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90 Y resin radioembolization is an emerging treatment in patients with liver-dominant metastatic neuroendocrine tumors (mNETs), despite the absence of level I data. The aim of this study was to evaluate the efficacy of this modality in a meta-analysis of the published literature. Methods: A comprehensive review protocol screened all reports in the literature. Strict selection criteria were applied to ensure consistency among the selected studies: human subjects, complete response data with time interval, resin microspheres, more than 5 patients, not a duplicate cohort, English language, and separate and complete data for resin-based 90 Y treatment of mNET if the study included multiple tumor and microsphere types. Selected studies were critically appraised on 50 study criteria, in accordance with the research reporting standards for radioembolization. Response data (Response Evaluation Criteria in Solid Tumors) were extracted and analyzed using both fixed and random-effects meta-analyses. Results: One hundred fifty-six studies were screened; 12 were selected, totaling 435 procedures for response assessment. Funnel plots showed no evidence of publication bias (P 5 0.841). Critical appraisal revealed a median of 75% of desired criteria included in selected studies. Very high between-study heterogeneity ruled out a fixed-effects model. The random-effects weighted average objective response rate (complete and partial responses, CR and PR, respectively) was 50% (95% confidence interval, 38%-62%), and weighted average disease control rate (CR, PR, and stable disease) was 86% (95% confidence interval, 78%-92%). The percentage of patients with pancreatic mNET was marginally associated with poorer response (P 5 0.030), accounting for approximately 23% of the heterogeneity among studies. The percentage of CR and PR correlated with median survival (R 5 0.85; P 5 0.008). Conclusion: This meta-analysis confirms radioembolization to be an effective treatment option for patients with hepatic mNET. The pooled data demonstrated a high response rate and improved survival for patients responding to therapy.

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INTRODUCTION Radioembolization is a treatment option for colorectal cancer (CRC) patients with inoperable, chemorefractory hepatic metastases. Personalized treatment requires established dose thresholds. Hence, the aim of this study was to explore the relation between dose and effect (i.e. response and toxicity) in CRC patients treated with holmium-166 (166 Ho) radioembolization. MATERIALS AND METHODS CRC patients treated in the HEPAR II and SIM studies were analyzed. Absorbed doses were estimated using the activity distribution on post-treatment 166 Ho-SPECT/CT. Metabolic response was assessed using the change in total lesion glycolysis on 18 FDG-PET/CT between baseline and threemonths follow-up. Toxicity between treatment and three months was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5, and its relation with parenchymalabsorbed dose was assessed using linear models. The relation between tumor-absorbed dose and patient-and tumor-level response was analyzed using linear mixed-models. Using a threshold of 100% sensitivity for response, the threshold for a minimal mean tumor-absorbed dose was determined and its impact on survival was assessed. RESULTS Forty patients were included. The median parenchymalabsorbed dose was 37 Gy (range 12-55 Gy). New CTCAE grade ≥3 clinical and laboratory toxicity were present in eight and seven patients, respectively. For any clinical toxicity (highest grade per patient), the mean difference in parenchymal dose (Gy) per step increase in CTCAE grade category was 5.75 (95% confidence interval (CI) 1.18-10.32). On a patient level, metabolic response was: complete response (CR) n=1, partial response (PR) n=11, stable disease (StD) n=17 and progressive disease (PD) n=8. The mean tumor-absorbed dose was 84% higher in patients with CR/PR than in patients with PD (95%CI: 20-180%). Survival for patients with a mean tumor-absorbed dose >90 Gy was significantly better than for patients with a mean tumor-absorbed dose <90 Gy (hazard ratio=0.16, 95%CI 0.06-0.511). CONCLUSION A significant dose-response relationship in CRC patients treated with 166 Ho-radioembolization was established and a positive association between toxicity and parenchymal dose was found. For future patients, it is advocated to use 166 Ho-scout to select patients and personalize the administered activity targeting a mean tumor-absorbed dose of >90 Gy and a parenchymal dose <55 Gy.