Recent Updates on Molecular Imaging Reporting and Data Systems (MI-RADS) for Theranostic Radiotracers-Navigating Pitfalls of SSTR- and PSMA-Targeted PET/CT

Abstract

The theranostic concept represents a paradigmatic example of personalized treatment. It is based on the use of radiolabeled compounds which can be applied for both diagnostic molecular imaging and subsequent treatment, using different radionuclides for labelling. Clinically relevant examples include somatostatin receptor (SSTR)-targeted imaging and therapy for the treatment of neuroendocrine tumors (NET), as well as prostate-specific membrane antigen (PSMA)-targeted imaging and therapy for the treatment of prostate cancer (PC). As such, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy using positron emission tomography (PET). While interpreting PSMA- or SSTR-targeted PET/computed tomography scans, the reader has to navigate certain pitfalls, including (I.) varying normal biodistribution between different PSMA- and SSTR-targeting PET radiotracers, (II.) varying radiotracer uptake in numerous kinds of both benign and malignant lesions, and (III.) resulting false-positive and false-negative findings. Thus, two novel reporting and data system (RADS) classifications for PSMA- and SSTR-targeted PET imaging (PSMA- and SSTR-RADS) have been recently introduced under the umbrella term molecular imaging reporting and data systems (MI-RADS). Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e., if the reader is familiar with one system, the other system can readily be applied. Learning objectives of the present case-based review are as follows: (I.) the theranostic concept for the treatment of NET and PC will be briefly introduced, (II.) the most common pitfalls on PSMA- and SSTR-targeted PET/CT will be identified, (III.) the novel framework system for theranostic radiotracers (MI-RADS) will be explained, applied to complex clinical cases and recent studies in the field will be highlighted. Finally, current treatment strategies based on MI-RADS will be proposed, which will demonstrate how such a generalizable framework system truly paves the way for clinically meaningful molecular imaging-guided treatment of either PC or NET. Thus, beyond an introduction of MI-RADS, the present review aims to provide an update of recently published studies which have further validated the concept of structured reporting systems in the field of theranostics.

Keywords: NET; PET; PSMA; PSMA-RADS; RADS; SSTR; SSTR-RADS; molecular imaging reporting and data systems (MI-RADS); neuroendocrine tumors; positron emission tomography; prostate carcinoma; prostate-specific membrane antigen; reporting and data system; somatostatin receptor; theragnostics; theranostics.

Figure 1

Theranostic concept in prostate carcinoma using prostate-membrane specific antigen (PSMA)-directed imaging and therapy. (A) PSMA-targeted positron emission tomography (PET) imaging before initiation of PSMA-targeted therapy showing widespread metastatic disease. Post-therapeutic scintigraphic scan after (B) one and (C) two cycles of PSMA-targeted therapy. (D) PSMA-targeted PET imaging after two cycles of therapy demonstrating high therapeutic efficacy and near-complete remission. Response was further corroborated by a decline in prostate specific antigen (PSA) level from 396.0 ng/mL to 7.35 ng/mL. PSMA: prostate-specific membrane antigen.

Figure 2

Evolution of molecular imaging reporting and data systems (MI-RADS). For theranostic radiotracers, two novel reporting and data system (RADS) classifications for PSMA- and SSTR-targeted PET imaging (PSMA- and SSTR-RADS) have been summarized under the umbrella term MI-RADS. SSTR: somatostatin receptor; RADS: reporting and data systems.

Figure 3

Whole-body maximum intensity projection images with normal biodistribution of (A) prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) using ⁶⁸Ga-PSMA-11 and (B) somatostatin receptor (SSTR)-targeted PET using ⁶⁸Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid-d-Phe(1)-Tyr(3)- octreotate (⁶⁸Ga-DOTATATE).

Figure 4

⁶⁸Ga-DOTATATE maximum intensity projection (MIP) of patients with (A) low tumor burden, and (B) high tumor burden. Spleen (S), liver (L) and kidneys (K) are indicated, and the threshold has been set to a SUV of 15 in both scans. Red arrows indicate tumor lesions, which can be detected on the MIP: In Patient A SSTR-positive liver lesions and the SSTR-avid tail of the pancreas are highlighted. In Patient B several thoracic lymph node metastases are shown, but also several hepatic and bone lesions (e.g., in the acetabulum) can be detected. As ⁶⁸Ga-DOTATATE has been used, a moderate tumor-sink effect can be appreciated, e.g. when comparing the kidneys of both patients [42]. Nonetheless, the visual assessed uptake in normal organs (visible for liver, kidneys, and spleen) does not differ substantially among the different patients. Thus, in patients with extensive tumor involvement, subtle lesions close to normal organs or other tumor lesions with high uptake can be missed, which in turn may decrease absolute lesion detection rate.

