Background: Unresectable intrahepatic cholangiocarcinoma (IHC) is associated with poor overall survival (OS). Prior studies have suggested improved outcomes with hepatic artery infusion chemotherapy (HAIC), with or without systemic (SYS) compared to SYS alone, but the role of HAIC continues to evolve. This study compares outcome of HAIC when used as 1^st line treatment compared to 2^nd line therapy in patients with advanced IHC. Methods: In this retrospective review, 722 consecutive biopsy-proven, liver limited IHC were evaluated from 2000-2018. Patients undergoing upfront surgery or those with metastatic disease beyond regional lymph nodes were excluded. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox regression model was used to examine the association of HAIC given at any time point with OS. To further dissect the timing of HAIC therapy (1^st vs 2^nd line) on OS, multi-state models using parametric Cox regression, as well as separate Cause-specific hazard model to intergrade the transition to 2^nd line HAIC from the 1^st line SYS state were used to estimate the mean survival time from diagnosis. Results: 336 patients eligible for HAIC were analyzed: 137 patients began treatment with 1^st line HAIC (median age 63, 40% male) and 199 patients received 1^st line SYS (median age 64, 46% male). Median time to first treatment initiation was 1.8 vs 1.2 months for 1^st line HAIC and SYS, respectively. Median OS of all patients was 22 months (95% CI: 20-25 months), and HAIC given at any time was associated with reduced all-cause mortality by 34% (HR: 0.66, 95%CI: 0.52-0.84). Multi-states analyses revealed that patients who received 1^st line HAIC had a mean OS of 33 months from disease diagnosis. Patients who transitioned to 2^nd line HAIC after 1^st line SYS had a mean OS of 36 months from diagnosis, while those who failed 1^st line SYS and continued 2^nd line SYS had a mean OS of 22 months from diagnosis. Patients who received no further treatment after 1^st line SYS had a mean OS of 9 months. Median OS from the start of 2^nd line for patients who received 2^nd line HAIC was 18 months and 8 months for patients who started 2^nd line SYS therapy. The sites of progression of disease (POD) in different treatment groups has been described in the Table. Conclusions: HAIC treatment of unresectable liver-dominant IHC at any time was associated with reduced mortality by 34%. Mean OS in patients treated with 2^nd line HAIC did not appear to be significantly different than those receiving HAIC as 1^st line therapy and both appeared to be superior to 2^nd line SYS. The survival benefits of HAIC appear to be maintained after failure of 1^st line systemic chemotherapy.

*At the time of transition from 1^st line SYS to 2^nd line SYS.