First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer

  • Jens KurthEmail author
  • Bernd Joachim Krause
  • Sarah M. Schwarzenböck
  • Carina Bergner
  • Oliver W. Hakenberg
  • Martin Heuschkel
Original Article
Part of the following topical collections:
  1. Oncology – Genitourinary



Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [177Lu]Lu-PSMA-617 therapy.


Thirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [68Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68 years) were treated with [177Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9 GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72 h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline.


Therapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1 h. Mean absorbed organ doses were 1.08 ± 0.44 Gy/GBq in the pancreas, 0.35 ± 0.14 Gy/GBq in the kidneys, 0.05 ± 0.02 Gy/GBq in the liver, 0.07 ± 0.02 Gy/GBq in the gallbladder wall, 0.10 ± 0.06 Gy/GBq in the spleen, and 0.02 ± 0.01 Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00 Gy/GBq.


Application of GRPr antagonist [177Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.


177Lu-RM2 Dosimetry Prostate cancer Dosimetry Radionuclide therapy Theranostics Gastrin-releasing peptide receptor 



The authors are grateful to the radiopharmacy group for the production of [177Lu]Lu-RM-2 and the excellent technical support by the technicians.

Authors’ contributions

All authors made substantial contributions to the conception of the study, analysis of the data, and/or interpretation of the results. J.K., B.J.K., and M.H. drafted the manuscript, and all other authors revised it critically. The final manuscript has been read and approved by all authors.

Funding information

The establishment of synthesis and quality control for in-house production of [177Lu]Lu-RM2 was supported by Life Molecular Imaging GmbH (LMI; formerly Piramal Imaging). The precursor RM2-TFA was provided by LMI.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The need for a formal review of this retrospective study was waived by the Ethical Committee of the University of Rostock (file no. A 2018-0240).

Informed consent

Written informed consent to undergo therapy with subsequent follow-up was obtained from all patients included in the study.

Supplementary material

259_2019_4504_MOESM1_ESM.pdf (83 kb)
ESM 1 (PDF 82.5 kb)


