Abstract
This dosimetry guideline has been prepared based on the guidelines of the European Association of Nuclear Medicine, aiming to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labeled with Lutetium-177 (Lu-177), particularly ligands for somatostatin receptors and small-molecule prostate specific membrane antigen (PSMA)-targeted ligands, are increasingly used for therapeutic applications in the treatment of metastatic neuroendocrine tumors and prostate adenocarcinoma. This guideline provides an overview of the reported dosimetry data for these therapies and summarizes the current knowledge on radiation-induced side effects in normal tissues and dose-response relationships in tumors. Dosimetry methods and data are summarized for the kidneys, bone marrow, salivary glands, lacrimal glands, pituitary gland and tumors.Where appropriate, guidance is provided considering the current state of the field and the latest evidence in the literature. The goal of these recommendations is to promote the implementation of patient-specific dosimetry in therapies involving Lu-177-labeled compounds. The proposed methods should fall within the scope of centers offering therapy with ligands for somatostatin receptors or small-molecule Lu-177 PSMA-targeted ligands.
Keywords: Lu-177 dosimetry, Lu-177 somatostatin receptor ligands, Lu-177 PSMA-targeted ligands, neuroendocrine tumors, prostate adenocarcinoma
References
Sjögreen Gleisner K, Chouin N, Gabina PM, et al. EANM dosimetry committee recommendations for dosimetry of Lu-177-labelled somatostatin-receptor- and PSMA-targeting ligands. Eur J Nucl Med Mol Imaging. 2022;49:1778-1809.
Kondev FG. Nuclear data sheets for A=177. Nuclear Data Sheets. 2019;159:147-149.
Berger MJH, Seltzer JH, Chang SM, et al. Photon cross section database (version 1.5). Available link: http://physics.nist.gov/xcom National Institute of Standards and Technology, Gaithersburg, MD; 2010.
de Jong M, Bakker WH, Krenning EP, et al. Yttrium-90 and indium-111 label- ling, receptor binding and biodistribution of [DOTA0, d-Phe1, Tyr3]octreotide, a promising somatostatin analogue for radionu- clide therapy. Eur J Nucl Med. 1997;24:368-371.
Kwekkeboom DJ, Bakker WH, Kooij PP, et al. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur J Nucl Med. 2001;28:1319-1325.
Bodei L, Mueller-Brand J, Baum RP, et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;40:800-816.
Carter R, Feldman A, Coyle J. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic char- acteristics of a neuropeptidase. Proc Natl Acad Sci U S A. 1996;93:749-753.
Chang SS, Gaudin PB, Reuter VE, O’Keefe DS, Bacich DJ, Hes- ton WD. Prostate-specific membrane antigen: much more than a prostate cancer marker. Mol Urol. 1999;3:313-320.
Grant CL, Caromile LA, Ho V, et al. Prostate specific membrane antigen (PSMA) regulates angiogenesis independently of VEGF during ocular neovascu- larization. PLoS One. 2012;7:e41285.
Yadav MP, Ballal S, Tripathi M, et al. (177)Lu-DKFZ-PSMA-617 therapy in metastatic castra- tion resistant prostate cancer: safety, efficacy, and quality of life assessment. Eur J Nucl Med Mol Imaging. 2017;44:81-91.
Garske-Roman U, Sandstrom M, Fross Baron K, et al. Prospective observational study of (177) Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity. Eur J Nucl Med Mol Imaging. 2018;45:970-988.
Lassmann M, Hanscheid H, Chiesa C, 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.
Reidy-Lagunes D, Pandit-Taskar N, O’Donoghue JA, et al. Phase I trial of well-differentiated neuroendocrine tumors (NETs) with radiolabeled somatostatin antagonist (177)Lu-satoreotide tetraxetan. Clin Cancer Res. 2019;25:6939-6947.
Vegt E, de Jong M, Wetzels JF, et al. Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. J Nucl Med. 2010;51:1049-1058.
Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109-122.
Lenain R, Hamroun A, Lion G, et al. Description of a transient proximal tubulopathy induced by amino acids perfusion in peptide receptor radionuclide therapy: a case report. Medicine (Baltimore). 2019;98:e18478.
