octreotate really achieve relevant somatostatin receptor saturation in target tumor lesions?: insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors

Background: Peptide receptor radionuclide therapy (PRRT) with Lu-[DOTA,Tyr]octreotate (Lu-octreotate) is generally performed using a fixed activity of 7.4 GBq (200 mCi) per course bound to 180 to 300 μg of the peptide. While this single activity may lead to suboptimal radiation doses in neuroendocrine tumors (NET) with advanced or bulky disease, dose escalation has been withheld due to concerns on potential tumor somatostatin receptor saturation with reduced efficacy of the added activity. In vivo saturation effects during standard-dose PRRT based on quantification of preand intra-therapeutic Ga-DOTATOC positron emission tomography (PET) imaging might guide potential dose escalation. Methods: Five patients with metastatic NET of the pancreas underwent Ga-DOTATOC PET/CT before and directly after standard-dose PRRT with Lu-octreotate. In each patient, four target tumor lesions, normal liver parenchyma, and the spleen were evaluated and the ratios of SUVmax of the target lesions to liver (SUVT/L) and spleen (SUVT/S) were calculated; paired Student's t test was performed with p < 0.05 for pre-/intra-PRRT comparisons. Results: The mean intra-therapeutic tumor SUVmax showed no significant change (per-lesion paired t test) compared to pretreatment values (−9.1%, p = 0.226). In contrast, the SUVmax of the normal liver parenchyma and spleen were significantly lower directly after infusion of 7.4 GBq Lu-octreotate. Consequently, SUVT/L and SUVT/S increased significantly from pretreatment to intra-therapeutic examination: SUVT/L (p < 0.001) from 2.8 ± 1.3 (1.3 to 5.8) to 4.7 ± 3.0 (2.1 to 12.7) and SUVT/S (p < 0.001) from 1.2 ± 0.7 (0.4 to 3.0) to 3.5 ± 1.5 (1.6 to 7.9). Conclusions: This small retrospective study provides preliminary evidence for the absence of relevant in vivo saturation of somatostatin receptor subtype 2 (sst2) in tumor lesions during PRRT with standard activities of Lu-octreotate in contrast to normal tissue (liver, spleen) showing limited receptor capacity. After being confirmed by larger series, this observation will have significant implications for PRRT: (1) Higher activities of Lu-octreotate might be considered feasible in patients with high tumor disease burden or clinical need for remission, and (2) striving to reduce the amount of peptide used in standard preparations of Lu-octreotate appears futile. * Correspondence: [email protected] Department of Nuclear Medicine, University Hospital, Sigmund-Freud-Str. 25, Bonn 53105, Germany Full list of author information is available at the end of the article © 2013 Sabet et al.; licensee Springer. This is an Attribution License (http://creativecommons.or in any medium, provided the original work is p Open Access article distributed under the terms of the Creative Commons g/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction roperly cited. Sabet et al. EJNMMI Research 2013, 3:82 Page 2 of 6 http://www.ejnmmires.com/content/3/1/82 Background Neuroendocrine tumors (NET) commonly overexpress somatostatin receptors, in particular the subtype 2 (sst2), which are targeted for tumor-directed imaging and therapy [1-4]. Ga-labeled somatostatin analogues with high affinity to sst2 such as Ga-DOTA-D-Phe-Tyr-octreotate or Ga-DOTA-D-Phe-Tyr-octreotide are widely used for positron emission tomography (PET) imaging of NET [5-7]. The same sst2 ligands coupled to β-emitters Y or Lu are successfully utilized for targeted radionuclide therapy, peptide receptor radionuclide therapy (PRRT) comprising a well-established, effective systemic treatment modality in patients with inoperable, metastatic gastroenteropancreatic NET (GEP NET) [8-11]. Standard PRRT with Lu-[DOTA,Tyr]octreotate (Lu-octreotate) is performed with administration of a fixed activity of 7.4 GBq (200 mCi) per course [12-15]. This amount of activity is usually bound to 180 to 300 μg of the peptide with the chelator DOTA, [DOTA,Tyr] octreotate. One argument against dose escalation has been the concern on receptor saturation effects in the tumor lesions leading to reduced uptake and efficacy of the added activity [12,16-18]. This assumption has left PRRT with Lu-octreotate with an upper limit of activity per cycle of 7.4 GBq that until date has not been challenged; to the best of our knowledge, there are no reports of treatment with higher activities. However, it can be expected that this will lead to suboptimal treatment in some patients with more advanced/bulky tumor disease and a clinical need for tumor remission. The objective of this retrospective study was to investigate potential in vivo saturation of somatostatin receptors observed during standard PRRT according to quantification of intra-treatment PET studies.