Small bowel NETs are commonly metastatic at presentation and/or are not amenable to complete surgical resection. Somatostatin analogues are the first-line treatment for metastatic small bowel NETs, as they offer both antiproliferative effects and carcinoid syndrome symptom control. The US Food and Drug Administration (FDA) approval of peptide receptor radionuclide therapy (PRRT) led to a paradigm shift in the treatment of these NETs beyond first-line therapy. Like nuclear medicine functional imaging, PRRT uses somatostatin receptors as a target. 

Several PRRTs have been under study, but, thus far, lutetium-177 (¹⁷⁷Lu)–DOTATATE is the only one that has been approved by the FDA. The approval in 2018 was for somatostatin receptor–positive gastroenteropancreatic NETs. I was involved with one of the studies that led to FDA approval, the NETTER-1 study, in which 229 patients with metastatic, well-differentiated, midgut NETs were randomly assigned to treatment with ¹⁷⁷Lu-DOTATATE plus 30 mg per month of octreotide long-acting repeatable (LAR) or to 60 mg per month of octreotide LAR alone. 

We observed a 79% improvement in the primary end point, progression-free survival, in the ¹⁷⁷Lu-DOTATATE group as compared with the high-dose octreotide LAR group. This was highly statistically and clinically significant. The study was not well powered for overall survival (OS), and certainly not with crossover. We have not seen survival benefit in NETs with any of the drugs being studied, and this likely reflects the relatively small trial sizes and the many patients who are able to cross over to receive the investigational therapy. This was true of the NETTER-1 study as well. There was a numerical improvement of approximately 1 year in median OS from 3 years to 4 years, which was associated with ¹⁷⁷Lu-DOTATATE vs high-dose octreotide, but this was not statistically significant. OS benefits would have been difficult to show, as more than one-third of patients crossed over from receiving high-dose octreotide to eventually receiving PRRT. Additionally, there was a relatively small number of deaths to include in the analysis. Although the final OS did not reach statistical significance, the 11.7-month difference in median OS with ¹⁷⁷Lu-DOTATATE treatment vs treatment with high-dose octreotide LAR alone might be considered clinically relevant. Further, there were no new safety signals reported during long-term follow-up.

PRRT with ¹⁷⁷Lu-DOTATATE is not a particularly toxic therapy in terms of day-to-day tolerability. In fact, it is fairly well tolerated. The real main concern is long-term hematological toxicity. NETTER-1 included 1 patient who had a history of monoclonal gammopathy of unknown clinical significance and had cytopenias and, subsequently, underwent a bone marrow biopsy that revealed histologic changes that were consistent with the myelodysplastic syndrome that was considered to be possibly related to the investigational therapy. Performance status may also be a consideration in that, although we can treat a patient with a relatively poor performance status, once the performance status reaches 3 or 4, the chances of achieving benefits with any treatment, including PRRT, are fairly minimal. 

For patients who continue to progress and have fewer options available to them, the question of retreatment naturally arises. We conducted a review and meta-analysis to examine published evidence of PRRT retreatment efficacy and safety in patients with advanced NETs. We found that retreatment with PRRT with ¹⁷⁷Lu-DOTATATE provided encouraging median progression-free survival in patients with NETs, with a safety profile that is similar to initial PRRT. Patients who experienced at least 1 year of disease stabilization following the completion of the initial treatment seemed to benefit the most from retreatment.