Sundlöv A, Sjögreen-Gleisner K, Svensson J, et al. Individualised 177 Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. Eur J Nucl Med Mol Imaging. 2017;44:1480-1489.
Dawson LA, Kavanagh BD, Paulino AC, et al. Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S108-S115.
Bodei L, Cremonesi M, Grana C, et al. Receptor radionuclide therapy with 90Y-[DOTA]0- Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2004;31:1038-1046.
Barone R, Borson-Chazot F, Valkema R, et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship. J Nucl Med. 2005;46:99S-106S.
Brabander T, van der Zwan WA, Teunissen JJM, et al. Pitfalls in the response evaluation after peptide receptor radionuclide therapy with [(177)Lu-DOTA(0), Tyr(3)]octreotate. Endocr-Relat Cancer. 2017;24:243-251.
Pichard A, Marcatili S, Karam J, et al. The therapeutic effectiveness of (177)Lu- lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest. Leukemia. 2020;34:1315-1328.
Pan CC, Kavanagh BD, Dawson LA, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S94-S100.
Valstar MH, de Bakker BS, Steenbakkers R, et al. The tubarial salivary glands: a potential new organ at risk for radiotherapy. Radiother Oncol. 2021;154:292-298.
Deasy JO, Moiseenko V, Marks L, Chao KS, Nam J, Eisbruch A. Radiotherapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S58-S63.
Paganelli G, Sarnelli A, Severi S, et al. Dosimetry and safety of (177)Lu PSMA-617 along with polyglutamate parotid gland protector: preliminary results in metastatic castration-resistant prostate cancer patients. Eur J Nucl Med Mol Imaging. 2020;47:3008-3017.
Klein Nulent TJW, Valstar MH, de Keizer B, et al. Physiologic distribution of PSMA- ligand in salivary glands and seromucous glands of the head and neck on PET/CT. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125:478-486.
Kratochwil C, Bruchertseifer F, Rathke H, et al. Targeted alpha-therapy of metastatic castration-resistant prostate cancer with (225)Ac-PSMA-617: dosimetry estimate and empiric dose finding. J Nucl Med. 2017;58:1624-1631.
Lambrecht M, Eekers DBP, Alapetite C, et al. Radiation dose constraints for organs at risk in neuro-oncology; the European particle therapy network consensus. Radiother Oncol. 2018;128:26-36.
Pauwels S, Barone R, Walrand S, et al. Practical dosimetry of peptide receptor radionuclide therapy with (90)Y-labeled somatostatin analogs. J Nucl Med. 2005;46(Suppl 1):92S-98S.
Jahn U, Ilan E, Sandström M, Lubberink M, Garske-Roman U, Sundin A. Peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE; differences in tumor dosimetry, vascular- ity and lesion metrics in pancreatic and small intestinal neuroen- docrine neoplasms. Cancers (Basel). 2021;13:962.
Violet J, Jackson P, Ferdinandus J, et al. Dosimetry of (177)Lu-PSMA-617 in metastatic cas- tration-resistant prostate cancer: correlations between prethera- peutic imaging and whole-body tumor dosimetry with treatment outcomes. J Nucl Med. 2019;60:517-523.
Loevinger R, Berman M. A formalism for calculation of absorbed dose from radionuclides. Phys Med Biol. 1968;13:205-217.
Loevinger R, Budinger TF, Watson EE. MIRD primer for absorbed dose calculations. New York, NY: Society of Nuclear Medicine; 1991.
Bolch WE, Eckerman KF, Sgouros G, Thomas SR. MIRD pamphlet No. 21: a generalized schema for radiopharmaceutical dosimetry--standardization of nomenclature. J Nucl Med. 2009;50:477-484.
Saldarriaga Vargas C, Bauwens M, Pooters INA, et al. An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theragnostics. EJNMMI Phys. 2020;7:69.
Garkavij M, Nickel M, Sjogreen-Gleisner K, et al. 177Lu-[DOTA0, Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer. 2010;116(4 Suppl):1084-1092.