Figure 5

Equivocal uptake in bone lesion on SSTR-targeted positron emission tomography (PET)/computed tomography (CT). ⁶⁸Ga-DOTATATE PET/CT for restaging in a 52-year-old woman with a history of ileal neuroendocrine carcinoma. Whole-body maximum intensity projection image showing multiple metastases to lymph nodes with clearly pathologic radiotracer uptake (yellow arrows), consistent with SSTR-RADS 5 lesions and a faint osteolytic bone lesion (red arrow) (A). Axial low-dose bone-window CT image (B), soft-tissue window CT image (C), PET image (D), and fused PET/CT image (E) further show this faint osteolytic bone lesion on anatomic imaging with equivocal uptake (red arrows), consistent with a SSTR-RADS-3B lesion.

Figure 6

Lesion suggestive of malignancy on anatomic imaging but lacking uptake on SSTR-targeted positron emission tomography (PET)/computed tomography (CT). ⁶⁸Ga-DOTATATE PET/CT for restaging in a 67-year-old man with a history of pancreatic neuroendocrine carcinoma. Whole-body maximum intensity projection image with no evidence of disease (A). Axial low-dose CT (B), contrast-enhanced CT (C), PET (D), and fused PET/CT (E) showing a peritoneal lesion suggestive of malignancy on anatomic imaging, but lacking uptake (red arrows), consistent with a SSTR-RADS-3D lesion.

Figure 7

Equivocal uptake in soft-tissue lesion typical of prostate cancer lesion on PSMA-targeted positron emission tomography (PET)/computed tomography (CT). ⁶⁸Ga-PSMA-11 PET/CT for restaging in a 73-year-old man with a history of a prostate cancer. Whole-body maximum intensity projection image showing absence of clearly pathologic radiotracer uptake (A). Axial low-dose CT (B), contrast-enhanced CT (C), PET (D), and fused PET/CT (E) showing an iliac lymph node typical of a prostate cancer lesion on anatomic imaging, but with equivocal uptake (red arrows), consistent with a PSMA-RADS-3A lesion.

Figure 8

Equivocal uptake in soft-tissue and bone lesions on PSMA-targeted positron emission tomography (PET)/computed tomography (CT). ⁶⁸Ga-PSMA-11 PET/CT for restaging in a 66-year-old man with a history of a prostate cancer. Whole-body maximum intensity projection image showing multiple metastases to lymph nodes and to the bone with both clearly pathologic radiotracer uptake and equivocal radiotracer uptake (A). Axial low-dose CT image (B), contrast-enhanced CT image (C), PET image (D), and fused PET/CT image (E) showing a mediastinal lymph node typical of a prostate cancer lesion on anatomic imaging, but with equivocal uptake (red arrows), consistent with a PSMA-RADS-3A lesion. Axial soft-tissue window CT image (F), bone-window CT image (G), PET image (H) and fused PET/CT image (I) showing a bone marrow lesion not atypical of a prostate cancer lesion on anatomic imaging, but with equivocal uptake (yellow arrows), consistent with a PSMA-RADS-3B lesion.

Figure 9

Lesion suggestive of malignancy on anatomic imaging but lacking uptake on PSMA-targeted positron emission tomography (PET)/computed tomography (CT). ⁶⁸Ga-PSMA-11 PET/CT for restaging in a 52-year-old man with a history of a prostate cancer. Whole-body maximum intensity projection image demonstrating intense radiotracer uptake in metastases in the liver, lymph nodes and bone (A). Axial low-dose CT (B), contrast-enhanced CT (C), PET (D), and fused PET/CT (E) showing a hepatic lesion suggestive of malignancy on anatomic imaging, but lacking uptake (red arrows), consistent with a PSMA-RADS-3D lesion. In addition, there are numerous hepatic lesions with intense tracer uptake, consistent with a classification as PSMA-RADS-5 lesions.

Figure 10

(A) Overview of target lesion (TL) assessment (identical target lesion included by all four readers on 50 PSMA-positron emission tomography (PET)/computed tomography (CT) scans with ¹⁸F-DCFPyL). The following organ compartments were defined: lymph nodes (LN), skeleton, prostate/local recurrence, soft tissue (other than LN), liver, thyroid, and lung. A PSMA-RADS Score had to be assigned to every target lesion by every blinded reader (ER, experienced reader, IR, inexperienced reader). Often, characterizing a lesion as PSMA-RADS-1B involves previous conventional imaging or histologic diagnosis; as such, PSMA-RADS-1A and -1B were subsumed under PSMA-RADS-1 in the present blinded interobserver agreement study. (B) Overview of overall PSMA RADS scoring for four blinded readers (ER, IR, assessment of 50 ¹⁸F-DCFPyL PET/CT scans). For the TL and overall scan impression, a high interreader agreement rate, even among IRs, was noted. Modified from Werner et al. [70], © by the Society of Nuclear Medicine and Molecular Imaging, Inc.