Does PRRT with standard activities of 177Lu-octreotate really achieve relevant somatostatin receptor saturation in target tumor lesions?: insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors

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Abstract
Background: Peptide receptor radionuclide therapy (PRRT) with 177Lu-[DOTA0,Tyr3]octreotate (177Lu-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 pre- and intra-therapeutic 68Ga-DOTATOC positron emission tomography (PET) imaging might guide potential dose escalation. Methods: Five patients with metastatic NET of the pancreas underwent 68Ga-DOTATOC PET/CT before and directly after standard-dose PRRT with 177Lu-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 177Lu-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 177Lu-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 177Lu-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 177Lu-octreotate appears futile.

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