Dewaraja YK, Frey EC, Sgouros G, et al. MIRD pamphlet no. 23: quantitative SPECT for patient-specifc 3-dimensional dosimetry in internal radionuclide therapy. J Nucl Med. 2012;53:1310-1325.
Ljungberg M, Celler A, Konijnenberg MW, Eckerman KF, Dewaraja YK, Sjogreen-Gleisner K. MIRD pamphlet no. 26: joint EANM/MIRD guidelines for quantitative Lu-177 SPECT applied for dosimetry of radiopharmaceutical therapy. J Nucl Med. 2016;57:151-162.
Uribe CF, Esquinas PL, Gonzalez M, Zhao W, Tanguay J, Celler A. Deadtime efects in quantifcation of (177)Lu activity for radionuclide therapy. EJNMMI Phys. 2018;5:2.
Sundlöv A, Gustafsson J, Brolin G, et al. Feasibility of simplifying renal dosimetry in (177)Lu peptide receptor radionuclide therapy. EJNMMI Phys. 2018;5:19.
Finocchiaro D, Berenato S, Grassi E, et al. Partial volume effect of SPECT images in PRRT with 177Lu labelled somatostatin analogues: a practical solution. Phys Med. 2019;57:153-159.
Tran-Gia J, Lassmann M. Optimizing image quantification for (177)Lu SPECT/CT based on a 3D printed 2-compartment kidney phantom. J Nucl Med. 2018;59:616-624.
Wevrett J, Fenwick A, Scufham J, et al. Inter-comparison of quantitative imaging of lutetium-177 ((177)Lu) in European hospitals. EJNMMI Phys. 2018;5:17.
Siegel JA, Thomas SR, Stubbs JB, et al. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40:37S-61S.
Pacilio M, Cassano B, Chiesa C, et al. The Italian multicentre dosimetric study for lesion dosimetry in 223Ra therapy of bone metastases: calibration protocol of gamma cameras and patient eligibility criteria. Phys Med. 2016;32:1731-1737.
Larsson M, Bernhardt P, Svensson JB, Wangberg B, Ahlman H, Forssell-Aronsson E. Estimation of absorbed dose to the kidneys in patients after treatment with 177Lu-octreotate: comparison between methods based on planar scintigraphy. EJNMMI Res. 2012;2:49.
Buijs WC, Siegel JA, Boerman OC, Corstens FH. Absolute organ activity estimated by five diferent methods of background correction. J Nucl Med. 1998;39:2167-2172.
Koral KF, Zasadny KR, Kessler ML, et al. CT-SPECT fusion plus conjugate views for determining dosimetry in iodine-131-monoclonal antibody therapy of lymphoma patients. J Nucl Med. 1994;35:1714-1720.
Huizing DMV, de Wit-van der Veen BJ, Verheij M, Stokkel MPM. Dosimetry methods and clinical applications in peptide receptor radionuclide therapy for neuroendocrine tumours: a literatüre review. EJNMMI Res. 2018;8:89.
Gear JI, Cox MG, Gustafsson J, et al. EANM practical guidance on uncertainty analysis for molecular radiotherapy absorbed dose calculations. Eur J Nucl Med Mol Imaging. 2018;45:2456-2474.
Bentzen SM, Dorr W, Gahbauer R, et al. Bioeffect modeling and equieffective dose concepts in radiation oncology–terminology, quantities and units. Radiother Oncol. 2012;105:266-268.
Fowler JF. The linear-quadratic formula and progress in fraction- ated radiotherapy. Br J Radiol. 1989;62:679-694.
Wessels BW, Konijnenberg MW, Dale RG, et al. MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy. J Nucl Med. 2008;49:1884-1899.
Minguez P, Gustafsson J, Flux G, Gleisner KS. Biologically effective dose in fractionated molecular radiotherapy-applica- tion to treatment of neuroblastoma with (131)I-mIBG. Phys Med Biol. 2016;61:2532-2551.
Gustafsson J, Nilsson P, Gleisner KS. On the biologically effective dose (BED)-using convolution for calculating the effects of repair: II. Numerical considerations. Phys Med Biol. 2013;58:1529-1548.
