First in-human radiation dosimetry of the gastrin-releasing peptide (GRP) receptor antagonist 68Ga-NODAGA-MJ9

Silvano Gnesin, Francesco Cicone, Periklis Mitsakis, Axel Van der Gucht, Sébastien Baechler, Raymond Miralbell, Valentina Garibotto, Thomas Zilli, John O Prior, Silvano Gnesin, Francesco Cicone, Periklis Mitsakis, Axel Van der Gucht, Sébastien Baechler, Raymond Miralbell, Valentina Garibotto, Thomas Zilli, John O Prior

Abstract

Background: Gastrin-releasing peptide receptor antagonists have promise in theranostics of several highly incident tumours, including prostate and breast. This study presents the first human dosimetry of 68Ga-NODAGA-MJ9 in the first five consecutive patients with recurrent prostate cancer included in a dual-tracer positron emission tomography (PET) protocol. Five male patients with biochemical relapse of prostate adenocarcinoma underwent four whole-body time-of-flight PET/CT scans within 2 h after tracer injection. To be used as input in OLINDA/EXM 2.0, time-integrated activity coefficients were derived from manually drawn regions of interest over the following body regions: brain, thyroid, lungs, heart, liver, gallbladder, spleen, stomach, kidneys, adrenals, red marrow, pancreas, intestines, urinary bladder and whole body. Organ absorbed doses and effective dose (ED) were calculated with OLINDA/EXM 2.0 using the NURBS voxelized phantoms adjusted to the ICRP-89 organ masses and ICRP103 tissue-weighting factors. Additional absorbed dose estimations were performed with OLINDA/EXM 1.1 to be comparable with similar previous publications.

Results: The body regions receiving the highest absorbed doses were the pancreas, the urinary bladder wall, the small intestine and the kidneys (260, 69.8, 38.8 and 34.8 μGy/MBq respectively). The ED considering a 30-min urinary voiding cycle was 17.6 μSv/MBq in male patients. The increment of voiding time interval produced a significant increase of absorbed doses in bladder, prostate and testes, as well as an increase of ED. ED also increased if calculated with OLINDA/EXM 1.1. These results have been discussed in view of similar publications on bombesin analogues or on other commonly used theranostic peptides.

Conclusions: The pancreas is the most irradiated organ after the injection of 68Ga-NODAGA-MJ9, followed by the urinary bladder wall, the small intestine and the kidneys. ED is in the same range of other common 68Ga-labelled peptides. Differences with similarly published studies on bombesin analogues exist, and are mainly dependent on the methodology used for absorbed dose calculations.

Trial registration: Clinicaltrial.Gov identifier: NCT02111954 , posted on 11/042014.

Keywords: 68Ga-NODAGA-MJ9; Biochemical relapse; Bombesin; Dosimetry; GRP antagonist; Gastrin-releasing peptide receptor; OLINDA/EXM; PET/CT; Prostate cancer; Theranostics.

Conflict of interest statement

Ethics approval and consent to participate

All procedures performed in the study were in accordance with the standards of the institutional ethical committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

The study was authorised by the Ethical Committee of Canton Vaud, Swissmedic and the Federal Office of Public Health (FOPH) (clinicaltrial.gov identifier NCT02111954, start date: April 2014).

Informed consent for the dosimetric procedures and for publication of the results was obtained from all individual participants included in the study. This article does not contain any studies with animals performed by any of the authors.

