title: Peptide receptor radionuclide therapy (PRRT) with [(177)Lu-DOTA(0),Tyr(3)]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model.
abstract: BACKGROUND
  Previously, we reported on the unexpected development of distant metastases in the subcutaneous rat pancreas CA20948 tumor model after 4.5 weeks of treatment with RAD001-only or in combination with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-DOTATATE) (Cancer Res. 73:12-8, 2013). Moreover, the combination therapy was less effective compared to (177)Lu-DOTATATE-only. In the current study, we address the following questions: (1) Why was the combination therapy less effective? Is (177)Lu-DOTATATE tumor uptake affected by pretreatment with RAD001? (2) Could sudden cessation of RAD001 therapy cause the development of distant metastases? (3) Is (177)Lu-DOTATATE an effective treatment option for these metastases?
  
  
  METHODS
  Lewis rats (HanHsd or SsNHsd substrain with a slight difference in immune response) bearing subcutaneous CA20948 tumors were treated with either 125 or 275 MBq (177)Lu-DOTATATE, RAD001, or their combination. RAD001 was given twice a week for 4.5 or 12 weeks, whereas (177)Lu-DOTATATE was given as a single injection. When combined, RAD001 was started either 3 days prior to or 3 days post administration of (177)Lu-DOTATATE. SPECT/CT was performed to quantify (177)Lu-DOTATATE tumor uptake. Where indicated, primary tumors were surgically removed when tumor size is >6,000 mm(3) to enable monitoring for possible metastasis. If metastases were suspected, an (111)In-DTPA-octreotide SPECT/CT scan was performed. Seven rats with metastases were treated with 400 MBq (177)Lu-DOTATATE.
  
  
  RESULTS
  Lu-DOTATATE tumor uptake was not significantly affected by RAD001 pretreatment. The occurrence of metastases after RAD001 treatment was not dose dependent in the dose range tested, nor was it related to the duration of RAD001 treatment. In the experiment in which the LEW/SsNsd substrain was used, only 12.5% of RAD001-treated rats showed complete response (CR), compared to 50% tumor regression in the control group. Re-treatment with a high dose of (177)Lu-DOTATATE resulted in CR in only two out of seven animals.
  
  
  CONCLUSIONS
  Less effective anti-tumor effects after the combination of RAD001 + (177)Lu-DOTATATE could not be explained by reduced (177)Lu-DOTATATE tumor uptake after RAD001. Our current data support RAD001-induced immune suppression as the reason for this observation. No evidence was found that cessation of RAD001 treatment caused development of metastases. Metastases appeared to be less sensitive to (177)Lu-DOTATATE treatment than primary tumors.
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam 3000, CA, the Netherlands ; Department of Radiology, Erasmus MC, Rotterdam 3000, CA, the Netherlands ; Department of Medical Informatics, Erasmus MC, Rotterdam 3000, CA, the Netherlands.
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.
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Pool
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam 3000, CA, the Netherlands.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Koelewijn
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam 3000, CA, the Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: van der Graaf
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam 3000, CA, the Netherlands ; Department of Radiology, Erasmus MC, Rotterdam 3000, CA, the Netherlands.
authors.forename: Harald C
authors.initials: HC
authors.lastname: Groen
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam 3000, CA, the Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Melis
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam 3000, CA, the Netherlands ; Department of Radiology, Erasmus MC, Rotterdam 3000, CA, the Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
keywords: 177Lu-DOTATATE; Affinitor; Everolimus; Metastasis; RAD001