Background <p>Recent data demonstrate that one possibility for increasing Peptide Receptor Radionuclide Therapy (PRRT) results lies in the combination of PRRT with chemotherapy. This study aimed to evaluate response and outcome in [¹⁸F]FDG-positive metastatic neuroendocrine tumor (mNET) patients treated with PRRT alone or in combination with temozolomide (TEM) plus/minus capecitabine (CAP).</p> Methods <p>All mNET patients presented with [¹⁸F]FDG-positive disease prior to treatment (or retreatment) with PRRT alone or in combination with chemotherapy were retrospectively included in this single-center study. Patients received [¹⁷⁷Lu]Lu-DOTATATE with an activity of 7.4 GBq alone or combined with TEM (200&#xa0;mg/kg/5d) plus/minus CAP (1500&#xa0;mg/kg/14d). Contrast-enhancement CT (ceCT), [⁶⁸Ga]Ga-DOTATOC and [¹⁸F]FDG PET/CT studies were performed at baseline, after treatment, and every 6 months thereafter. Overall response rate (ORR) and disease control rate (DCR) were calculated for each group. Survival analysis was performed using the Kaplan-Meier method. Adverse events were collected and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.</p> Results <p>A total of 24 patients were included in the final analysis. Group 1 received PRRT with [¹⁷⁷Lu]Lu-DOTATATE alone (<i>n</i> = 10), group 2 received [¹⁷⁷Lu]Lu-DOTATATE plus TEM (<i>n</i> = 7), and group 3 received [¹⁷⁷Lu]Lu-DOTATATE plus CAPTEM (<i>n</i> = 7). There were no differences between groups in terms of clinicopathological features before treatment. The pancreas was the primary tumor site in 58%, and 92% of patients had more than three liver metastases. Based on [⁶⁸Ga]Ga-DOTATOC PET/CT and ceCT, in group 1 the ORR and DCR were 10% and 50%, respectively. [¹⁸F]FDG PET/CT showed 2 responders (1 CR, 1 PR). In group 2, the ORR and DCR were 14% and 43%, respectively. [¹⁸F]FDG PET/CT showed 2 responders (1 CR, 1 PR). In group 3, the ORR and DCR were 71%, respectively. [¹⁸F]FDG PET/CT showed 5 responders (3 CR, 2 PR). In the latter group, 4/7 patients had not progressed and 5/7 were still alive at the time of analysis after a median follow-up of 31 months.</p> Conclusion <p>Our results show PRRT combined with CAPTEM as the most promising regimen, achieving higher response rates in [¹⁸F]FDG-positive mNETs compared with PRRT alone or PRRT plus TEM. Further studies are required to confirm its added value in terms of survival outcomes. No increased toxicity seems to be associated with combination therapy compared to PRRT alone.</p>