Peptidradiorezeptor-Therapie (PRRT)

Zusammenfassung

Neuroendokrine Neoplasien (NEN) stellen ein komplexes, heterogenes Krankheitsbild dar, wobei der Primärtumorlokation meist im Gastrointestinaltrakt lokalisiert ist. Als „Orphan Disease“ sind NEN zwar selten, werden aber primär durch eine verbesserte bildgebende Diagnostik in den letzten Jahren verstärkt diagnostiziert. Hierbei spielt die Somatostatinrezeptor (SSTR)-gerichtete molekulare Bildgebung eine große Rolle, insbesondere die Einzelphotonen-Emissions-Computertomografie (SPECT) sowie die Positronen-Emissions-Tomografie (PET). Neben einer exakten Ausbreitungsdiagnostik generiert die SSTR-gerichtete Bildgebung auch eine Therapierationale für eine Peptidradiorezeptortherapie (PRRT) in einem sog. „theranostischen“ Ansatz. Hierbei wird ein β-Strahler mit dem identischen Peptid des diagnostischen SPECT-/PET-Gegenstücks gekoppelt, um somit eine gezielte, SSTR-gerichtete Bestrahlung von NEN und metastatischer Läsionen zu ermöglichen. Das daraus resultierende „heiße“ Somatostatinanalogon kann als hocheffektives Radiotherapeutikum mit akzeptablem Nebenwirkungsprofil eingesetzt werden, was bereits in einer randomisierten, prospektiven, multizentrischen Studie belegt wurde. Die PRRT erfolgt in Deutschland stationär auf einer nuklearmedizinischen Isotopenstation, wobei Indikation, Durchführung und Nachsorge dieser zielgerichteten Therapie in einem interdisziplinären Ansatz in enger Absprache mit Kolleg*innen der Inneren Medizin, der Medizinphysik und Nuklearmedizin erfolgen sollte. Mit Lutathera (¹⁷⁷Lu-Oxodotreotid) steht seit Kurzem ein in Deutschland zugelassenes Arzneimittel zur SSTR-gerichteten Therapie zur Verfügung, womit die PRRT verstärkt Anwendung finden dürfte.

Abstract

The umbrella term neuroendocrine neoplasia (NEN) encompasses a heterogenous and complex spectrum of various tumor entities, with the vast majority being located in the gastrointestinal tract. As an “orphan malignancy”, recent years have witnessed an increased incidence of NEN, mainly due to an improved diagnostic work-up. In this regard, somatostatin receptor (SSTR) directed molecular imaging is increasingly utilized, in particular single photon emission computed tomography and positron emission tomography. These molecular imaging techniques provide an exact read-out of the entire tumor burden, but also lay the foundations for a theranostic approach (peptide receptor radionuclide therapy [PRRT]). By using the β-emitting equivalent of the diagnostic image agent, such highly effective, therapeutic radiolabeled compounds can be safely administered, and their therapeutic efficacy has already been demonstrated in a large, prospective multicenter trial. In Germany, PRRT is routinely conducted at a nuclear medicine ward. Nonetheless, PRRT is a multidisciplinary team effort and should be performed in close collaboration with physicists, referring treating internal medicine physicians and nuclear medicine experts. Moreover, the SSTR-targeted therapeutic compound Lutathera (¹⁷⁷Lu-labeled oxodotreotide) has been recently approved in Germany, which will make PRRT more widely available in the future.

Schlüsselwörter

Peptidradiorezeptortherapie - PRRT - Neuroendokrine Tumore - NEN - NET - Theranostics - SSTR - Somatostatinrezeptor

Keywords

peptide receptor radionuclide therapy - PRRT - Neuroendocrine Tumors - NEN - NET - theranostics - SSTR - somatostatin receptor

