Der Nuklearmediziner 2018; 41(04): 348-359
DOI: 10.1055/a-0671-5500
Radiochemie in Klinik und Praxis
© Georg Thieme Verlag KG Stuttgart · New York

Molekulare Radiotherapie mit neuen Radiopharmaka: Präzisionsonkologie zur personalisierten Patientenbehandlung

Molecular radiotherapy using novel radiopharmaceuticals: precision oncology for personalized patient treatment
Thomas Langbein
Klinik für Molekulare Radiotherapie, Zentralklinik Bad Berka, Bad Berka
,
Harshad R. Kulkarni
Klinik für Molekulare Radiotherapie, Zentralklinik Bad Berka, Bad Berka
,
Jingjing Zhang
Klinik für Molekulare Radiotherapie, Zentralklinik Bad Berka, Bad Berka
,
Richard P. Baum
Klinik für Molekulare Radiotherapie, Zentralklinik Bad Berka, Bad Berka
› Author Affiliations
Further Information

Publication History

Publication Date:
21 December 2018 (online)

Zusammenfassung

Maligne Erkrankungen sind mit Veränderungen auf der molekularen Ebene assoziiert. Präzisionsonkologie meint einen personalisierten Therapieansatz, der auf spezifische molekulare Signale in Tumorzellen abzielt und mit optimaler Wirksamkeit bei minimalen Nebenwirkungen verbunden ist. Tumore können hochwirksam mit Radiopharmaka behandelt werden, die auf spezifische, zelluläre Mechanismen abzielen (z. B. Metastasen von gut differenzierten neuroendokrinen Neoplasmen mittels 177Lu markierten Somatostatinanaloga). Die molekulare Bildgebung mit PET/CT oder PET/MRT spielt eine entscheidende Rolle bei der Patientenauswahl sowie bei der Überwachung des Therapieansprechens und ist daher in der Lage, die molekulare Radiotherapie zu steuern („wir sehen, was wir behandeln“ und umgekehrt). Theranostik in der Nuklearmedizin fügt sich daher in die Definition der Präzisionsonkologie ein, da sie beispielhaft die Kombination von molekularer Bildgebung und molekularer Radiotherapie beinhaltet, wobei derselbe Vektor, markiert mit unterschiedlichen Radionukliden, zum einen für die Diagnose und zum anderen für die Behandlung verwendet wird. Während die Anwendung von 131I durch Saul Hertz Mitte des letzten Jahrhunderts erstmals den Weg für eine gezielte molekulare Radiotherapie eröffnete, fasst dieser Übersichtsartikel die Therapie mit in den letzten Jahren neuentwickelten Radiopharmaka zusammen.

Abstract

Cancer is associated with alterations at the molecular level. Precision oncology refers to a personalized therapy approach, which targets specific molecular signals in tumor cells, and is associated with maximal efficacy and minimal side effects. Tumors can be effectively treated using radiopharmaceuticals, which specifically target cellular mechanisms, for e. g., treatment of metastases of well-differentiated neuroendocrine neoplasms using 177Lu labelled somatostatin analogs. Molecular imaging with PET/CT or PET/MRI plays a vital role in patient selection as well as monitoring of therapy response and therefore is able to guide molecular radiotherapy (“we see what we treat” and vice versa). Theranostics in nuclear medicine therefore is part of precision oncology, because it exemplifies the combination of molecular imaging and molecular radiotherapy, utilizing the same vector with distinct radionuclides for diagnosis and treatment, respectively. Whereas 131I (conceived for medical use by Saul Hertz in 1936) paved the way to targeted molecular radiotherapy around the middle of the previous century, this review summarizes the clinical use of novel radiopharmaceuticals developed over the last two decades.

