPECT applied for dosimetry of radiopharmaceutical therapy. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2016;57:151–162. doi: 10.2967/jnumed.115.159012. PubMed DOI

Bergsma H, Konijnenberg MW, van der Zwan WA, Kam BL, Teunissen JJ, Kooij PP, et al. Nephrotoxicity after PRRT with (177) Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging. 2016;43:1802–1811. doi: 10.1007/s00259-016-3382-9. PubMed DOI PMC

Ilan E, Sandstrom M, Wassberg C, Sundin A, Garske-Roman U, Eriksson B, et al. Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177 Lu-DOTATATE. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2015;56:177–182. doi: 10.2967/jnumed.114.148437. PubMed DOI

Hindorf C, Chittenden S, Aksnes AK, Parker C, Flux GD. Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun. 2012;33:726–732. doi: 10.1097/MNM.0b013e328353bb6e. PubMed DOI

Carrasquillo JA, O'Donoghue JA, Pandit-Taskar N, Humm JL, Rathkopf DE, Slovin SF, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of (2)(2)(3) Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40:1384–1393. doi: 10.1007/s00259-013-2427-6. PubMed DOI PMC

Chittenden SJ, Hindorf C, Parker CC, Lewington VJ, Pratt BE, Johnson B, et al. A phase 1, open-label study of the biodistribution, pharmacokinetics, and dosimetry of 223 Ra-dichloride in patients with hormone-refractory prostate cancer and skeletal metastases. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2015;56:1304–1309. doi: 10.2967/jnumed.115.157123. PubMed DOI

Pacilio M, Ventroni G, De Vincentis G, Cassano B, Pellegrini R, Di Castro E, et al. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting (223)Ra-dichloride. Eur J Nucl Med Mol Imaging. 2016;43:21–33. doi: 10.1007/s00259-015-3150-2. PubMed DOI

Giammarile F, Bodei L, Chiesa C, Flux G, Forrer F, Kraeber-Bodere F, et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. Eur J Nucl Med Mol Imaging. 2011;38:1393–1406. doi: 10.1007/s00259-011-1812-2. PubMed DOI

Cremonesi M, Chiesa C, Strigari L, Ferrari M, Botta F, Guerriero F, et al. Radioembolization of hepatic lesions from a radiobiology and dosimetric perspective. Front Oncol. 2014;4:210. doi: 10.3389/fonc.2014.00210. PubMed DOI PMC

Elschot M, Vermolen BJ, Lam MG, de Keizer B, van den Bosch MA, de Jong HW. Quantitative comparison of PET and bremsstrahlung SPECT for imaging the in vivo yttrium-90 microsphere distribution after liver radioembolization. PLoS One. 2013;8:e55742. doi: 10.1371/journal.pone.0055742. PubMed DOI PMC

Willowson KP, Tapner M, Team QI, Bailey DLA. Multicentre comparison of quantitative (90)Y PET/CT for dosimetric purposes after radioembolization with resin microspheres : the QUEST phantom study. Eur J Nucl Med Mol Imaging. 2015;42:1202–1222. doi: 10.1007/s00259-015-3059-9. PubMed DOI PMC

Chiesa C, Mira M, Maccauro M, Spreafico C, Romito R, Morosi C, et al. Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology. Eur J Nucl Med Mol Imaging. 2015;42:1718–1738. doi: 10.1007/s00259-015-3068-8. PubMed DOI

Garin E, Lenoir L, Edeline J, Laffont S, Mesbah H, Poree P, et al. Boosted selective internal radiation therapy with 90Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept. Eur J Nucl Med Mol Imaging. 2013;40:1057–1068. doi: 10.1007/s00259-013-2395-x. PubMed DOI PMC

Strigari L, Sciuto R, Rea S, Carpanese L, Pizzi G, Soriani A, et al. Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations. J. Nucl. Med.: off Publ., Soc Nucl. Med. 51:1377–85. PubMed

Flamen P, Vanderlinden B, Delatte P, Ghanem G, Ameye L, Van Den Eynde M, et al. CORRIGENDUM: multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with yttrium-90 labeled resin microspheres. Phys Med Biol. 2014;59:2549. doi: 10.1088/0031-9155/59/10/2549. PubMed DOI

van den Hoven AF, Rosenbaum CE, Elias SG, de Jong HW, Koopman M, Verkooijen HM, et al. Insights into the dose-response relationship of radioembolization with resin 90Y-microspheres: a prospective cohort study in patients with colorectal cancer liver metastases. J. Nucl. Med.: off Publ., Soc Nucl. Med. 2016;57:1014–1019. doi: 10.2967/jnumed.115.166942. PubMed DOI

Results from an EANM survey on time estimates and personnel responsible for main tasks in molecular radiotherapy dosimetry