• Literatur

• 1 Oronsky B, Ma PC, Morgensztern D. et al. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 2017; 19: 991-1002
• 2 Deutsche Gesellschaft für Gastroenterologie V-uS, Netzwerk Neuroendokrine Tumoren e V, Bundesorganisation Selbsthilfe NeuroEndokrine Tumoren e V, Deutsche Gesellschaft für Hamatologie und Medizinische Onkologie e.V uAIOdDKeV, Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie e V, Deutsche Gesellschaft für C, et al. [Practice guideline neuroendocrine tumors - AWMF-Reg. 021-27]. Z Gastroenterol 2018; 56: 583-681
• 3 Perren A, Couvelard A, Scoazec JY. et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pathology: Diagnosis and Prognostic Stratification. Neuroendocrinology 2017; 105: 196-200
• 4 Inzani F, Petrone G, Rindi G. The New World Health Organization Classification for Pancreatic Neuroendocrine Neoplasia. Endocrinol Metab Clin North Am 2018; 47: 463-470
• 5 Kim JY, Hong SM. Recent Updates on Neuroendocrine Tumors From the Gastrointestinal and Pancreatobiliary Tracts. Arch Pathol Lab Med 2016; 140: 437-448
• 6 Hallet J, Law CH, Cukier M. et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015; 121: 589-597
• 7 Falconi M, Eriksson B, Kaltsas G. 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: 153-171
• 8 Wells Jr SA, Asa SL, Dralle H. et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610
• 9 Pavel M, Oberg K, Falconi M. et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31: 844-860
• 10 Niederle MB, Hackl M, Kaserer K. et al. Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer 2010; 17: 909-918
• 11 Yao JC, Hassan M, Phan A. et al. One hundred years after „carcinoid“: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26: 3063-3072
• 12 Werner RA, Bengel FM, Derlin T. [Theranostics and hybrid imaging for somatostatin receptor-expressing tumors]. Radiologe 2020; 60: 413-420
• 13 Deppen SA, Blume J, Bobbey AJ. et al. ⁶⁸Ga-DOTATATE Compared with 111In-DTPA-Octreotide and Conventional Imaging for Pulmonary and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. J Nucl Med 2016; 57: 872-878
• 14 Chiti A, Fanti S, Savelli G. et al. Comparison of somatostatin receptor imaging, computed tomography and ultrasound in the clinical management of neuroendocrine gastro-entero-pancreatic tumours. Eur J Nucl Med 1998; 25: 1396-1403
• 15 Ilhan H, Lindner S, Todica A. et al. Biodistribution and first clinical results of (18)F-SiFAlin-TATE PET: a novel (18)F-labeled somatostatin analog for imaging of neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2020; 47: 870-880
• 16 Werner RA, Chen X, Rowe SP. et al. Recent paradigm shifts in molecular cardiac imaging-Establishing precision cardiology through novel (18)F-labeled PET radiotracers. Trends Cardiovasc Med 2020; 30: 11-19
• 17 Ducharme J, Goertzen AL, Patterson J. et al. Practical Aspects of 18F-FDG PET When Receiving ¹⁸F-FDG from a Distant Supplier. J Nucl Med Technol 2009; 37: 164-169
• 18 Ambrosini V, Kunikowska J, Baudin E. et al. Consensus on molecular imaging and theranostics in neuroendocrine neoplasms. Eur J Cancer 2021; 146: 56-73
• 19 Poeppel TD, Boy C, Bockisch A. et al. [Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1)]. Nuklearmedizin 2015; 54: 1-11 ; quiz N2
• 20 Bodei L, Mueller-Brand J, Baum RP. et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013; 40: 800-816
• 21 Werner RA, Bluemel C, Lassmann M. et al. SPECT- and PET-based patient-tailored treatment in neuroendocrine tumors: a comprehensive multidisciplinary team approach. Clin Nucl Med 2015; 40: e271-277
• 22 Hanscheid H, Lapa C, Buck AK. et al. Absorbed dose estimates from a single measurement one to three days after the administration of 177Lu-DOTATATE/-TOC. Nuklearmedizin 2017; 56: 219-224
• 23 Strosberg J, El-Haddad G, Wolin E. et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376: 125-135
• 24 Strosberg J, Wolin E, Chasen B. et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With (177)Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol 2018; 36: 2578-2584
• 25 Fachinformation (Zusammenfassung der Merkmale des Arzneimittels/SmPC) Lutathera^® 370 MBq/ml Infusionslösung. Verfügbar unter (Stand 04.07.2021): https://wwwfachinfode/pdf/023084