 
  • Literatur

  • 1 Desai AM, Lichtman SM. Systemic therapy of non-colorectal gastrointestinal malignancies in the elderly. Cancer Biol Med 2015; 12: 284-291
  • 2 Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988; 6: 1746-1752
  • 3 Hertz SRA, Evans RD. Radioactive iodine as an indicator in the study of thyroid physiology. Exp Biol Med 1938; 38: 510-513
  • 4 Strosberg J, El-Haddad G, Wolin E. et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. The New England journal of medicine 2017; 376: 125-135
  • 5 Imhof A, Brunner P, Marincek N. et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011; 29: 2416-2423
  • 6 Baum RP, Kulkarni HR, Schuchardt C. et al. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med 2016; 57: 1006-1013
  • 7 Kratochwil C, Bruchertseifer F, Giesel FL. et al. 225Ac-PSMA-617 for PSMA-Targeted alpha-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med 2016; 57: 1941-1944
  • 8 Turner JH. Recent advances in theranostics and challenges for the future. The British journal of radiology 2018; 91: 20170893
  • 9 Romer A, Seiler D, Marincek N. et al. Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2014; 41: 214-222
  • 10 Schuchardt C, Kulkarni HR, Prasad V. et al. The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC. Recent Results Cancer Res 2013; 194: 519-536
  • 11 Krenning EP, Kooij PP, Bakker WH. et al. Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide. A case history. Ann N Y Acad Sci 1994; 733: 496-506
  • 12 Severi S, Grassi I, Nicolini S. et al. Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life. OncoTargets and therapy 2017; 10: 551-557
  • 13 Rolleman EJ, Valkema R, de Jong M. et al. Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. Eur J Nucl Med Mol Imaging 2003; 30: 9-15
  • 14 Sathekge M, Bruchertseifer F, Knoesen O. et al. (225)Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging 2018; DOI: 10.1007/s00259-018-4167-0.
  • 15 Kratochwil C, Bruchertseifer F, Rathke H. et al. Targeted Alpha Therapy of mCRPC with225Actinium-PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control. J Nucl Med 2018; 59: 795-802 (Epub)
  • 16 Kratochwil C, Schmidt K, Afshar-Oromieh A. et al. Targeted alpha therapy of mCRPC: Dosimetry estimate of (213)Bismuth-PSMA-617. Eur J Nucl Med Mol Imaging 2018; 45: 31-37
  • 17 Singh A, van der Meulen NP, Muller C. et al. First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced (44)Sc-DOTATOC: A Proof-of-Concept Study. Cancer Biother Radiopharm 2017; 32: 124-132
  • 18 Baum RP, Singh A, Benesova M. et al. Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with (152)Tb-DOTATOC. Dalton Trans 2017; 46: 14638-14646
  • 19 Muller C, Domnanich KA, Umbricht CA. et al. Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application. The British journal of radiology 2018; 91: 20180074
  • 20 Singh A, Kulkarni HR, Baum RP. Imaging of Prostate Cancer Using (64)Cu-Labeled Prostate-Specific Membrane Antigen Ligand. PET Clin 2017; 12: 193-203
  • 21 Grubmuller B, Baum RP, Capasso E. et al. (64)Cu-PSMA-617 PET/CT Imaging of Prostate Adenocarcinoma: First In-Human Studies. Cancer Biother Radiopharm 2016; DOI: 10.1089/cbr.2015.1964. [Epub ahead of print]
  • 22 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
  • 23 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
  • 24 Poeppel TD BC, Bockisch A. et al. DGN-Handlungsempfehlung (S1-Leitlinie) Peptid-Rezeptor-Radionuklid-Therapie (PRRT) somatostatinrezeptorexprimierender Tumore. Deutsche Gesellschaft für Nuklearmedizin; 2013
  • 25 Kulkarni HR, Baum RP. Patient selection for personalized peptide receptor radionuclide therapy using Ga-68 somatostatin receptor PET/CT. PET Clin 2014; 9: 83-90
  • 26 Baum RP, Kluge AW, Kulkarni H. et al. [(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study. Theranostics 2016; 6: 501-510
  • 27 Kwekkeboom DJ, de Herder WW, Kam BL. et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26: 2124-2130
  • 28 Bodei L, Cremonesi M, Ferrari M. et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging 2008; 35: 1847-1856
