Theranostic radiopharmaceutical therapy has moved from niche practice to mainstream oncology, anchored by approvals of lutetium Lu 177 dotatate for somatostatin receptor-positive neuroendocrine tumors and lutetium Lu 177 vipivotide tetraxetan for PSMA-positive prostate cancer. Yet the field's future depends on rigorous clinical trial design, realistic operational planning, and workforce readiness. This review summarizes how theranostics evolved, outlines current regulatory and trial-design yardsticks (including dose optimization and expectations for assessment of late-toxicity), and provides a practical framework for nuclear medicine physicians to assess protocols and prepare their practices for expanding indications and combinations.

P1, N=10, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2026 --> Sep 2027 | Trial primary completion date: Sep 2026 --> Sep 2027

P=N/A, N=164, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

We herein present a patient of grade I pancreatic NET showing atypical low somatostatin receptor expression on 68 Ga-DOTATATE PET/CT (positron emission tomography/computed tomography) but intense fluorine-18-deoxyglucose ( 18 FDG) avidity, and when interpreted together, these findings showed discordance with histopathology. The case highlights the crucial role of dual-tracer PET/CT in navigating the tumor biology and landscape of NET and the need for novel strategies to complement traditional histopathology that would enable better therapeutic decision-making.

Baseline NSE elevation and early post-treatment declines may serve as potential prognostic indicators. These results are hypothesis-generating and warrant validation in larger, multicenter studies.

This comprehensive review examines the current state of theranostics in NENs, encompassing the molecular basis of somatostatin receptors (SSTR) targeting, diagnostic imaging modalities, therapeutic radiopharmaceuticals, dosimetry methodologies, patient selection criteria, treatment outcomes, toxicity profiles, and emerging innovations including α-emitting radionuclides and SSTR antagonists. By integrating these multifaceted aspects, this review aims to provide clinicians and researchers with a holistic understanding of theranostics in NENs and its transformative impact on precision oncology.

P1, N=31, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

P3, N=240, Recruiting, Novartis Pharmaceuticals | N=100 --> 240

P1, N=1, Completed, Institut Claudius Regaud | Recruiting --> Completed | N=18 --> 1

After everolimus failure, he received 177Lu-DOTATATE (Lutathera®). Stable disease was maintained for 12 months without severe adverse events, preserving quality of life. 177Lu-PRRT is a promising therapeutic option for high-grade, somatostatin receptor-positive renal NET when other treatments fail.

P2, N=42, Recruiting, Mayo Clinic | Trial completion date: Jan 2031 --> Mar 2032 | Trial primary completion date: Jul 2026 --> Sep 2027

P2, N=70, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2033 --> Jul 2027 | Trial primary completion date: Jul 2026 --> Jul 2027