Medical College of Wisconsin, Milwaukee, WI A Systematic Review and Meta-Analysis of Hepatic Artery Based Therapy for Intrahepatic Cholangiocarcinoma Boehm L PharmD, Jayakrishnan T MD, Muira J MD, Johnston F MD MHS, Turaga KK MD MPH, Gamblin TC MD MS Medical College of Wisconsin, Milwaukee, WI

Author Disclosure T Clark Gamblin, MD MS Consultant, Angiodynamics and Covidien Kiran K Turaga, MD Honorarium, Castle Biosciences Inc Other Authors No relevant financial or other relevant disclosures

Background Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary tumor of the liver arising from biliary epithelium with typical survival times ranging from 5-13 months with standard systemic chemotherapies. Hepatic artery based therapies (HAT) have been shown to prolong survival in unresectable hepatic malignancies. HAT includes hepatic artery infusion (HAI), transcatheter arterial chemoembolization (TACE), drug-eluding bead TACE (DEB-TACE), and Yttrium90 radioembolization (Y90). Figure 1. Cross sectional CT image of a patient with ICC demonstrating lesion between right and left lobes of the liver Figure 1. Cross sectional CT image of a patient with ICC demonstrating lesion between right and left lobes of the liver

Purpose and Methods Purpose Methods: Outcomes: The objective was to perform a qualitative and semi-quantitative systematic review and meta-analysis of hepatic artery directed therapies for patients with unresectable ICC. Methods: The study was prospectively registered at PROSPERO Outcomes: Primary Outcome: Cumulative Median Overall Survival (OS) in months Secondary Outcomes: Tumor response to therapy (RECIST criteria) and toxicities

Results Records identified through database searching (n = 790) Screening Included Eligibility Identification Additional records identified through other sources (n = 3) Records after filters applied (n = 385) Records screened (n = 385) Records excluded on the basis of title and abstract screening (n = 343) Full-text articles assessed for eligibility (n = 42) Full-text articles excluded, with reasons (n = 22) -Concomitant systemic chemotherapy -Concomitant radiotherapy -Results not stratified by cancer type -Patients had resectable disease -Outcomes of interest not reported Studies included in qualitative synthesis (n = 20) Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

Baseline Characteristics The mean age of subjects across all four HAT treatment arms was 62.5 years (SD ± 4.65). Of the patients evaluated 54.6% had an ECOG performance status of 0. The median KPI of patients in the DEB-TACE treatment arm was 100 (70-100). HAI TACE DEB-TACE Y-90 Number of Articles 4 10 2 5 Number of Patients (n) n=64 n=399 n=37 n=127 Mean Age (Years) 58.5 (±3.34) 61.8 (±5.07) 67.5 (±1.06) 63.7(±4.06) Performance Status ECOG 1 3 n=25 19 (76%) 5 (20%) 1 (4%) n=200 116 (58%) 71 (35.5%) 12 (6%) 1 (0.5%) NR n=101 43 (42.6%) 40 (39.6%) 18 (17.8%) KPI Median (range) n=28 80 (40-90) n=10 100 (70-100) n=26 Extrahepatic Disease (%) 21.9% 29.2% 42% 37%

Results Cumulative median OS was highest for HAI (21 months, 11-31). Tumor response per RECIST was highest for HAI with 87.3% of patients exhibiting either a partial response or stable disease. Y-90 therapy had a similar tumor response profile (85.1%) HAI TACE DEB-TACE Y-90 Cumulative Median OS (Months) 21 13 12 14 RECIST Tumor Response Complete Response Partial Response Stable Disease Progressive Disease n=63 26 (41.3%) 29 (46%) 8 (12.7%) n=333 1 (0.3%) 41 (12.3%) 206 (61.9%) 85 (25.5%) n=34 1 (2.9%) 10 (29.4%) 16 (47%) 7 (20.6%) n=121 32 (26.4%) 71 (58.7%) 18 (14.9%)

Results Grade I/II complication rates were highest among those treated with HAI therapy (2.84 per patient) Grade III/IV complication rates were low across all treatment groups in general. Highest for HAI (0.35 per patient) Lowest for TACE (0.26 per patient) Rates of hepatic complications were highest among those treated with HAI therapy Complication Rates per Patient Treated

Conclusion Hepatic artery infusion reported the best outcomes in terms of: Median overall survival Overall response to therapy TACE was associated with lowest incidence of complications

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