  • 29 Severi S, Nanni O, Bodei L. et al. Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013; 40: 881-888
  • 30 Claringbold PG, Brayshaw PA, Price RA. et al. Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2011; 38: 302-311
  • 31 van Essen M, Krenning EP, Kam BL. et al. 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: 743-748
  • 32 Horsch D, Ezziddin S, Haug A. et al. Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up. Eur J Cancer 2016; 58: 41-51
  • 33 Ezziddin S, Attassi M, Yong-Hing CJ. et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med 2014; 55: 183-190
  • 34 Strosberg JWE, Chasen B. et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol 2018; 36: 2578-2584
  • 35 Kunikowska J, Krolicki L, Hubalewska-Dydejczyk A. et al. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option?. Eur J Nucl Med Mol Imaging 2011; 38: 1788-1797
  • 36 Villard L, Romer A, Marincek N. et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol 2012; 30: 1100-1106
  • 37 Cybulla M, Weiner SM, Otte A. End-stage renal disease after treatment with 90Y-DOTATOC. Eur J Nucl Med 2001; 28: 1552-1554
  • 38 Bodei L, Cremonesi M, Grana C. et al. Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2004; 31: 1038-1046
  • 39 Valkema R, Pauwels SA, Kvols LK. et al. Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate. J Nucl Med 2005; 46 (Suppl. 01) 83S-91S
  • 40 Zhang J, Kulkarni H, Singh A. et al. Long-term Nephrotoxicity After PRRT: Fact or Fiction?. Eur J Nucl Med Mol Imaging 2018; 45 (Suppl. 01) 184
  • 41 Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 1995; 31: 1249-1256
  • 42 Barone R, Borson-Chazot F, Valkema R. et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship. J Nucl Med 2005; 46 (Suppl. 01) 99S-106S
  • 43 Brabander T, van der Zwan WA, Teunissen JJM. et al. Long-Term Efficacy, Survival, and Safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res 2017; 23: 4617-4624
  • 44 Singh A, Zhang J, Kulkarni H. et al. Survival and safety analysis of intra-arterial PRRT of SSTRexpressing tumors in over 50 patients: targeting NEN and beyond. Eur J Nucl Med Mol Imaging 2018; 45 (Suppl. 01) 183
  • 45 Limouris GS, Chatziioannou A, Kontogeorgakos D. et al. Selective hepatic arterial infusion of In-111-DTPA-Phe1-octreotide in neuroendocrine liver metastases. Eur J Nucl Med Mol Imaging 2008; 35: 1827-1837
  • 46 Kaemmerer D, Prasad V, Daffner W. et al. Neoadjuvant peptide receptor radionuclide therapy for an inoperable neuroendocrine pancreatic tumor. World J Gastroenterol 2009; 15: 5867-5870
  • 47 Wild D, Fani M, Fischer R. et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med 2014; 55: 1248-1252
  • 48 Robert Koch Institut (RKI) GdeKiD, (GEKID). Krebs in Deutschland für 2013/2014. Berlin: RKI; 2017
  • 49 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF). Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 5.0. AWMF Registernummer: 043/022OL, 2018 http://www.leitlinienprogramm-onkologie.de/leitlinien/prostatakarzinom
  • 50 Pfister D, Bolla M, Briganti A. et al. Early salvage radiotherapy following radical prostatectomy. Eur Urol 2014; 65: 1034-1043
  • 51 Fornara P. PSA-Rezidiv nach radikaler Prostatektomie. Journal für Urologie und Urogynäkologie 2006; 13: 21-23
  • 52 D'Amico AV, Whittington R, Malkowicz SB. et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969-974
  • 53 Loeb S, Schaeffer EM, Trock BJ. et al. What are the outcomes of radical prostatectomy for high-risk prostate cancer?. Urology 2010; 76: 710-714
  • 54 Sundi D, Wang V, Pierorazio PM. et al. Identification of men with the highest risk of early disease recurrence after radical prostatectomy. The Prostate 2014; 74: 628-636
  • 55 Weiner AB, Matulewicz RS, Eggener SE. et al. Increasing incidence of metastatic prostate cancer in the United States (2004-2013). Prostate cancer and prostatic diseases 2016; 19: 395-397
