Is there a role for early SSTR-targeting PRRT in GEP-NET?

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, such as [¹⁷⁷Lu]Lu-DOTATATE, is approved as a second-line treatment for progressive, gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, emerging evidence suggests potential earlier roles for PRRT.

Materials and methods: A systematic review was conducted in accordance with the PRISMA guidelines, including case reports, original papers, and clinical trial protocols evaluating neoadjuvant, adjuvant, or first-line PRRT in GEP-NETs. A systematic search of PubMed and clinicaltrials.gov (up to May 31, 2025) finally identified 25 eligible papers. For each paper, data were extracted regarding clinical setting, patient characteristics, treatment regimen, and oncologic and surgical outcomes.

Results: The available preliminary data, comprising case reports, retrospective and prospective cohorts, show that neoadjuvant PRRT can induce tumor shrinkage, regression of vascular involvement, and conversion from unresectable to resectable disease in up to 45% of patients. Reported outcomes include high objective response rates (up to 70%), improved surgical feasibility, and a promising survival benefit, especially in patients who received PRRT before surgery. Also, preliminary results from the NETTER-2 trial support the use of [¹⁷⁷Lu]Lu-DOTATATE as first-line therapy in SSTR-positive G2-G3 GEP-NET, showing significant improvement in progression-free survival. Differently, the evidence for adjuvant use is missing.

Conclusion: Current data suggest that PRRT, traditionally approved as a later-line therapy, may play a promising role in neoadjuvant and first-line settings for selected GEP-NET patients, enhancing resectability, improving surgical outcomes, and potentially prolonging survival. Further prospective, randomized studies are needed to define selection criteria, determine optimal timing, and assess the long-term impact on disease trajectory.