Associations between patterns of neuroendocrine liver metastatic burden and outcomes after liver-directed therapy, systemic chemotherapy and systemic radiotherapy.

Patients with metastatic neuroendocrine tumor (NET) have multiple options for liver-directed therapy (LDT) and systemic therapies. Post hoc analysis of NETTER-1 suggested that tumor size but not tumor burden predicted response and PFS after Peptide Receptor Radionuclide Therapy (PRRT), whereas a multicenter analysis of LDT found that tumor burden was predictive. We analyzed imaging datasets from two completed multicenter prospective clinical trials, ECOG-ACRIN E2211 and RETNET, and an institutional cohort of patients treated with PRRT to investigate whether morphologic subgroups of NET liver metastatic disease based on lesion size, lesion number and tumor burden might be more optimally treated with liver-directed therapy, systemic chemotherapy or systemic radiotherapy.

Materials and Methods:

Images from all patients with liver metastases from the Capecitabine + Temozolomide (CapTem) arm of E2211 were reviewed and categorized by liver metastasis number, maximum lesion diameter, and tumor burden as a fraction of liver volume (N=67). Diameters of up to five index metastases were measured before and after therapy to assess response at the lesion level.  A similar number of cases from the RETNET trial imaging archive (N=76) and from an institutional cohort of patients treated with PRRT (N=77) were analyzed. Morphologic categories were then correlated with RECIST 1.1 response and PFS. Descriptive and graphical analyses were followed by multivariable modeling to test treatment by stratum interaction. Patient-level random intercepts were used to account for correlation between lesions from the same individual.

Results:

Lesion number, maximum lesion diameter, and liver tumor burden were not associated with differences in response or PFS for any therapy or for the population as a whole. Lesion size as a continuous variable did not correlate with tumor response for any therapy (p = 0.4).

The ORR for LDT, PRRT and CapTem were 65%, 38% and 25% respectively (p < 0.001) with an odds ratio favoring LDT of 5.66.  Median PFS were LDT 18.9 months [95% CI 16.3-24], PRRT 21.6 mo [14.3-26.7], and 16.6 [11.5-29] for CapTem (p=0.99 for all comparisons).

Conclusion:

No morphologic features were identified that correlated with treatment outcome within a particular modality nor to favor one over another when triaging patients. Diameter of individual metastases did not correlate with response rate for any modality. Liver-directed therapy was associated with a higher response rate than the systemic therapies. PFS was similar for all three modalities.