title: Influence of tumour size on the efficacy of targeted alpha therapy with (213)Bi-[DOTA(0),Tyr(3)]-octreotate.
abstract: BACKGROUND
  Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR2), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR2 in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with (213)Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm(3)) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour).
  
  
  METHODS
  Pharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm(3) were euthanized at 10, 30, 60 and 120 min post injection of a single dose of (213)Bi-DOTATATE (1.5-4.8 MBq). To investigate the therapeutic efficacy of (213)Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm(3) were administered daily with a therapeutic dose of (213)Bi-DOTATATE (0.3 nmol, 2-4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq (99m)Tc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to (213)Bi-DOTATATE treatment.
  
  
  RESULTS
  Higher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69 tumour-bearing mice, the survival rate was higher. Furthermore, in the small tumour groups, no regrowth of tumour was found in two H69 tumour-bearing mice and in one of the CA20948 tumour-bearing mice. No renal dysfunction was observed in (213)Bi-DOTATATE-treated mice after the doses were applied.
  
  
  CONCLUSIONS
  (213)Bi-DOTATATE demonstrated a great therapeutic effect in both small and larger tumour lesions. Higher probability for stable disease was found in animals with small tumours. (213)Bi-DOTATATE was effective in different neuroendocrine (H69 and CA20948) tumour models with overexpression of SSTR2 in mice.
authors.affiliation: Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. h.s.chan1982@gmail.com.
authors.forename: Ho Sze
authors.initials: HS
authors.lastname: Chan
authors.affiliation: Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Konijnenberg
authors.affiliation: Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.affiliation: Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Stuart
authors.initials: S
authors.lastname: Koelewijn
authors.affiliation: Department of Nuclear Medicine/Center for PET/CT, Zentralklinik, Bad Berka, Germany.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Baum
authors.affiliation: Institute for Transuranium Elements (ITU), Joint Research Centre, European Commission, Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Institute for Transuranium Elements (ITU), Joint Research Centre, European Commission, Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: Breeman
authors.affiliation: Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong