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

<b>Rationale:</b> 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. <b>Methods:</b> 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). <b>Results:</b> 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 (<i>p =</i> 0.009). The correlation persisted also after rechallenge (<i>p <</i> 0.001), suggesting that FDG positivity increased progressively in G3 NET patients (<i>p =</i> 0.020). The presence of bone metastases statistically correlated with FDG positivity before (<i>p <</i> 0.001) and after (<i>p =</i> 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 (<i>p <</i> 0.001) and second (<i>p <</i> 0.001) periods of PRRT as independent predictors of poor OS. <b>Conclusions:</b> 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.