  • 56 Halabi S, Vogelzang NJ, Kornblith AB. et al. Pain predicts overall survival in men with metastatic castration-refractory prostate cancer. J Clin Oncol 2008; 26: 2544-2549
  • 57 de Bono JS, Logothetis CJ, Molina A. et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine 2011; 364: 1995-2005
  • 58 Scher HI, Fizazi K, Saad F. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England journal of medicine 2012; 367: 1187-1197
  • 59 Seruga B, Tannock IF. Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol 2011; 29: 3686-3694
  • 60 Mannweiler S, Amersdorfer P, Trajanoski S. et al. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res 2009; 15: 167-172
  • 61 Bander NH, Trabulsi EJ, Kostakoglu L. et al. Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. J Urol 2003; 170: 1717-1721
  • 62 Demirci E, Sahin OE, Ocak M. et al. Normal distribution pattern and physiological variants of 68Ga-PSMA-11 PET/CT imaging. Nuclear medicine communications 2016; 37: 1169-1179
  • 63 Haffner MC, Kronberger IE, Ross JS. et al. Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers. Hum Pathol 2009; 40: 1754-1761
  • 64 Bander NH, Milowsky MI, Nanus DM. et al. Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 2005; 23: 4591-4601
  • 65 Afshar-Oromieh A, Hetzheim H, Kratochwil C. 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: 1697-1705
  • 66 Zechmann CM, Afshar-Oromieh A, Armor T. et al. Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging 2014; 41: 1280-1292
  • 67 Heck MM, Retz M, D'Alessandria C. et al. Systemic Radioligand Therapy with (177)Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer. J Urol 2016; 196: 382-391
  • 68 Kratochwil C, Giesel FL, Stefanova M. et al. PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617. J Nucl Med 2016; 57: 1170-1176
  • 69 Ahmadzadehfar H, Eppard E, Kurpig S. et al. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget 2016; 7: 12477-12488
  • 70 Rahbar K, Bode A, Weckesser M. et al. Radioligand Therapy With 177Lu-PSMA-617 as A Novel Therapeutic Option in Patients With Metastatic Castration Resistant Prostate Cancer. Clin Nucl Med 2016; 41: 522-528
  • 71 Rahbar K, Ahmadzadehfar H, Kratochwil C. et al. German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. J Nucl Med 2017; 58: 85-90
  • 72 Fendler WP, Kratochwil C, Ahmadzadehfar H. et al. [177Lu-PSMA-617 therapy, dosimetry and follow-up in patients with metastatic castration-resistant prostate cancer]. Nuklearmedizin 2016; 55: 123-128
  • 73 Kulkarni HR, Singh A, Langbein T. et al. Theranostics of prostate cancer: from molecular imaging to precision molecular radiotherapy targeting the prostate specific membrane antigen. Br J Radiol. 2018; DOI: 10.1259/bjr.20180308. (Epub)
  • 74 Kulkarni H, Zhang J, Singh A. et al. De novo Radioligand Therapy using Lu-177 labelled PSMA Small Molecules in Patients with Metastatic Prostate Cancer. Eur J Nucl Med Mol Imaging 2018; 45 (Suppl. 01) 126
  • 75 Okamoto S, Thieme A, Allmann J. et al. Radiation Dosimetry for (177)Lu-PSMA I&T in Metastatic Castration-Resistant Prostate Cancer: Absorbed Dose in Normal Organs and Tumor Lesions. J Nucl Med 2017; 58: 445-450
  • 76 Hofman MS, Violet J, Hicks RJ. et al. [ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. The Lancet Oncology 2018; 19: 825-833
  • 77 Sathekge M, Knoesen O, Meckel M. et al. (213)Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 2017; 44: 1099-1100
  • 78 Kratochwil C, Bruchertseifer F, Rathke H. et al. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with (225)Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding. J Nucl Med 2017; 58: 1624-1631
  • 79 Langbein T, Chausse G, Baum RP. Salivary gland toxicity of PSMA Radioligand Therapy: relevance and preventive strategies. J Nucl Med 2018; 59: 1172-1173 (Epub)
  • 80 Taieb D, Foletti JM, Bardies M. et al. PSMA-Targeted Radionuclide Therapy and Salivary Gland Toxicity: Why Does It Matter?. J Nucl Med 2018; 59: 747-748
  • 81 van Kalmthout LWM, Lam M, de Keizer B. et al. Impact of external cooling with icepacks on (68)Ga-PSMA uptake in salivary glands. EJNMMI Res 2018; 8: 56
