title: Optimization of combined temozolomide and peptide receptor radionuclide therapy (PRRT) in mice after multimodality molecular imaging studies.
abstract: BACKGROUND
  Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate ((177)Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ.
  
  
  METHODS
  We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq (177)Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of (111)In-octreotide was quantified using SPECT/CT until day 39 after treatment. Based on these results, seven different (177)Lu-octreotate and TMZ combination schemes were evaluated for therapy response, varying the order and time interval of the two therapies and compared with single treatments.
  
  
  RESULTS
  PRRT and TMZ both resulted in tumour size reduction, accompanied by significant changes in MRI characteristics such as an enhanced tumour perfusion. Moreover, TMZ treatment also resulted in increased uptake of the SST analogue (111)In-octreotide until day 13. In the subsequent therapy study, 90 % of animals receiving (177)Lu-TATE at day 14 after TMZ treatment showed complete response, being the best anti-tumour results among groups.
  
  
  CONCLUSIONS
  Molecular imaging studies indicated that PRRT after TMZ treatment could induce optimal therapeutic effects because of enhanced tumour uptake of radioactivity after TMZ, which was confirmed by therapy responses. Therefore, clinical translation of TMZ treatment prior to PRRT might increase tumour responses in NET patients as well.
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands. s.bison@eramusmc.nl.|Department of Radiology, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands. s.bison@eramusmc.nl.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Bison
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands. j.haeck@erasmusmc.nl.|Department of Radiology, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands. j.haeck@erasmusmc.nl.
authors.forename: Joost C
authors.initials: JC
authors.lastname: Haeck
authors.affiliation: Department of Radiology, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.|Department of Medical Informatics, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Bol
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: S J
authors.initials: SJ
authors.lastname: Koelewijn
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Groen
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Melis
authors.affiliation: Department of Radiology, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.|Department of Medical Informatics, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Veenland
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.|Department of Radiology, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: M R
authors.initials: MR
authors.lastname: Bernsen
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.|Department of Radiology, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Jong
keywords: Combination therapy; Multimodality imaging; NETs; PRRT; Temozolomide; Tumour perfusion