Consent for publication

All patients gave written informed consent for publication of their individual data, if adequately anonymised.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Maximum intensity projections acquired 10, 45, 70 and 100 min after 68Ga-NODAGA-MJ9 injection (a–d, respectively) in a 56-year-old patient with biochemical relapse of prostate cancer (patient #5). The typical 68Ga-NODAGA-MJ9 biodistribution is observed, including visualisation of the urinary system, as well as fast and prominent uptake by the pancreas and the biliary tract
Fig. 2
Fig. 2
68Ga-NODAGA-MJ9 normalised time-activity curves for most relevant abdominal organs. The organ activity was normalised to the patient administered activity. Coloured squares indicate patient-related data points. Blue dots indicate the normalised activity (mean ± SD) obtained at each time point. The coefficient of determination (R2) of the mono-exponential fit (except for the gallbladder, see methods) is reported for each organ. Due to previous surgery, gallbladder and pancreatic normalised time-activity curves were available for two and four patients only, respectively
Fig. 3
Fig. 3
Biological organ kinetic of 68Ga-NODAGA-MJ9 corrected for 68Ga physical decay. Colour bars represent the average percent of injected activity per gram of tissue (%IA/g) ± 1SD, for each time point
Fig. 4
Fig. 4
Dosimetry comparison between our study and those of Roivainen et al. [30] and Zhang et al. [34] based on OLINDA/EXM 1.0. The absorbed dose estimations reported in this figure are based on either a 3.5-h urinary voiding cycle (our study and that of Roivainen et al. [30]) or on a 1-h voiding cycle (Zhang et al. [34]). It should be noted that, for the organs reported, variations of urinary voiding cycle do not produce significant changes of absorbed dose estimations. Error bars represent ± 2SD

