The theranostic promise for Neuroendocrine Tumors in the late 2010s - Where do we stand, where do we go?

Abstract

More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.

Keywords: PRRT; neuroendocrine tumor; peptide receptor radionuclide therapy; somatostatin receptor; theranostics.

Figure 1

Display of [¹⁸F]-FDG PET/CT and somatostatin receptor-directed PET/CT with [⁶⁸Ga]-DOTATOC before and 1 year after initiation of peptide receptor radionuclide therapy with [¹⁷⁷Lu]-DOTATOC in a patient suffering from sarcoidosis. After a total of four cycles, stable disease (with a slight reduction in somatostatin receptor expression and increasing activity in the spleen) was recorded. Both PET projections are displayed with the same intensity. From Lapa et al., Theranostics, .

Figure 2

Tumor heterogeneity in a patient with a G3 gastric NET and liver metastases in a 67 year old patient suffering from gastric NET with liver metastases (Ki67 = 90%, G3 NET). In accordance with G3 NET, hypermetabolic hepatic metastases demonstrate loss of SSTR and up-regulation of CXCR4 expression (solid arrows). Moreover, [⁶⁸Ga]-Pentixafor provides additional information on disease extent by exclusively detecting a coeliac lymph node suspicious for metastatic disease (dotted arrows). From Werner et al., Theranostics, .

Figure 3

Flow-chart for potential further workup and treatment based on somatostatin receptor reporting and data system (SSTR-RADS) classification . MRI = magnetic resonance imaging.

Figure 4

Application of somatostatin receptor reporting and data system (SSTR-RADS) for the interpretation of SSTR-targeted PET/CT . 76 year-old male with history of a cancer of unknown primary (most likely primary hepatic NET), which underwent [⁶⁸Ga]-DOTATOC PET/CT for staging. (A) Whole body maximum intensity projection demonstrated multiple suspicious uptake sites (arrowheads). On (B) axial CT, (CT) axial PET and (D) axial PET/CT, mild radiotracer uptake is seen in a left supraclavicular lymph node (thin arrow). This lesion was classified as SSTR-RADS 3A by an experienced reader. On (F) axial PET and (G) axial PET/CT, intense radiotracer uptake is visualized in the head of the 7th right rib (double thin arrows). As this site of radiotracer uptake did not show corresponding findings on (E) axial CT, this finding was classified as SSTR-RADS-4. On (H) axial CT, (I) axial PET and (J) axial PET/CT, intense radiotracer uptake is visualized in a liver lesion (segment VII/VIII, arrow), which shows central necrosis and subtle hypodensity on (H) axial CT. Thus, this lesion was classified as SSTR-RADS Score 5. Another liver lesion in segment VIII/IVa (arrowhead) also demonstrated intense radiotracer uptake on (I) axial PET and (J) axial PET/CT, but without corresponding findings on (H) axial CT, i.e. SSTR-RADS-4. The Overall SSTR-RADS Score was 5. Based on this scoring, peptide receptor radionuclide therapy may be considered .