• 26 Bergsma H, Konijnenberg MW, van der Zwan WA. et al. Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging 2016; 43: 1802-1811
• 27 Bodei L, Kidd M, Paganelli G. 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: 5-19
• 28 Bodei L, Kwekkeboom DJ, Kidd M. et al. Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer. Semin Nucl Med 2016; 46: 225-238
• 29 Centers of Excellence (CoE) Interactive Map, European Neuroendocrine Tumor Society (ENETS). Verfügbar unter (Stand 04.07.2021): https://wwwenetsorg/coe_maphtml
• 30 About Centers of Excellence (CoE), European Neuroendocrine Tumor Society (ENETS). Verfügbar unter (Stand 07.04.2021): https://wwwenetsorg/about_enets_coehtml
• 31 Werner RA, Weich A, Kircher M. et al. The theranostic promise for Neuroendocrine Tumors in the late 2010s – Where do we stand, where do we go?. Theranostics 2018; 8: 6088-6100
• 32 Kwekkeboom DJ, Krenning EP. Somatostatin receptor imaging. Semin Nucl Med 2002; 32: 84-91
• 33 Sorbye H, Kong G, Grozinsky-Glasberg S. PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Endocr Relat Cancer 2020; 27: R67-R77
• 34 Carlsen EA, Fazio N, Granberg D. et al. Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocr Relat Cancer 2019; 26: 227-239
• 35 Chan DL, Pavlakis N, Schembri GP. et al. Dual Somatostatin Receptor/FDG PET/CT Imaging in Metastatic Neuroendocrine Tumours: Proposal for a Novel Grading Scheme with Prognostic Significance. Theranostics 2017; 7: 1149-1158
• 36 Al-Toubah T, Sikaria D, Jesurajan J. et al. Comparison of Nausea and Vomiting Associated With Amino Acid Formulations Coinfused With Peptide Receptor Radionuclide Therapy: Commercial Parenteral Nutrition Formulas Versus Compounded Arginine/Lysine. Pancreas 2021; 50: 513-515
• 37 Bergsma H, Konijnenberg MW, Kam BL. et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging 2016; 43: 453-463
• 38 Martini C, Buxbaum S, Rodrigues M. 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: 1566-1573
• 39 Bergsma H, van Lom K, Raaijmakers M. et al. Persistent Hematologic Dysfunction after Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE: Incidence, Course, and Predicting Factors in Patients with Gastroenteropancreatic Neuroendocrine Tumors. J Nucl Med 2018; 59: 452-458
• 40 Riff BP, Yang YX, Soulen MC. et al. Peptide Receptor Radionuclide Therapy-Induced Hepatotoxicity in Patients With Metastatic Neuroendocrine Tumors. Clin Nucl Med 2015; 40: 845-850
• 41 Lassmann M, Eberlein U. The Relevance of Dosimetry in Precision Medicine. J Nucl Med 2018; 59: 1494-1499
• 42 Hanscheid H, Lapa C, Buck AK. et al. Dose Mapping After Endoradiotherapy with (177)Lu-DOTATATE/DOTATOC by a Single Measurement After 4 Days. J Nucl Med 2018; 59: 75-81
• 43 Yordanova A, Mayer K, Brossart P. et al. Safety of multiple repeated cycles of (177)Lu-octreotate in patients with recurrent neuroendocrine tumour. Eur J Nucl Med Mol Imaging 2017; 44: 1207-1214
• 44 Levey AS, Eckardt KU, Dorman NM. et al. Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference. Kidney Int 2020; 97: 1117-1129
• 45 Efficacy and Safety of ¹⁷⁷Lu-edotreotide PRRT in GEP-NET Patients (COMPETE). Verfügbar unter (Stand 07.04.2021): https://clinicaltrialsgov/ct2/show/NCT03049189
• 46 Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET (NETTER-2). Verfügbar unter (Stand 04.07.2021): https://clinicaltrialsgov/ct2/show/NCT03972488
• 47 Baum RP, Zhang J, Schuchardt C. et al. First-in-human study of novel SSTR antagonist (177)Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with metastatic neuroendocrine neoplasms: dosimetry, safety and efficacy. J Nucl Med 2021;
• 48 Fani M, Nicolas GP, Wild D. Somatostatin Receptor Antagonists for Imaging and Therapy. J Nucl Med 2017; 58 (Suppl. 02) 61S-6S
• 49 Zidan L, Iravani A, Oleinikov K. et al. Efficacy and safety of (177)Lu-DOTATATE in lung neuroendocrine tumors: a bi-center study. J Nucl Med 2021;
• 50 Lapa C, Kircher M, Hanscheid H. et al. Peptide receptor radionuclide therapy as a new tool in treatment-refractory sarcoidosis – initial experience in two patients. Theranostics 2018; 8: 644-649