References

    1. Bevins CL, Zasloff M. Peptides from frog skin. Annu Rev Biochem. 1990;59:395–414. doi: 10.1146/annurev.bi.59.070190.002143.
    1. Erspamer V, Melchiorri P, Broccardo M, Erspamer GF, Falaschi P, Improota G, et al. The brain-gut-skin triangle: new peptides. Peptides. 1981;2(Suppl 2):7–16. doi: 10.1016/0196-9781(81)90003-6.
    1. Anastasi A, Erspamer V, Bucci M. Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia. 1971;27(2):166–167. doi: 10.1007/BF02145873.
    1. McDonald TJ, Jornvall H, Nilsson G, Vagne M, Ghatei M, Bloom SR, et al. Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun. 1979;90(1):227–233. doi: 10.1016/0006-291X(79)91614-0.
    1. 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. doi: 10.1124/pr.107.07108.
    1. Cuttitta F, Carney DN, Mulshine J, Moody TW, Fedorko J, Fischler A, et al. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature. 1985;316(6031):823–826. doi: 10.1038/316823a0.
    1. Bologna M, Festuccia C, Muzi P, Biordi L, Ciomei M. Bombesin stimulates growth of human prostatic cancer cells in vitro. Cancer. 1989;63(9):1714–1720. doi: 10.1002/1097-0142(19900501)63:9<1714::AID-CNCR2820630912>;2-H.
    1. Ramos-Alvarez I, Moreno P, Mantey SA, Nakamura T, Nuche-Berenguer B, Moody TW, et al. Insights into bombesin receptors and ligands: highlighting recent advances. Peptides. 2015;72:128–144. doi: 10.1016/j.peptides.2015.04.026.
    1. Moreno P, Ramos-Alvarez I, Moody TW, Jensen RT. Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin Ther Targets. 2016;20(9):1055–1073. doi: 10.1517/14728222.2016.1164694.
    1. Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res. 1999;59(5):1152–1159.
    1. Van de Wiele C, Dumont F, Vanden Broecke R, Oosterlinck W, Cocquyt V, Serreyn R, et al. Technetium-99m RP527, a GRP analogue for visualisation of GRP receptor-expressing malignancies: a feasibility study. Eur J Nucl Med. 2000;27(11):1694–1699. doi: 10.1007/s002590000355.
    1. Scopinaro F, De Vincentis G, Varvarigou AD, Laurenti C, Iori F, Remediani S, et al. 99mTc-bombesin detects prostate cancer and invasion of pelvic lymph nodes. Eur J Nucl Med Mol Imaging. 2003;30(10):1378–1382. doi: 10.1007/s00259-003-1261-7.
    1. Cescato R, Maina T, Nock B, Nikolopoulou A, Charalambidis D, Piccand V, et al. Bombesin receptor antagonists may be preferable to agonists for tumor targeting. J Nucl Med. 2008;49(2):318–326. doi: 10.2967/jnumed.107.045054.
    1. Mansi R, Minamimoto R, Macke H, Iagaru AH. Bombesin-targeted PET of prostate cancer. J Nucl Med. 2016;57(Suppl 3):67S–72S. doi: 10.2967/jnumed.115.170977.
    1. Iagaru A. Will GRPR compete with PSMA as a target in prostate cancer? J Nucl Med. 2017;58(12):1883–1884. doi: 10.2967/jnumed.117.198192.
    1. Gourni E, Mansi R, Jamous M, Waser B, Smerling C, Burian A, et al. N-terminal modifications improve the receptor affinity and pharmacokinetics of radiolabeled peptidic gastrin-releasing peptide receptor antagonists: examples of 68Ga- and 64Cu-labeled peptides for PET imaging. J Nucl Med. 2014;55(10):1719–1725. doi: 10.2967/jnumed.114.141242.
    1. Icrp. Radiation dose to patients from radiopharmaceuticals. Addendum 4 to ICRP Publication 53. ICRP Publication 106 Approved by the Commission in October 2007. Ann ICRP. 2008;38(1–2):1–197.
    1. Roach M, 3rd, Hanks G, Thames H, Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys. 2006;65(4):965–974. doi: 10.1016/j.ijrobp.2006.04.029.
    1. Bettinardi V, Presotto L, Rapisarda E, Picchio M, Gianolli L, Gilardi MC. Physical performance of the new hybrid PETCT Discovery-690. Med Phys. 2011;38(10):5394–5411. doi: 10.1118/1.3635220.
    1. Gnesin S, Mitsakis P, Cicone F, Deshayes E, Dunet V, Gallino AF, et al. First in-human radiation dosimetry of (68)Ga-NODAGA-RGDyK. EJNMMI Res. 2017;7(1):43. doi: 10.1186/s13550-017-0288-x.
    1. Basic anatomical and physiological data for use in radiological protection reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP. 2002;32(3–4):5–265.
    1. Stabin MG, Siegel JA. RADAR dose estimate report: a compendium of radiopharmaceutical dose estimates based on OLINDA/EXM version 2.0. J Nucl Med. 2018;59(1):154–160. doi: 10.2967/jnumed.117.196261.
    1. Segars JP. University of North Carolina. 2001. Development and application of the new dynamic NURBS-based cardiac-torso (NCAT) phantom [dissertation]
    1. The 2007 Recommendations of the International Commission on Radiological Protection ICRP publication 103. Ann ICRP. 2007;37(2–4):1–332.
    1. Scopinaro F, Varvarigou AD, Ussof W, De Vincentis G, Sourlingas TG, Evangelatos GP, et al. Technetium labeled bombesin-like peptide: preliminary report on breast cancer uptake in patients. Cancer Biother Radiopharm. 2002;17(3):327–335. doi: 10.1089/10849780260179297.
