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Molecular Imaging and Therapy for Neuroendocrine Tumors

  • Hemant Desai
  • Salvador Borges-Neto
  • Terence Z. WongEmail author
Lower Gastrointestinal Cancers (AB Benson, Section Editor)
  • 109 Downloads
Part of the following topical collections:
  1. Topical Collection on Lower Gastrointestinal Cancers

Opinion statement

Neuroendocrine tumors (NETs) are relatively rare, with 12,000–15,000 new cases diagnosed annually in the USA. Although NETs are a diverse group of neoplasms, they share common molecular targets that can be exploited using nuclear medicine techniques for both imaging and therapy. NETs have traditionally been imaged with SPECT imaging using 111In-labeled octreotide analogs to detect neoplasms with somatostatin receptors. In addition, certain NETs (pheochromocytomas, paragangliomas, and neuroblastomas) are also effectively imaged using 123I- or 131I-labeled metaiodobenzylguanidine (MIBG), an analog of guanethidine. More recently, PET imaging with 68Ga-labeled somatostatin receptor (SSR) analogs allows neuroendocrine tumors to be imaged with much higher sensitivity. 68Ga-DOTATATE was approved as a PET tracer by the FDA in June 2016. In addition to imaging, both MIBG and DOTATATE can be labeled with therapeutic radionuclides to deliver targeted radiation selectively to macroscopic and microscopic tumor sites. The incorporation of the same molecular probe for imaging and therapy provides a radio-theranostic approach to identifying, targeting, and treating tumors. Over the years, several centers have experience treating NETs with high-dose 131I-MIBG. 177Lu-DOTATATE was approved by the FDA in 2018 for treatment of gastroenteropancreatic NETs and constitutes a major advancement in the treatment of these diseases. In this paper, we provide an overview of imaging and treating neuroendocrine tumors using MIBG and SSR probes. Although uncommon, neuroendocrine tumors have provided the largest experience for targeted radionuclide imaging and therapy (with the exception of radioiodine treatment for thyroid disease). In addition to benefitting patients with these rare tumors, the knowledge gained provides a blueprint for the development of future paired diagnostic/therapeutic probes for treating other diseases, such as prostate cancer.

