Has management of locally advanced intrahepatic cholangiocarcinoma evolved with the evidence? Trends and practice patterns from the National Cancer Database.
Authors: Schleimer Lauren E. , Kalvin Hannah L , Kingham T. Peter , Soares Kevin , D'Angelica Michael Ian , Balachandran Vinod P. , Drebin Jeffrey A. , Cercek Andrea , Abou-Alfa Ghassan K. , O'Reilly Eileen Mary , Harding James J. , Gonen Mithat , Wei Alice Chia-Chi , Jarnagin William R. 
Published: January 2024

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Background: Intrahepatic cholangiocarcinoma (IHC) is often advanced at presentation. Mounting evidence suggests a limited role for surgical resection in the setting of multifocal hepatic and regional lymph node involvement in favor of initial treatment with systemic therapy. We sought to characterize trends and practice patterns in the management of patients with locally advanced IHC without distant extrahepatic metastasis. Methods: We queried the National Cancer Database (NCDB) for patients with IHC between 2004-2020. Patients with inadequate data quality, carcinoma in situ, other primary cancers prior to IHC diagnosis, distant metastasis (M1), unknown M status (MX), and no treatment were excluded. Lymph node involvement was categorized using clinical N stage to reflect clinical decision-making. Due to AJCC staging updates and coding limitations, subgroup analysis of patients with multifocal disease (T2bNXM0 in the 7th AJCC edition) was confined to 2010-2017. A two-sided Cochran-Armitage test was used to evaluate time trends and Kaplan Meier methods were used to summarize overall survival (OS). Results: Of 11,368 patients treated for IHC without distant metastasis between 2004-2020, 2,467 / 10,183 (24%) with clinical lymph node staging had positive nodes; the subgroup with multifocal disease comprised 1,384 patients staged T2bNXM0 between 2010-2017. Overall, 36% of patients received formal resection as first treating modality and 59% received systemic or radiation therapy first. The use of perioperative chemotherapy in combination with formal resection increased from 39% pre 2010 to 70% in 2018-2020 (p<0.001), most often delivered post-operatively: 49% received adjuvant, 13% neoadjuvant, and 8% both in 2018-2020. Among those with clinically positive lymph nodes, there was a decreasing trend in upfront resection (p<0.001) and an increase in systemic or radiation therapy first (p<0.001). Similarly, in the multifocal disease subgroup analysis, the proportion of upfront formal resection trended down from 33% in 2010 to 12% in 2017 (p<0.001). Across the entire cohort, median OS improved from 16 months (IQR 15, 18) to 27 months (IQR 26, 29) for patients diagnosed 2018-2019 compared to <2010. Conclusions: Over the last decade, increasing evidence has demonstrated unfavorable outcomes of surgical resection in locally advanced IHC even without distant extrahepatic disease, and supported the use of multimodality therapy. The most significant overall trends have been increasing use of perioperative systemic therapy in combination with formal resection compared to resection alone and an improvement in overall survival. On subgroup analysis, there was a significant and appropriate trend away from resection as first treatment modality for patients with clinically positive lymph nodes or multifocal disease.