title: Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up.
abstract: BACKGROUND
  Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany.
  
  
  METHODS
  A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models.
  
  
  RESULTS
  Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2-1.5% of patients.
  
  
  CONCLUSIONS
  These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.
authors.affiliation: Department of Gastroenterology/Endocrinology, Center for Neuroendocrine Tumors Bad Berka - ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany. Electronic address: dieter.hoersch@zentralklinik.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Hörsch
authors.affiliation: Klinik für Nuklearmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße, Gebäude 50, D-66421 Homburg, Germany.
authors.forename: Samer
authors.initials: S
authors.lastname: Ezziddin
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin, Ludwig Maximilian Universität München, Ziemssenstraße 1, 80336 München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Haug
authors.affiliation: Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Klaus Friedrich
authors.initials: KF
authors.lastname: Gratz
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Rostock, Gertrudenplatz 1, D-18057 Rostock, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Dunkelmann
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Miederer
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schreckenberger
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Rostock, Gertrudenplatz 1, D-18057 Rostock, Germany.
authors.forename: Bernd Joachim
authors.initials: BJ
authors.lastname: Krause
authors.affiliation: Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Bengel
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin, Ludwig Maximilian Universität München, Ziemssenstraße 1, 80336 München, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: Klinik und Poliklinik für Nuklearmedizin am Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Biersack
authors.affiliation: Klinik für Nuklearmedizin, Katharinenhospital Stuttgart, Kriegsbergstraße 60, 70174 Stuttgart, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pöpperl
authors.affiliation: Clinic of Molecular Radiotherapy, Center for Neuroendocrine Tumors Bad Berka - ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany.
authors.forename: R P
authors.initials: RP
authors.lastname: Baum
mesh_terms: D000328:Adult; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005710:Gallium Radioisotopes / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D015282:Octreotide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012042:Registries; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C496730:90Y-octreotide, DOTA-Tyr(3)-; C447941:lutetium Lu 177 dotatate; D015282:Octreotide; C106246:Edotreotide
keywords: Functional syndromes; Neuroendocrine neoplasm; Oncology; Peptide receptor radionuclide therapy; Radiotherapy