Purpose of Review: This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT). Recent Findings: Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. Summary: PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients’ quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.

Somatostatin receptor (SST) positron emission tomography with computed tomography (PET/CT) is the gold standard for functional imaging of neuroendocrine tumors (NETs), but FDG PET/CT is increasingly recognized for its prognostic value, particularly for higher‐grade NETs and to detect disease heterogeneity. Despite the established role of pathological grading, clinical heterogeneity within the tumor burden often complicates accurate prognostication. Evidence suggests FDG PET/CT can outperform WHO grading in predicting outcomes by identifying aggressive, undifferentiated tumor clones that influence long‐term prognosis and treatment decisions. Several grading systems integrating both SST and FDG PET/CT have been proposed to better capture tumor heterogeneity and guide clinical management. Studies demonstrate that FDG PET/CT can influence management in a significant subset of patients, although variably reported. Its use remains variable across centers, also affected by different reimbursement policies and local clinical practices. This review explores the indications to FDG PET/CT in NET and the clinical impact of combined SST and FDG PET/CT imaging.

Purpose: To evaluate the role of PSMA PET/CT-guided salvage radiotherapy (sRT) in improving long-term biochemical recurrence-free survival (bRFS) in patients with biochemical recurrence (BCR) or PSA persistence (PERS) after radical prostatectomy (RP) for localized prostate cancer. Methods: This single-center retrospective study included 100 patients with BCR or PERS after RP who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT and sRT according to EAU guidelines. The primary endpoint was bRFS (PSA ≤ 0.2 ng/ml). Results: Sixty-three patients had BCR and 37 had PERS. Fifteen patients had PSA pre-RT < 0.5 ng/ml, while 75 had PSA pre-RT ≥ 0.5 ng/ml. [⁶⁸Ga]Ga-PSMA-11 PET/CT was positive in 52 patients, with BCR patients more frequently exhibiting local recurrence while PERS patients showed more nodal involvement. Patients with PERS received sRT and androgen deprivation therapy (ADT) in 57% of cases. The hazard ratio (HR) of treatment failure for patients with PSA pre-RT ≥ 0.5 ng/ml vs. < 0.5 ng/ml was 2.2 (p < 0.039). With a median follow-up of 59 months, treatment failure occurred in 36% of patients, with no difference between BCR and PERS groups. Among those with treatment failure, 64% were [⁶⁸Ga]Ga-PSMA-11 PET/CT positive at recurrence, and 39% received a new PSMA PET/CT-based RT. All patients were alive at the last analysis. Conclusion: [⁶⁸Ga]Ga-PSMA-11 PET/CT-guided sRT demonstrates significant long-term efficacy in patients with BCR or PERS after RP, leading to durable PSA response and guiding further treatment decisions. Trial registration: 244/2016/O/Oss8 November 2016 retrospectively registered.

The assessment of response to therapy in prostate cancer (PCa) patients is an ongoing, open issue. Prostate-specific antigen has limitations, especially in advanced metastatic PCa, which often displays intratumor variability in terms of response to therapy. Conventional imaging (i.e. computerized tomography and bone scan) is of limited use for its low sensitivity and specificity. Positron-emission tomography (PET) with prostate-specific membrane antigen (PSMA) demonstrated higher sensitivity and specificity, and novel PSMA-based criteria have been recently proposed for treatment response, with promising results in different scenarios, from chemotherapy to radioligand therapy. PSMA-based criteria have been found to outperform the current RECIST 1.1 and Prostate Cancer Working Group 3 frameworks in describing the behavior of PCa, precisely assessing tumor phenotypes through molecular-imaging-derived parameters. This review critically explores the current evidence about the role of PSMA PET/computed tomography in the assessment of treatment response.

Assessing treatment response in neuroendocrine tumors (NET) remains a significant challenge due to their typically indolent growth and heterogenity, the frequent occurrence of disease stabilization rather than tumor shrinkage after therapy, and the inherent limitations of conventional imaging criteria. While molecular imaging-primarily somatostatin receptor (SST) PET/CT-has improved lesion detection, the absence of standardized response criteria limits its clinical utility and prevents its use as full replacement of conventional imaging. Emerging strategies, including revised thresholds for dimensional changes, criteria evaluating different features, such as lesions' density and functional tumor volumes, offer potential improvements in response evaluation but require further validation for routine clinical implementation. This review examines the current challenges in assessing NET treatment response, evaluates the strengths and limitations of available imaging modalities, and discusses emerging approaches and future directions for optimizing therapeutic monitoring in the heterogeneous panorama of NET.

The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting.