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Biodistribution and radiation dose estimates for 68Ga-DOTA-JR11 in patients with metastatic neuroendocrine tumors

  • Simone KrebsEmail author
  • Neeta Pandit-Taskar
  • Diane Reidy
  • Bradley J. Beattie
  • Serge K. Lyashchenko
  • Jason S. Lewis
  • Lisa Bodei
  • Wolfgang A. Weber
  • Joseph A. O’Donoghue
Original Article

Abstract

Purpose

Somatostatin receptor antagonists have shown promise for imaging neuroendocrine tumors (NETs) in preclinical studies, but clinical data is still very limited. In this study, we assess the feasibility of using the novel somatostatin antagonist 68Ga-DOTA-JR11 for PET imaging of NETs.

Methods

Twenty patients with advanced NETs underwent whole-body PET/CT imaging 60 min after injection of 169 MBq (median) 68Ga-DOTA-JR11 as part of a prospective study. Volumes of interest were drawn around up to four 68Ga-DOTA-JR11-avid lesions per patient (with uptake greater than liver) and standardized uptake values were estimated. Additionally, target-to-normal tissue ratios were calculated. A subset of six patients had additional imaging (25-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney, and a whole-body PET/CT scan at 30 min post-injection) to determine the time course of tracer distribution and facilitate radiation dose estimates. Absorbed doses were calculated using OLINDA/EXM 1.0.

Results

In contrast to the known biodistribution of somatostatin receptor agonists, little or no uptake above background was seen in the pituitary gland, spleen, adrenals, and uninvolved liver; e.g., median spleen SUVmean 1.4 (range: 0.7–1.8), liver SUVmean 1.1 (0.7–1.9). A total of 42 tumor lesions were analyzed with median SUVmax 13.0 (range: 2.9–94), TNR blood 9.3 (1.8–87), TNR spleen 4.9 (1.9–48), TNR kidney 2.2 (0.52–28), and TNR liver 10.5 (2.3–107). Tumor uptake reached plateau levels by 20-30 min post-injection. The highest absorbed dose estimates (mGy/MBq) to normal tissues were: urinary bladder wall (0.30; SD 0.06) and kidneys (0.050; SD 0.013). The effective dose (ICRP 103) was 0.022 (SD 0.003) mSv/MBq.

Conclusions

68Ga-DOTA-JR11 demonstrated rapid tumor uptake, high tumor/background ratios, and rapid clearance from blood. The low liver background is advantageous and may facilitate detection of liver metastases. Dosimetric data compare favorably with published data for 68Ga-DOTATATE and 68Ga-DOTATOC.

Keywords

Somatostatin receptor antagonists JR11 PET/CT Neuroendocrine tumors 

Notes

Acknowledgements

This study was supported in part by the Geoffrey Beene Cancer Research Center at MSK and the MSK Radiochemistry and Molecular Imaging Probe Core, which is funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. We gratefully acknowledge funding by Caring for the Carcinoid/NETRF. SK was supported in part by the NIH/NCI Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746. The precursor used in this study was provided by Ipsen.

We gratefully acknowledge Rashid Ghani and members of the Nuclear Medicine Pharmacy; nuclear medicine nurses Ann Longing and Louise Harris for their help in patient management; RSAs Alicia Lashley, Hanh Pham, and Martha Ziolkowska and Clinical Research Manager Bolorsukh Gansukh for their excellent support with patient flow and protocol management; the radiation safety officers and nuclear medicine technologists for their excellent technical assistance; and members of the Department of Medicine at MSK for patient referral. We also thank Leah Bassity for her assistance in editing this manuscript.

Funding

This study was supported in part by the Geoffrey Beene Cancer Research Center at MSK, and the MSK Radiochemistry and Molecular Imaging Probe Core was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. We gratefully acknowledge the funding by Caring for the Carcinoid/NETRF. SK was supported in part by NIH/NCI Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746. The precursor used in this study was provided by Ipsen.

Compliance with ethical standards

Conflict of interest

DR was a member of the Advisory Board for Ipsen, Novartis, Advanced Accelerator Applications (AAA), and Lexicon Pharmaceuticals and has received research funding from Ipsen and Novartis. LB acted as a consultant for Advanced Accelerator Applications (AAA) and Ipsen. WW has served as a consultant for Endocyte, Ipsen, and Piramal Imaging. JAD has served as a consultant to WILEX AG, Algeta ASA, and Janssen Pharmaceuticals, Inc. SK, NP, BJB, SKL, and JSL declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed written consent was obtained from all individual participants included in the study.

