Peptide Receptor Radiotherapy: Current Approaches and Future Directions
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Neuroendocrine neoplasia (NEN) represents a heterogenous group of tumours. Guidelines regarding treatment choice and sequencing remain complex given varied primary sites, hormone-secretory status, tumour grade, disease heterogeneity, and paucity of rigorous comparative trials due to rarity of this condition. However, there is increasing evidence that peptide receptor radionuclide therapy (PRRT) is an effective treatment, especially for grade 1 and 2 NEN. Primary indications for treatment include oncologic control in patients with progressive disease and symptomatic control in the context of hormone-secretory syndromes or tumour-related pain. However, strategies are needed to further optimize efficacy and outcomes, and to expand treatment indications. Important considerations could include personalized PRRT regimens based on better characterization of the disease in an individual patient. Future directions should also focus on strategies to further enhance the efficacy of PRRT including combination treatments with other systemic therapies, such as radiosensitising chemotherapy, DNA repair–modifying agents and immunotherapy. Further evolution of therapeutic radiopharmaceuticals also offers promise.
KeywordsNeuroendocrine neoplasia Tumour PRRT Peptide receptor Metastatic Somatostatin
Compliance with Ethical Standards
Conflict of Interest
Grace Kong declares that she has no conflict of interest.
Rodney J. Hicks was issued shares in Telix Pharmaceuticals at its IPO as a member of its scientific board. These shares are held on behalf of Dr. Hicks’ institution; therefore, he receives no financial benefit from this holding.
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
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- 1.•• Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology. 2017;105(3):295–309 Recent international ENETS guidelines providing comprehensive overview, evidence and approaches for the use of PRRT in patients with NEN.PubMedGoogle Scholar
- 3.•Leoncini E, Boffetta P, Shafir M, Aleksovska K, Boccia S, Rindi G. Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine. 2017;58(2):368–79.Large review showing increasing incidence of NEN worldwide involving most anatomical sites and grades. PubMedPubMedCentralGoogle Scholar
- 10.•• Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35 First prospective phase 2 study confirming efficacy of PRRT in patients with midgut NEN compared with high-dose SSA. Results from this pivitol study and from prior multiple institutions have led to approval of 177Lu-DOTA-octreotate (LuTathera) in USA and many countries in Europe.PubMedPubMedCentralGoogle Scholar
- 19.Goncalves I, Burbury K, Michael M, Iravani A, Ravi Kumar AS, Akhurst T, et al. Characteristics and outcomes of therapy-related myeloid neoplasms after peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) for metastatic neuroendocrine neoplasia: a single-institution series. Eur J Nucl Med Mol Imaging. 2019;46:1902–10.PubMedGoogle Scholar
- 23.Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656–63.PubMedGoogle Scholar
- 26.Martini C, Buxbaum S, Rodrigues M, Nilica B, Scarpa L, Holzner B, et al. Quality of life in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy: information from a monitoring program in clinical routine. J Nucl Med. 2018;59(10):1566–73.PubMedGoogle Scholar
- 29.Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–71.PubMedPubMedCentralGoogle Scholar
- 33.Eldor R, Glaser B, Fraenkel M, Doviner V, Salmon A, Gross DJ. Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour. Clin Endocrinol. 2011;74(5):593–8.Google Scholar
- 35.Kong G, Callahan J, Hofman MS, Pattison DA, Akhurst T, Michael M, et al. High clinical and morphologic response using (90)Y-DOTA-octreotate sequenced with (177)Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2017;44(3):476–89.PubMedGoogle Scholar
- 37.Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, et al. The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104(1):85–93.PubMedGoogle Scholar
- 38.Tang LH, Basturk O, Sue JJ, Klimstra DS. A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192–202.PubMedPubMedCentralGoogle Scholar
- 42.•Thang SP, Lung MS, Kong G, Hofman MS, Callahan J, Michael M, et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging. 2018;45(2):262–77Clinical series showing potential effectiveness of PRRT in Grade 3 NEN particularly for Ki-67 21–55% subgroup.Google Scholar
- 44.• Carlsen EA, Fazio N, Granberg D, Grozinsky-Glasberg S, Ahmadzadehfar H, Grana CM, et al. Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocr Relat Cancer. 2019;26(2):227–39 More recent multicenter cohort study reporting favorable efficacy of PRRT in patients with G3 NEN.PubMedGoogle Scholar
- 50.Pool SE, Kam BL, Koning GA, Konijnenberg M, Ten Hagen TL, Breeman WA, et al. [(111)In-DTPA]octreotide tumor uptake in GEPNET liver metastases after intra-arterial administration: an overview of preclinical and clinical observations and implications for tumor radiation dose after peptide radionuclide therapy. Cancer Biother Radiopharm. 2014;29(4):179–87.PubMedGoogle Scholar
- 52.Hicks RJ, Jackson P, Kong G, Ware RE, Hofman MS, Pattison DA, et al. First-in-human trial of (64)Cu-SARTATE PET imaging of patients with neuroendocrine tumours demonstrates high tumor uptake and retention, potentially allowing prospective dosimetry for peptide receptor radionuclide therapy. J Nucl Med. 2019;60(6):777–85.Google Scholar
- 53.van Essen M, Krenning EP, Kam BL, de Herder WW, van Aken MO, Kwekkeboom DJ. Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2008;35(4):743–8.PubMedPubMedCentralGoogle Scholar
- 56.Kong G, Thompson M, Collins M, Herschtal A, Hofman MS, Johnston V, et al. Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging. 2014;41(10):1831–44.PubMedPubMedCentralGoogle Scholar
- 60.• Navalkissoor S, Grossman A. Targeted alpha particle therapy for neuroendocrine tumours: the next generation of peptide receptor radionuclide therapy. Neuroendocrinology. 2019;108(3):256–64 Review article providing a summary and comprehensive review of current status of Alpha Therapy for NEN. PubMedGoogle Scholar
- 63.Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. (2)(1)(3)Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41(11):2106–19.PubMedPubMedCentralGoogle Scholar
- 69.Béhé M, Behr TM. Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. Pept Sci. 2002;66(6):399–418.Google Scholar
- 77.Kroiss A, Putzer D, Uprimny C, Decristoforo C, Gabriel M, Santner W, et al. Functional imaging in phaeochromocytoma and neuroblastoma with (68)Ga-DOTA-Tyr (3)-octreotide positron emission tomography and (123)I-metaiodobenzylguanidine. Eur J Nucl Med Mol Imaging. 2011;38(5):865–73.PubMedGoogle Scholar