Keywords

Somatostatin receptor PET/CT Peptide receptor radionuclide therapy (PRRT) DOTATATE MIBG Theranostic 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncology. 2017;3:1335–42.  https://doi.org/10.1001/jamaoncol.2017.0589.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Pandit-Taskar N, Modak S. Norepinephrine transporter as a target for imaging and therapy. J Nucl Med. 2017;58:39S–53S.  https://doi.org/10.2967/jnumed.116.186833.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Taïeb D, Timmers HJ, Hindié E, Guillet BA, Neumann HP, Walz MK, et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2012;39:1977–95.  https://doi.org/10.1007/s00259-012-2215-8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, et al. Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. J Nucl Med. 2016;57:708–14.  https://doi.org/10.2967/jnumed.115.163865.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wild D, Bomanji JB, Benkert P, Maecke H, Ell PJ, Reubi JC, et al. Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT within patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2013;54:364–72.  https://doi.org/10.2967/jnumed.112.111724.CrossRefPubMedGoogle Scholar
  6. 6.
    Waldmann CM, Stuparu AD, Dam RMV, Slavik R. The search for an alternative to [68Ga]Ga-DOTA-TATE in neuroendocrine tumor theranostics: current state of 18F-labeled somatostatin analog development. Theranostics. 2019;9:1336–47.  https://doi.org/10.7150/thno.31806.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ. High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. J Med Imaging Radiat Oncol. 2012;56:40–7.  https://doi.org/10.1111/j.1754-9485.2011.02327.x.CrossRefPubMedGoogle Scholar
  8. 8.
    Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134:315–29.  https://doi.org/10.7326/0003-4819-134-4-200102200-00016.CrossRefPubMedGoogle Scholar
  9. 9.
    Vöö S, Bucerius J, Mottaghy FM. I-131-MIBG therapies. Methods. 2011;55:238–45.  https://doi.org/10.1016/j.ymeth.2011.10.006.CrossRefPubMedGoogle Scholar
  10. 10.
    Kwekkeboom DJ, Herder WWD, Kam BL, Eijck CHV, Essen MV, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.  https://doi.org/10.1200/jco.2007.15.2553.CrossRefPubMedGoogle Scholar
  11. 11.
    Grünwald F, Ezziddin S. 131I-Metaiodobenzylguanidine therapy of neuroblastoma and other neuroendocrine tumors. Semin Nucl Med. 2010;40:153–63.  https://doi.org/10.1053/j.semnuclmed.2009.11.004.CrossRefPubMedGoogle Scholar
  12. 12.
    • Pryma DA, Chin BB, Noto RB, et al. Efficacy and safety of high-specific-activity I-131 MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. J Nucl Med. 2018.  https://doi.org/10.2967/jnumed.118.217463 Study outlining the improved response rates of pheochromocytoma and paragangliomas to higher doses of 131I-MIBG.CrossRefGoogle Scholar
  13. 13.
    Noto RB, Pryma DA, Jensen J, Lin T, Stambler N, Strack T, et al. Phase 1 study of high-specific-activity I-131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2017;103:213–20.  https://doi.org/10.1210/jc.2017-02030.CrossRefGoogle Scholar
  14. 14.
    Kotecka-Blicharz A, Hasse-Lazar K, Handkiewicz-Junak D, Gawlik T. 131-I MIBG therapy of malignant pheochromocytoma and paraganglioma tumours - a single-centre study. Endokrynologia Pol. 2018;69:246–51.  https://doi.org/10.5603/EP.a2018.0024. CrossRefGoogle Scholar
  15. 15.
    Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol. 2009;27:4162–8.  https://doi.org/10.1200/JCO.2008.21.3496.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J, et al. Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with 131I-meta-iodobenzylguanidine (131I-mIBG). Clin Endocrinol. 2001;55:47–60.CrossRefGoogle Scholar
  17. 17.
    Kane A, Thorpe MP, Morse MA, Howard BA, Oldan JD, Zhu J, et al. Predictors of survival in 211 patients with stage IV pulmonary and Gastroenteropancreatic MIBG-positive neuroendocrine tumors treated with 131I-MIBG. J Nucl Med. 2018;59:1708–13.  https://doi.org/10.2967/jnumed.117.202150.CrossRefPubMedGoogle Scholar
  18. 18.
    Navalkissoor S, Alhashimi DM, Quigley A-M, Caplin ME, Buscombe JR. Efficacy of using a standard activity of 131I-MIBG therapy in patients with disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2010;37:904–91.  https://doi.org/10.1007/s00259-009-1326-3.CrossRefPubMedGoogle Scholar
  19. 19.
    Bomanji J, Wong W, Gaze MN, Cassoni A, Waddington W, Solano J, et al. Treatment of neuroendocrine tumours in adults with 131I-MIBG therapy. Clin Oncol. 2003;15:193–8.CrossRefGoogle Scholar
  20. 20.
    Ezziddin S, Sabet A, Logvinski T, Alkawaldeh K, Yong-Hing CJ, Ahmadzadehfar H, et al. Long-term outcome and toxicity after dose-intensified treatment with 131I-MIBG for advanced metastatic carcinoid tumors. J Nucl Med. 2013;54:2032–8.  https://doi.org/10.2967/jnumed.112.119313.CrossRefPubMedGoogle Scholar
  21. 21.
    Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, et al. One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98:4006–12.  https://doi.org/10.1210/jc.2013-1907.CrossRefPubMedGoogle Scholar
  22. 22.
    Pastor ER, Mousa SA. Current management of neuroblastoma and future direction. Crit Rev Oncol Hematol. 2019;138:38–43.  https://doi.org/10.1016/j.critrevonc.2019.03.013.CrossRefPubMedGoogle Scholar
  23. 23.
    Matthay KK, George RE, Yu A. Promising therapeutic targets in neuroblastoma. Clin Cancer Res. 2012;18:2740–53.  https://doi.org/10.1158/1078-0432.CCR-11-1939.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Johnson K, McGlynn B, Saggio J, Baniewicz D, Zhuang H, Maris JM, et al. Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. 2011;57:1124–9.  https://doi.org/10.1002/pbc.23062.CrossRefGoogle Scholar
  25. 25.
    Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, et al. Phase II study on the effect of disease sites, age, and prior therapy on response to Iodine-131-Metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007;25:1054–60.  https://doi.org/10.1200/JCO.2006.09.3484.CrossRefPubMedGoogle Scholar
  26. 26.
    Maqsood MH, Din ATU, Khan AH. Neuroendocrine tumor therapy with lutetium-177: a literature review. Cureus. 2019.  https://doi.org/10.7759/cureus.3986.
  27. 27.
    Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, et al. Erratum to: the joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;41:584.  https://doi.org/10.1007/s00259-013-2454-3.CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Bergsma H, Lom KV, Raaijmakers MH, Konijnenberg M, Kam BBL, Teunissen JJ, et al. Persistent hematologic dysfunction after peptide receptor radionuclide therapy with177Lu-DOTATATE: incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2017;59:452–8.  https://doi.org/10.2967/jnumed.117.189712.CrossRefPubMedGoogle Scholar
  29. 29.
    • Nastos K, Cheung VT, Toumpanakis C, Navalkissoor S, Quigley A-M, Caplin M, et al. Peptide receptor radionuclide treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas. J Surg Oncol. 2017;115:425–34.  https://doi.org/10.1002/jso.24553 Study comparing the effectiveness of 131I-MIBG and PRRT for pheochromocytomas and paragangliomas.CrossRefGoogle Scholar
  30. 30.
    Brabander T, Zwan WAVD, Teunissen JJ, Kam BL, Feelders RA, Herder WWD, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23:4617–24.  https://doi.org/10.1158/1078-0432.CCR-16-2743.CrossRefPubMedGoogle Scholar
  31. 31.
    •• Strosberg J, El-Haddad G, Wolin E, Hendifar A, Et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. The New England Journal of Medicine 2017:376:125–135. DOI:  https://doi.org/10.1056/NEJMoa1607427. Large clinical trial demonstrating the effectiveness of 177Lu-DOTATATE for midgut neuroendocrine tumors.CrossRefGoogle Scholar
  32. 32.
    Zhang J, Kulkarni HR, Singh A, Niepsch K, Müller D, Baum RP. Peptide receptor radionuclide therapy in grade 3 neuroendocrine neoplasms: safety and survival analysis in 69 patients. J Nucl Med. 2018;60:377–85.  https://doi.org/10.2967/jnumed.118.215848.CrossRefPubMedGoogle Scholar
  33. 33.
    Pinato DJ, Black JRM, Ramaswami R, Tan TM, Adjogatse D, Sharma R. Peptide receptor radionuclide therapy for metastatic paragangliomas. Med Oncol. 2016;33:47.  https://doi.org/10.1007/s12032-016-0737-9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hemant Desai
    • 1
  • Salvador Borges-Neto
    • 2
  • Terence Z. Wong
    • 3
    Email author
  1. 1.Department of RadiologyDuke University Medical CenterDurhamUSA
  2. 2.Division of Nuclear Medicine, Department of RadiologyDuke University Medical CenterDurhamUSA
  3. 3.Division of Nuclear Medicine, Department of Radiology, Duke Cancer InstituteDuke University Medical CenterDurhamUSA

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