Prognostic implications of [¹⁸F]FDG PET and metabolic changes in patients with advanced metastatic neuroendocrine tumors undergoing rechallenge PRRT: final results from a multicenter 10-year survival WARMTH study.

Rationale: Rechallenge peptide receptor radionuclide therapy (PRRT) is a valid therapeutic option for patients with advanced/metastatic neuroendocrine tumors (NETs) who previously benefited from initial PRRT. In this context, [18F]FDG PET may serve as a prognostic marker. This multicenter 10-year survival study aims to evaluate the prognostic implications of [18F]FDG PET and PRRT-induced changes in NET patients undergoing rechallenge PRRT.

Methods

This retrospective multicenter study included 100 patients (median age: 54 years, range: 29-83) treated with rechallenge PRRT. All patients underwent [68Ga]Ga-DOTA-TOC/TATE/NOC and [18F]FDG PET/CT prior to the first PRRT period, 3-4 months after PRRT, and every 6-9 months thereafter. Metabolic status and its changes (no change vs. FDG+/FDG- vs. FDG-/FDG+) before the first PRRT period and at each restaging were recorded and correlated to baseline characteristics, time to progression (TTP), and overall survival (OS).

Results

In 43 out of 100 patients, the primary tumor site was the pancreas; the liver was involved in more than 90% of patients. Biopsies revealed G1 NET in 16%, G2 NET in 66%, and G3 NET in 18% of cases. Before the first PRRT period, 50% of patients were FDG-positive. Following the first PRRT period, 27 patients exhibited a change in metabolic status: 20 converted to FDG-negative, whereas 7 became FDG-positive. After the second PRRT period, metabolic status changed in 41 patients, with 25 converting to FDG-negative and 16 to FDG-positive. Metabolic status after the first period was significantly correlated with NET grade (p = 0.009). The correlation persisted also after rechallenge (p < 0.001), suggesting that FDG positivity increased progressively in G3 NET patients (p = 0.020). The presence of bone metastases statistically correlated with FDG positivity before (p < 0.001) and after (p = 0.001) the first PRRT period. Multivariate Cox regression analysis revealed NET G3 and FDG status after the first PRRT course as independent factors for shorter TTP. After a median follow-up time of 117.6 months (range: 38.4-180 months), 37 patients had died. Multivariate Cox regression analysis revealed FDG positivity after the first (p < 0.001) and second (p < 0.001) periods of PRRT as independent predictors of poor OS.

Conclusions

Assessing [18F]FDG status before PRRT and during follow-up after treatment enables prediction of TTP and OS, even in patients considered for rechallenge PRRT. Standardizing the use of dual-tracer imaging in patients receiving PRRT seems a valuable approach to improve clinical decision-making in NET patients.