  1. 1.
    Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71(4):630–42.PubMedCrossRefGoogle Scholar
  2. 2.
    Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 5.1, 2019, AWMF Registernummer: 043/022OL. Accessed 15.07. 2019.
  3. 3.
    Emmett L, Willowson K, Violet J, Shin J, Blanksby A, Lee J. Lutetium (177) PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J Med Radiat Sci. 2017;64(1):52–60.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schafers M, Essler M, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58(1):85–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825–33.PubMedCrossRefGoogle Scholar
  6. 6. Identifier NCT03511664, Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer (VISION). Bethesda: National Library of Medicine (US). 2000. []. Accessed 01.03.2019.
  7. 7.
    Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res. 1999;59(5):1152–9.PubMedGoogle Scholar
  8. 8.
    Sun B, Halmos G, Schally AV, Wang X, Martinez M. Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers. Prostate. 2000;42(4):295–303.PubMedCrossRefGoogle Scholar
  9. 9.
    Mansi R, Wang X, Forrer F, Waser B, Cescato R, Graham K, et al. Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours. Eur J Nucl Med Mol Imaging. 2011;38(1):97–107.PubMedCrossRefGoogle Scholar
  10. 10.
    Kähkonen E, Jambor I, Kemppainen J, Lehtio K, Gronroos TJ, Kuisma A, et al. In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548. Clin Cancer Res. 2013;19(19):5434–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Minamimoto R, Hancock S, Schneider B, Chin FT, Jamali M, Loening A, et al. Pilot comparison of 68Ga-RM2 PET and 68Ga-PSMA-11 PET in patients with biochemically recurrent prostate cancer. J Nucl Med. 2016;57(4):557–62.PubMedCrossRefGoogle Scholar
  12. 12.
    Touijer KA, Michaud L, Alvarez HAV, Gopalan A, Kossatz S, Gonen M, et al. Prospective study of the radiolabeled GRPR antagonist BAY86-7548 for positron emission tomography/computed tomography imaging of newly diagnosed prostate cancer. Eur Urol Oncol. 2019;2(2):166–73.PubMedCrossRefGoogle Scholar
  13. 13.
    Minamimoto R, Sonni I, Hancock S, Vasanawala S, Loening A, Gambhir SS, et al. Prospective evaluation of (68)Ga-RM2 PET/MRI in patients with biochemical recurrence of prostate cancer and negative findings on conventional imaging. J Nucl Med. 2018;59(5):803–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Roivainen A, Kahkonen E, Luoto P, Borkowski S, Hofmann B, Jambor I, et al. Plasma pharmacokinetics, whole-body distribution, metabolism, and radiation dosimetry of 68Ga bombesin antagonist BAY 86-7548 in healthy men. J Nucl Med. 2013;54(6):867–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Gnesin S, Cicone F, Mitsakis P, Van der Gucht A, Baechler S, Miralbell R, et al. First in-human radiation dosimetry of the gastrin-releasing peptide (GRP) receptor antagonist (68)Ga-NODAGA-MJ9. EJNMMI Res. 2018;8(1):108.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Zhang J, Li D, Lang L, Zhu Z, Wang L, Wu P, et al. 68Ga-NOTA-aca-BBN(7-14) PET/CT in healthy volunteers and glioma patients. J Nucl Med. 2016;57(1):9–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang J, Niu G, Fan X, Lang L, Hou G, Chen L, et al. PET using a GRPR antagonist (68)Ga-RM26 in healthy volunteers and prostate cancer patients. J Nucl Med. 2018;59(6):922–8.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mansi R, Fleischmann A, Macke HR, Reubi JC. Targeting GRPR in urological cancers--from basic research to clinical application. Nat Rev Urol. 2013;10(4):235–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Dalm SU, Bakker IL, de Blois E, Doeswijk GN, Konijnenberg MW, Orlandi F, et al. 68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology. J Nucl Med. 2017;58(2):293–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev. 2008;60(1):1–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Sandstrom M, Garske-Roman U, Granberg D, Johansson S, Widstrom C, Eriksson B, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54(1):33–41.PubMedCrossRefGoogle Scholar
  22. 22.
    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 DOTA-NOC. Cancer Biother Radiopharm. 2007;22(3):406–16.PubMedCrossRefGoogle Scholar
  23. 23.
    Wild D, Schmitt JS, Ginj M, Macke HR, Bernard BF, Krenning E, et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur J Nucl Med Mol Imaging. 2003;30(10):1338–47.PubMedCrossRefGoogle Scholar
  24. 24.
    Benesova M, Schafer M, Bauder-Wust U, Afshar-Oromieh A, Kratochwil C, Mier W, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med. 2015;56(6):914–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Delker A, Fendler WP, Kratochwil C, Brunegraf A, Gosewisch A, Gildehaus FJ, 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(1):42–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Kabasakal L, AbuQbeitah M, Aygun A, Yeyin N, Ocak M, Demirci E, et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42(13):1976–83.PubMedCrossRefGoogle Scholar
  27. 27.
    World Medical Association (WMA) Declaration of Helsinki – Ethical Principles For Medical Research Involving Human Subjects. Accessed 03.03. 2019.
  28. 28.
    Macey DJ, Grant EJ, Bayouth JE, Giap HB, Danna SJ, Sirisriro R, et al. Improved conjugate view quantitation of I-131 by subtraction of scatter and septal penetration events with a triple energy window method. Med Phys. 1995;22(10):1637–43.PubMedCrossRefGoogle Scholar
  29. 29.
    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 177Lu SPECT applied for dosimetry of radiopharmaceutical therapy. J Nucl Med. 2016;57(1):151–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Zanzonico P. Routine quality control of clinical nuclear medicine instrumentation: a brief review. J Nucl Med. 2008;49(7):1114–31.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Stabin MG. Fundamentals for nuclear medicine dosimetry. New York: Springer; 2008.Google Scholar
  32. 32.
    Kanzow C, Yamashita N, Fukushima T. Levenberg-Marquardt methods with strong local convergence properties for solving nonlinear equations with convex constraints. J Comput Appl Math. 2004;172(2):375–97.CrossRefGoogle Scholar
  33. 33.