    1. Shariati F, Aryana K, Fattahi A, Forghani MN, Azarian A, Zakavi SR, et al. Diagnostic value of 99mTc-bombesin scintigraphy for differentiation of malignant from benign breast lesions. Nucl Med Commun. 2014;35(6):620–625. doi: 10.1097/MNM.0000000000000112.
    1. Morgat C, MacGrogan G, Brouste V, Velasco V, Sevenet N, Bonnefoi H, et al. Expression of gastrin-releasing peptide receptor in breast cancer and its association with pathologic, biologic, and clinical parameters: a study of 1,432 primary tumors. J Nucl Med. 2017;58(9):1401–1407. doi: 10.2967/jnumed.116.188011.
    1. Van de Wiele C, Dumont F, Dierckx RA, Peers SH, Thornback JR, Slegers G, et al. Biodistribution and dosimetry of (99m)Tc-RP527, a gastrin-releasing peptide (GRP) agonist for the visualization of GRP receptor-expressing malignancies. J Nucl Med. 2001;42(11):1722–1727.
    1. Santos-Cuevas CL, Ferro-Flores G, Arteaga de Murphy C, Pichardo-Romero PA. Targeted imaging of gastrin-releasing peptide receptors with 99mTc-EDDA/HYNIC-[Lys3]-bombesin: biokinetics and dosimetry in women. Nucl Med Commun. 2008;29(8):741–747. doi: 10.1097/MNM.0b013e3282ffb45c.
    1. 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):867–872. doi: 10.2967/jnumed.112.114082.
    1. Wieser G, Mansi R, Grosu AL, Schultze-Seemann W, Dumont-Walter RA, Meyer PT, et al. Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide receptor antagonist—from mice to men. Theranostics. 2014;4(4):412–419. doi: 10.7150/thno.7324.
    1. Sah BR, Burger IA, Schibli R, Friebe M, Dinkelborg L, Graham K, et al. Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer. J Nucl Med. 2015;56(3):372–378. doi: 10.2967/jnumed.114.147116.
    1. 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. doi: 10.2967/jnumed.115.165316.
    1. 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):922–928. doi: 10.2967/jnumed.117.198929.
    1. Cristy M, Eckerman KF. Specific absorbed fractions of energy at various ages from internal photon sources.: Oak Ridge National Lab., TN (USA) 1987.
    1. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46(6):1023–1027.
    1. Mitsakis P, Zilli T, Kosinski M, Delage J, Maecke H, Mansi R, et al. A direct comparison study of Ga-68-NODAGA-MJ9 (MJ9, Bombesin) to F-18-FCH (FCH) in recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42(1):S124.
    1. Kahkonen 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):5434–5443. doi: 10.1158/1078-0432.CCR-12-3490.
    1. Taieb D, Foletti JM, Bardies M, Rocchi P, Hicks RJ, Haberkorn U. PSMA-targeted radionuclide therapy and salivary gland toxicity: why does it matter? J Nucl Med. 2018;59(5):747–748. doi: 10.2967/jnumed.118.207993.
    1. 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):293–299. doi: 10.2967/jnumed.116.176636.
    1. Eom K, Chie EK, Kim K, Jang JJ, Kim SW, Oh DY, et al. Postoperative chemoradiotherapy following pancreaticoduodenectomy. Impact of dose-volumetric parameters on the development of diabetes mellitus. Strahlenther Onkol. 2013;189(9):753–758. doi: 10.1007/s00066-013-0405-3.
    1. Jingu K, Tanabe T, Nemoto K, Ariga H, Umezawa R, Ogawa Y, et al. Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. Int J Radiat Oncol Biol Phys. 2012;83(4):e507–e511. doi: 10.1016/j.ijrobp.2012.01.024.
    1. Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, et al. Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J Nucl Med. 2015;56(6):855–861. doi: 10.2967/jnumed.115.156133.
    1. Afshar-Oromieh A, Hetzheim H, Kratochwil C, Benesova M, Eder M, Neels OC, et al. The Theranostic PSMA ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first evaluation of tumor lesions. J Nucl Med. 2015;56(11):1697–1705. doi: 10.2967/jnumed.115.161299.
    1. Afshar-Oromieh A, Hetzheim H, Kubler W, Kratochwil C, Giesel FL, Hope TA, et al. Radiation dosimetry of (68)Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing. Eur J Nucl Med Mol Imaging. 2016;43(9):1611–1620. doi: 10.1007/s00259-016-3419-0.
    1. Pfob CH, Ziegler S, Graner FP, Kohner M, Schachoff S, Blechert B, et al. Biodistribution and radiation dosimetry of (68)Ga-PSMA HBED CC-a PSMA specific probe for PET imaging of prostate cancer. Eur J Nucl Med Mol Imaging. 2016;43(11):1962–1970. doi: 10.1007/s00259-016-3424-3.
    1. Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured human dosimetry of 68Ga-DOTATATE. J Nucl Med. 2013;54(6):855–860. doi: 10.2967/jnumed.112.114165.
    1. Josefsson A, Hobbs RF, Ranka S, Schwarz BC, Plyku D, de Carvalho JWA, et al. Comparative dosimetry for (68)Ga-DOTATATE: impact of using updated ICRP phantoms, S values and tissue weighting factors. J Nucl Med. 2018;59(8):1281-8.

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