Cremonesi M, Ferrari ME, Bodei L, et al. Correlation of dose with toxicity and tumour response to (90)Y- and (177)Lu-PRRT provides the basis for optimization through individualized treatment planning. Eur J Nucl Med Mol Imaging. 2018;45:2426-2441.
Marin G, Vanderlinden B, Karfis I, et al. A dosimetry procedure for organs-at-risk in (177)Lu peptide receptor radionuclide therapy of patients with neuroendocrine tumours. Phys Med. 2018;56:41-49.
Kratochwil C, Fendler WP, Eiber M, et al. EANM procedure guidelines for radionuclide therapy with (177)Lu-labelled PSMA-ligands ((177)Lu-PSMARLT). Eur J Nucl Med Mol Imaging. 2019;46:2536-2544.
Bergsma H, Konijnenberg MW, Kam BL, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2016;43:453-463.
Denoyer D, Lobachevsky P, Jackson P, Thompson M, Martin OA, Hicks RJ. Analysis of 177Lu-DOTA-octreotate therapy-induced DNA damage in peripheral blood lymphocytes of patients with neuroendocrine tumors. J Nucl Med. 2015;56:505-511.
Sandström M, Garske-Roman U, Granberg D, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54:33-41.
Wehrmann C, Senftleben S, Zachert C, Muller D, Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTANOC. Cancer Biother Radiopharm. 2007;22:406-416.
Forrer F, Krenning EP, Kooij PP, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0), Tyr(3)]octreotate. Eur J Nucl Med Mol Imaging. 2009;36:1138-1146.
Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with (1)(7)(7)Lu- DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125-2135.
Delker A, Fendler WP, Kratochwil C, et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2016;43:42-51.
Kabasakal L, Toklu T, Yeyin N, et al. Lu-177-PSMA-617 prostate-specific membrane antigen inhibitor therapy in patients with castration-resistant prostate cancer: stability, bio-distribution and dosimetry. Mol Imaging Radionucl Ther. 2017;26:62-68.
Okamoto S, Thieme A, Allmann J, et al. Radiation dosimetry for (177)Lu-PSMA I&T in metastatic castration-resistant prostate cancer: absorbed dose in normal organs and tumor lesions. J Nucl Med. 2017;58:445-450.
Sarnelli A, Belli ML, Di Iorio V, et al. Dosimetry of 177Lu-PSMA-617 after mannitol infusion and glutamate tablet administration: preliminary results of EUDRACT/RSO 2016-002732-32 IRST Protocol. Molecules. 2019;24:621.
Gosewisch A, Ilhan H, Tattenberg S, et al. 3D Monte Carlo bone marrow dosimetry for Lu-177-PSMA therapy with guidance of non-invasive 3D localization of active bone marrow via Tc-99m-anti-granulocyte antibody SPECT/CT. EJNMMI Res. 2019;9:76.
Scarpa L, Buxbaum S, Kendler D, et al. The 68 Ga/177 Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUV max values and absorbed dose estimates. Eur J Nucl Med Mol Imaging. 2017;44:788-800.
Sundlöv A, Sjögreen-Gleisner K, Tennvall J, et al. Pituitary function after high-dose 177Lu- DOTATATE therapy and long-term follow-up. Neuroendocrinology. 2021;111:344-353.
Del Prete M, Buteau FA, Arsenault F, et al. Personalized (177)Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial. Eur J Nucl Med Mol Imaging. 2019;46:728-742.
Ilan E, Sandstrom M, Wassberg C, et al. Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE. J Nucl Med. 2015;56:177-182.
Jackson PA, Beauregard JM, Hofman MS, Kron T, Hogg A, Hicks RJ. An automated voxelized dosimetry tool for radionuclide therapy based on serial quantitative SPECT/CT imaging. Med Phys. 2013;40:112503.
Kupitz D, Wetz C, Wissel H, et al. Software-assisted dosimetry in peptide receptor radionuclide therapy with 177Lutetium-DOTATATE for various imaging scenarios. PLoS One. 2017;12:e0187570.
Baum RP, Kulkarni HR, Schuchardt C, et al. 177Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. J Nucl Med. 2016;57:1006-1013.