Supplementary material

259_2018_4193_MOESM1_ESM.pdf (31 kb)
ESM 1 (PDF 31 kb)
259_2018_4193_MOESM2_ESM.pdf (16 kb)
ESM 2 (PDF 15 kb)
259_2018_4193_MOESM3_ESM.pdf (18 kb)
ESM 3 (PDF 18 kb)

References

  1. 1.
    Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40:1–18 vii.CrossRefGoogle Scholar
  2. 2.
    Kaltsas GA, Mukherjee JJ, Grossman AB. The value of radiolabelled MIBG and octreotide in the diagnosis and management of neuroendocrine tumours. Ann Oncol. 2001;12(Suppl 2):S47–50.CrossRefGoogle Scholar
  3. 3.
    Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured human dosimetry of 68Ga-DOTATATE. J Nucl Med. 2013;54:855–60.CrossRefGoogle Scholar
  4. 4.
    Ginj M, Zhang H, Waser B, Cescato R, Wild D, Wang X, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103:16436–41.CrossRefGoogle Scholar
  5. 5.
    Cescato R, Waser B, Fani M, Reubi JC. Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. J Nucl Med. 2011;52:1886–90.CrossRefGoogle Scholar
  6. 6.
    Wild D, Fani M, Fischer R, Del Pozzo L, Kaul F, Krebs S, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med. 2014;55:1248–52.CrossRefGoogle Scholar
  7. 7.
    Fani M, Braun F, Waser B, Beetschen K, Cescato R, Erchegyi J, et al. Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications. J Nucl Med. 2012;53:1481–9.CrossRefGoogle Scholar
  8. 8.
    Nicolas GP, Beykan S, Bouterfa H, Kaufmann J, Bauman A, Lassmann M, et al. Safety, biodistribution, and radiation dosimetry of (68)Ga-OPS202 ((68)Ga-NODAGA-JR11) in patients with gastroenteropancreatic neuroendocrine tumors: a prospective phase I imaging study. J Nucl Med. 2017;59(6):909–14.CrossRefGoogle Scholar
  9. 9.
    Nicolas GP, Schreiter N, Kaul F, Uiters J, Bouterfa H, Kaufmann J, et al. Sensitivity comparison of (68)Ga-OPS202 and (68)Ga-DOTATOC PET/CT in patients with gastroenteropancreatic neuroendocrine tumors: a prospective phase II imaging study. J Nucl Med. 2018;59:915–21.CrossRefGoogle Scholar
  10. 10.
    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;36:1138–46.CrossRefGoogle Scholar
  11. 11.
    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;46:1023–7.Google Scholar
  12. 12.
    IRCP. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP. 2007;37:1–332.Google Scholar
  13. 13.
    Nicolas GP, Mansi R, McDougall L, Kaufmann J, Bouterfa H, Wild D, et al. Biodistribution, pharmacokinetics, and dosimetry of (177)Lu-, (90)Y-, and (111)in-labeled somatostatin receptor antagonist OPS201 in comparison to the agonist (177)Lu-DOTATATE: the mass effect. J Nucl Med. 2017;58:1435–41.CrossRefGoogle Scholar
  14. 14.
    Sandstrom M, Velikyan I, Garske-Roman U, Sorensen J, Eriksson B, Granberg D, et al. Comparative biodistribution and radiation dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in patients with neuroendocrine tumors. J Nucl Med. 2013;54:1755–9.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Simone Krebs
    • 1
    Email author
  • Neeta Pandit-Taskar
    • 1
    • 2
  • Diane Reidy
    • 2
    • 3
  • Bradley J. Beattie
    • 4
  • Serge K. Lyashchenko
    • 1
    • 2
    • 5
  • Jason S. Lewis
    • 1
    • 2
    • 5
  • Lisa Bodei
    • 1
    • 2
  • Wolfgang A. Weber
    • 1
    • 2
    • 6
  • Joseph A. O’Donoghue
    • 4
  1. 1.Department of RadiologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Department of RadiologyWeill Cornell Medical CollegeNew YorkUSA
  3. 3.Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  4. 4.Department of Medical PhysicsMemorial Sloan Kettering Cancer CenterNew YorkUSA
  5. 5.Radiochemistry and Molecular Imaging Probes CoreMemorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Department of Nuclear MedicineTechnical University of MunichMunichGermany

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