    Lourakis M. levmar: Levenberg-Marquardt nonlinear least squares algorithms in C/C++. 2004. Accessed 22.03. 2019.
  34. 34.
    Stabin MG, Farmer A. OLINDA/EXM 2.0: The new generation dosimetry modeling code [abstract]. J Nucl Med. 2012;53(5):supplement 1 585.Google Scholar
  35. 35.
    Stabin MG, Xu XG, Emmons MA, Segars WP, Shi C, Fernald MJ. RADAR reference adult, pediatric, and pregnant female phantom series for internal and external dosimetry. J Nucl Med. 2012;53(11):1807–13.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Menzel HG, Clement C, DeLuca P. ICRP Publication 110. Realistic reference phantoms: an ICRP/ICRU joint effort. A report of adult reference computational phantoms. Ann ICRP. 2009;39(2):1–164.PubMedCrossRefGoogle Scholar
  37. 37.
    Stabin MG, Konijnenberg MW. Re-evaluation of absorbed fractions for photons and electrons in spheres of various sizes. J Nucl Med. 2000;41(1):149–60.PubMedGoogle Scholar
  38. 38.
    Kojima A, Takaki Y, Matsumoto M, Tomiguchi S, Hara M, Shimomura O, et al. A preliminary phantom study on a proposed model for quantification of renal planar scintigraphy. Med Phys. 1993;20(1):33–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, 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(2):37S–61S.PubMedGoogle Scholar
  40. 40.
    Hindorf C, Glatting G, Chiesa C, Linden O, Flux G. EANM Dosimetry Committee guidelines for bone marrow and whole-body dosimetry. Eur J Nucl Med Mol Imaging. 2010;37(6):1238–50.PubMedCrossRefGoogle Scholar
  41. 41.
    Traino AC, Ferrari M, Cremonesi M, Stabin MG. Influence of total-body mass on the scaling of S-factors for patient-specific, blood-based red-marrow dosimetry. Phys Med Biol. 2007;52(17):5231–48.PubMedCrossRefGoogle Scholar
  42. 42.
    Gosewisch A, Delker A, Tattenberg S, Ilhan H, Todica A, Brosch J, et al. Patient-specific image-based bone marrow dosimetry in Lu-177-[DOTA(0),Tyr(3)]-octreotate and Lu-177-DKFZ-PSMA-617 therapy: investigation of a new hybrid image approach. EJNMMI Res. 2018;8(1):76.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kurth J, Krause BJ, Schwarzenbock SM, Stegger L, Schafers M, Rahbar K. External radiation exposure, excretion, and effective half-life in (177)Lu-PSMA-targeted therapies. EJNMMI Res. 2018;8(1):32.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Bentzen SM, Constine LS, Deasy JO, Eisbruch A, Jackson A, Marks LB, et al. Quantitative Analyses of normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S3–9.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Bresciani S, Garibaldi E, Cattari G, Maggio A, Di Dia A, Delmastro E, et al. Dose to organs at risk in the upper abdomen in patients treated with extended fields by helical tomotherapy: a dosimetric and clinical preliminary study. Radiat Oncol. 2013;8:247.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Gemici C, Yaprak G, Ozdemir S, Baysal T, Seseogullari OO, Ozyurt H. Volumetric decrease of pancreas after abdominal irradiation, it is time to consider pancreas as an organ at risk for radiotherapy planning. Radiat Oncol. 2018;13(1):238.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Wydmanski J, Polanowski P, Tukiendorf A, Maslyk B. Radiation-induced injury of the exocrine pancreas after chemoradiotherapy for gastric cancer. Radiother Oncol. 2016;118(3):535–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Forrer F, Krenning EP, Kooij PP, Bernard BF, Konijnenberg M, Bakker WH, 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(7):1138–46.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–30.PubMedCrossRefGoogle Scholar
  51. 51.
    Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42(1):5–19.PubMedCrossRefGoogle Scholar
  52. 52.
    Coleman CN, Blakely WF, Fike JR, MacVittie TJ, Metting NF, Mitchell JB, et al. Molecular and cellular biology of moderate-dose (1–10 Gy) radiation and potential mechanisms of radiation protection: report of a workshop at Bethesda, Maryland, December 17–18, 2001. Radiat Res. 2003;159(6):812–34.PubMedCrossRefGoogle Scholar
  53. 53.
    Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo RK, Seth A, et al. Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. Nucl Med Commun. 2017;38(1):91–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Cremonesi M, Ferrari M, Bodei L, Tosi G, Paganelli G. Dosimetry in peptide radionuclide receptor therapy: a review. J Nucl Med. 2006;47(9):1467–75.PubMedGoogle Scholar
  55. 55.
    Barone R, Borson-Chazot F, Valkema R, Walrand S, Chauvin F, Gogou L, 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(Suppl 1):99S–106S.PubMedGoogle Scholar
  56. 56.
    Van Binnebeek S, Baete K, Vanbilloen B, Terwinghe C, Koole M, Mottaghy FM, et al. Individualized dosimetry-based activity reduction of (9)(0)Y-DOTATOC prevents severe and rapid kidney function deterioration from peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2014;41(6):1141–57.PubMedGoogle Scholar
  57. 57.
    Sundlov A, Sjogreen-Gleisner K, Svensson J, Ljungberg M, Olsson T, Bernhardt P, et al. Individualised (177)Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. Eur J Nucl Med Mol Imaging. 2017;44(9):1480–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Hohberg M, Eschner W, Schmidt M, Dietlein M, Kobe C, Fischer T, et al. Lacrimal glands may represent organs at risk for radionuclide therapy of prostate cancer with [(177)Lu]DKFZ-PSMA-617. Mol Imaging Biol. 2016;18(3):437–45.PubMedCrossRefGoogle Scholar
  59. 59.
    Fitschen J, Knoop BO, Behrendt R, Knapp WH, Geworski L. External radiation exposure and effective half-life in Lu-177-Dota-Tate therapy. Z Med Phys. 2011;21(4):266–73.PubMedCrossRefGoogle Scholar
  60. 60.
    Delker A, Ilhan H, Zach C, Brosch J, Gildehaus FJ, Lehner S, et al. The influence of early measurements onto the estimated kidney dose in [(177)Lu][DOTA(0),Tyr(3)]octreotate peptide receptor radiotherapy of neuroendocrine tumors. Mol Imaging Biol. 2015;17(5):726–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nuclear MedicineRostock University Medical CenterRostockGermany
  2. 2.Department of UrologyRostock University Medical CenterRostockGermany

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