  • 82 Rousseau E, Lau J, Kuo HT. et al. Monosodium glutamate reduces (68)Ga-PSMA-11 uptake in salivary glands and kidneys in preclinical prostate cancer model. J Nucl Med 2018; DOI: 10.2967/jnumed.118.215350. [Epub ahead of print]
  • 83 Baum RP, Langbein T, Singh A. et al. Injection of Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy: an Empirical Proof of a Promising Concept. Nuclear medicine and molecular imaging 2018; 52: 80-81
  • 84 Rathke H, Kratochwil C, Hohenberger R. et al. Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing (225)Ac-PSMA-617 RLT. Eur J Nucl Med Mol Imaging 2018; 46: 139-147
  • 85 Kulkarni H, Schuchardt C, Langbein T. et al. First Clinical and Dosimetry Results of Tandem Alpha-Beta PSMA Radioligand Therapy (TABPRLT) Using a Combination of Ac-225 and Lu-177 Labelled PSMA-617 for Progressive End-Stage Metastatic Prostate Cancer. Eur J Nucl Med Mol Imaging 2018; 45 (Suppl. 01) 110
  • 86 Murga JD, Moorji SM, Han AQ. et al. Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. The Prostate 2015; 75: 242-254
  • 87 Nonnekens J, van Kranenburg M, Beerens CE. et al. Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib. Theranostics 2016; 6: 1821-1832
  • 88 Serganova I, Moroz E, Cohen I. et al. Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade. Mol Ther Oncolytics 2017; 4: 41-54
  • 89 Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer (VISION) . ClinicalTrials.gov Identifier: NCT03511664 https://clinicaltrials.gov/ct2/show/NCT03511664
  • 90 Ogawa K, Kawashima H, Shiba K. et al. Development of [(90)Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases. Nucl Med Biol 2009; 36: 129-135
  • 91 Traboulsi SL, Saad F. The role of bone-targeted therapies for prostate cancer in 2017. Curr Opin Support Palliat Care 2017; 11: 216-224
  • 92 Kutzner J, Grimm W, Hahn K. [Palliative radiotherapy with Strontium-89 in case of extended formation of skeleton metastases (author's transl)]. Strahlentherapie 1978; 154: 317-322
  • 93 Pfannkuchen N, Meckel M, Kubicek V. et al. 68Ga- und 177Lu-markierte Bisphosphonate als Knochenmetastasen-Theranostika. Der Nuklearmediziner 2015; 38: 138-144
  • 94 Bergmann R, Meckel M, Kubicek V. et al. (177)Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment. EJNMMI Res 2016; 6: 5
  • 95 Bubendorf L, Schopfer A, Wagner U. et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31: 578-583
  • 96 Baum RP, Kulkarni H, Schuchardt C. et al. First Clinical Experience using 177Lu-BPAMD for the Treatment of Skeletal Metastases in Prostate Cancer. European Journal of Nuclear Medicine and Molecular Imaging 2011; 38: 225
  • 97 Baum RP, Singh A, Schuchardt C. et al. 177Lu-3BP-227 for Neurotensin Receptor 1–Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results. J Nucl Med 2018; 59: 809
  • 98 Schottelius M, Osl T, Poschenrieder A. et al. [(177)Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent. Theranostics 2017; 7: 2350-2362
  • 99 Herrmann K, Schottelius M, Lapa C. et al. First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease. J Nucl Med 2016; 57: 248-251
  • 100 Lapa C, Herrmann K, Schirbel A. et al. CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma. Theranostics 2017; 7: 1589-1597
  • 101 Lapa C, Hanscheid H, Kircher M. et al. Feasibility of CXCR4-directed radioligand therapy in advanced diffuse large B cell lymphoma. J Nucl Med 2018; DOI: 10.2967/jnumed.118.210997. [Epub ahead of print]
  • 102 Habringer S, Lapa C, Herhaus P. et al. Dual Targeting of Acute Leukemia and Supporting Niche by CXCR4-Directed Theranostics. Theranostics 2018; 8: 369-383
  • 103 Velikyan I, Bulenga TN, Selvaraju R. et al. Dosimetry of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 - impact on the feasibility of insulinoma internal radiotherapy. Am J Nucl Med Mol Imaging 2015; 5: 109-126
  • 104 Muller C, Struthers H, Winiger C. et al. DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted 177Lu-radionuclide tumor therapy in mice. J Nucl Med 2013; 54: 124-131