Supplementary Material for: Associations between patterns of neuroendocrine liver metastatic burden and outcomes after liver-directed therapy, systemic chemotherapy and peptide receptor radionuclide therapy.

Introduction
Patients with liver-dominant metastatic neuroendocrine tumor (NET) have multiple treatment options. Post hoc analysis of NETTER-1 suggested that tumor size but not tumor burden predicted progression-free survival (PFS), contrary to prior publications. Analysis of imaging datasets from two completed multicenter prospective clinical trials for capecitabine-temozolomide (CapTem) and liver-directed therapy (LDT), and an institutional cohort of patients treated with peptide receptor radionuclide therapy (PRRT) was performed to investigate whether subgroups of liver metastatic disease based on lesion size, lesion number and tumor burden may guide treatment selection.
Methods
Image review from a similar number of patients with liver metastases from each cohort were categorized by number, maximum diameter, and tumor burden as a fraction of liver volume (n=219). Morphologic categories were then correlated with response and PFS by RECIST criteria. Descriptive and graphical analyses were followed by multivariable modeling to test treatment-by-stratum interaction.
Results
Imaging features were not associated with statistically significant differences in response or PFS for the three therapies or the entire analyzed population. The ORR for LDT, PRRT and CapTem were 65%, 38% and 25% (p<0.001), respectively, with an odds ratio favoring LDT of 5.45 vs. CapTem and 3.0 vs. PRRT. The respective median PFS were LDT 18.9 months [95%CI 16.3-24], PRRT 21.6 [14.3-26.7], and 16.6 [11.5-29] for CapTem (p=0.99).
Conclusion
LDT had the highest response rate of these distinct cohorts. PFS was not different between modalities. Imaging features did not predict treatment outcome within a particular modality nor to favor one over another when triaging patients.