Prediction of 90Y selective internal radiation therapy outcome using pre-therapeutic biomarkers in unresectable and refractory intra-hepatic cholangiocarcinoma patients

Objectives: An important proportion of patients presenting an intra-hepatic Cholangiocarcinoma (IH-CCA) will relapse post-surgery and/or post chemotherapy. For this subset of refractory patients selective internal radiation therapy (SIRT) has emerged as an effective treatment modality with median survivals ranging from 7 to 22 months. However, contrasting results after SIRT enlightens the lack of prognostic and predictive biomarkers for patient stratification and treatment optimization. The aim of this study is to assess the prognostic value of pretherapeutic clinical, biological and imaging biomarkers extracted from unresectable and refractory IH-CCA patients treated with SIRT and to determine the added value of using a more personalized model: partition-model (PM), for the calculation of the individual activity of ⁹⁰Y-microspheres, compared to the utilization of the standard Body-Surface-Area (BSA) method. Materials and Methods: This retrospective multicenter study enrolled 58 patients with unresectable IH-CCA, refractory to surgery and/or chemotherapy, treated with resin ⁹⁰Y-microsphere, in 4 European SIRT expert centers. Clinicopathologic data were collected from patient’s records. Metabolic parameters as well as presence of hypermetabolic lymph nodes were measured at baseline FDG-PET/CT. Lesion volume delineation was performed on baseline FDG-PET/CT and then projected on the anatomically registered ^99mTc-MAA-SPECT/CT. MAA lesion uptake to non-tumoral-liver uptake ratio (TLR_MAA) was computed for each lesion as well as their mean absorbed dose (D_mean). Univariate associations between variables and OS were examined by the log rank test. Continuous variables were dichotomized by using their respective median as cut-off value. Multivariate Cox’s proportional hazards model was then performed to determine the independent prognostic significance of each parameter. Finally, differences between patients treated by BSA and patients treated with PM were investigated using appropriate statistics.

Results: The median OS post-SIRT of the entire cohort was 10.3 months. One-year and the 2-years survival rates were 39.8% and 21.6%. Biological parameters associated with significant differences in terms of OS were albumin (hazard-ratio(HR)=2.78, p=0.002), total bilirubin (HR=2.17, p=0.009), aspartate-aminotransferase ( HR=2.96, p<0.001), alanine-aminotransferase (HR=2.02, p=0.01) and γ-GT (HR=2.61, p<0.001). Absence of hypermetabolic lymph nodes was associated to a longer OS (HR=2.35, p=0.008), as well as a TLR_MAA≥1.87 (HR=2.92, p=0.009). No other imaging biomarkers were found to be associated with OS. Finally, OS was significantly higher in patients treated according to PM (HR= 2.52, p<0.001). Results of the multivariate analysis showed that Total Bilirubin, Aspartate-aminotransferase and γ-GT were statistically significant with p of 0.03, 0.006 and 0.01 respectively. The method of calculation of individual activity (BSA vs PM) was also statistically significant even if we adjusted for standard biological parameters (Total Bilirubin, Aspartate aminotransferase and γ-GT) with HR=2.26 and p=0.03. No difference in terms of clinical, biological and imaging biomarkers were observed between patients treated by BSA or PM. However, as expected, patients treated with PM had significantly higher lesion D_mean than patients treated with BSA (average-D_mean of 86Gy vs 38Gy, p<0.001).

Conclusions: To the best of our knowledge, this is the largest European multicenter study realized to date on patients with unresectable, refractory to surgery and/or chemotherapy, IH-CCA treated with resin 90Y-microsphere. Our results demonstrated that personalized SIRT improves outcome in refractory intra-hepatic cholangiocarcinoma treated with SIRT. And that several baseline biomarkers could be used for patient’s stratification.