Importance of PET with ⁶⁸Ga-Labeled Somatostatin Analogs (perspective on “⁶⁸Ga-DOTA-Tyr3-Octreotide PET in Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and CT” J Nucl Med. 2007;48:508–518)

Neuroendocrine tumors (NETs) still represent a diagnostic challenge because their clinical presentation is often nonspecific and usually occurs late in the disease, when metastases are already present (1). Imaging modalities such as CT, MRI, and transabdominal ultrasound are fundamental for diagnosis and staging. However, molecular imaging, including scintigraphy (¹¹¹In-pentetreotide or ^99mTc-HYNIC-Tyr³-octreotide) and PET with ⁶⁸Ga-labeled somatostatin analogs (SSA), is now playing an increasingly important role. In the last 20 years, the molecular imaging of NETs has been changed by the introduction of PET with the ⁶⁸Ga-labeled octreotide derivatives (⁶⁸Ga-SSA). Compared with CT and receptor scintigraphy, PET exhibits higher sensitivity, especially in patients with small tumors at the nodal or bone level. Today, the development of PET/CT scanners, whereby molecular and anatomic details are superimposed, has increased diagnostic accuracy, and PET/CT with ⁶⁸Ga-SSA (⁶⁸Ga-SSA PET/CT) has become a decision-making technique in the clinical management of NETs. In this regard, the 2007 study by Gabriel et al. that was published in The Journal of Nuclear Medicine was the first prospective phase IIb study on a large series of patients comparing the performance of ⁶⁸Ga-SSA PET, CT diagnostics, and scintigraphy with SSAs labeled with both ^99mTc and ¹¹¹In (2). The study was performed on patients at 3 different times in the natural history of NETs: diagnosis (patients with clinical or biochemical suspicion of neuroendocrine neoplasia), staging, and follow-up.

The results obtained from the analysis of 84 consecutive patients showed a high sensitivity, specificity, and accuracy for ⁶⁸Ga-SSA PET, with values of 97%, 92%, and 96%, respectively—statistically significant with respect to both SPECT and CT.

In particular, the authors showed that ⁶⁸Ga-SSA PET was superior to SPECT in 32 patients (38%), especially in the visualization of lesions in the liver and in lymph nodes that were smaller than the γ-camera–resolving power.

The comparison between the accuracy of ⁶⁸Ga-SSA PET and CT showed a discrepancy in 34 patients (40.5%): in particular, CT was falsely negative on a skeletal level, with loss of 50% of the lesions. ⁶⁸Ga-SSA PET was also able to identify small lesions in unusual locations such as the breast and myocardium. ⁶⁸Ga-SSA PET was particularly useful in the visualization of bone metastases, with a higher sensitivity, specificity, and accuracy than a CT scan. In this study of 84 patients (116 PET-positive lesions), only 84 lesions (72.5%) were evident at conventional scintigraphy and only 58 (50%) at CT.

The different diagnostic performances of the 3 investigated methods led to a significant change in patient management and in a different prognostic stratification.

The study, albeit showing some limitations relating mainly to the use of 2 different tracers for scintigraphy, nevertheless demonstrated the fundamental role of molecular imaging with ⁶⁸Ga-SSA PET in the management of NET patients. Notably, PET was performed with a PET scanner (GE Healthcare Advance), and the images were sequentially fused with CT. The conclusions, supported by the data presented, were that ⁶⁸Ga-SSA PET was superior to SPECT and CT and that the best results were achieved by the combination of PET and CT. The advent of the hybrid PET/CT scanner was a further step forward.

The interest aroused by this work therefore led to an increased number of articles on this topic—articles that have significantly changed the approach to patients with NETs. Furthermore, the development of peptide receptor radionuclide therapy with peptides labeled with β-emitting isotopes such as ⁹⁰Y or ¹⁷⁷Lu has paved the way to a more substantial role for nuclear medicine in the management of these tumors, with a significant improvement in the quality of life and outcome of patients (3,4).

Given the scientific evidence produced in the last decade, it was therefore possible to review the guidelines on the management of patients with NETs. Currently, both European and U.S. guidelines (5,6) recommend SSTR PET/CT for diagnosis, staging, and restaging of patients with NETs. Furthermore, the method is mandatory for correct evaluation of the patients who are most likely to benefit from peptide receptor radionuclide therapy.

• © 2020 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication July 31, 2020.
• Accepted for publication August 19, 2020.