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TUMOR BURDEN PREDICTS OUTCOMES AFTER CURATIVE RESECTION OF MULTIFOCAL INTRAHEPATIC CHOLANGIOCARCINOMA
Jun Kawashima^*1,2, Miho Akabane¹, Zayed Rashid¹, Abdullah Altaf¹, Selamawit Woldesenbet¹, Mujtaba Khalil¹, Azza Sarfraz¹, Diamantis Tsilimigras¹, Odysseas Chatzipanagiotou¹, François Cauchy³, Federico Aucejo⁴, Hugo P. Marques⁵, Tom Hugh⁶, Feng Shen⁷, Shishir K. Maithel⁸, B. Groot Koerkamp⁹, Irinel Popescu¹⁰, Minoru Kitago¹¹, Matthew Weiss¹², Guillaume Martel¹³, Carlo Pulitano¹⁴, Luca Aldrighetti¹⁵, George A. Poultsides¹⁶, Andrea Ruzzenente¹⁷, Todd W. Bauer¹⁸, Ana Gleisner¹⁹, Itaru Endo², Timothy M. Pawlik^1
1The Ohio State University Wexner Medical Center, Columbus, OH; ²Yokohama Shiritsu Daigaku, Yokohama, Kanagawa, Japan; ³Hopital Beaujon, Clichy, Île-de-France, France; ⁴Cleveland Clinic, Cleveland, OH; ⁵Hospital Curry Cabral, Lisboa, Lisboa, Portugal; ⁶The University of Sydney, Sydney, New South Wales, Australia; ⁷Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China; ⁸Emory University, Atlanta, GA; ⁹Erasmus Universiteit Rotterdam, Rotterdam, Zuid-Holland, Netherlands; ¹⁰Institutul Clinic Fundeni, Bucuresti, Romania; ¹¹Keio Gijuku Daigaku, Minato-ku, Tokyo, Japan; ¹²Northwell Health Feinstein Institutes for Medical Research, Manhasset, NY; ¹³University of Ottawa, Ottawa, ON, Canada; ¹⁴Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; ¹⁵IRCCS Ospedale San Raffaele, Milano, Italy; ¹⁶Stanford University, Stanford, CA; ¹⁷Universita degli Studi di Verona, Verona, Veneto, Italy; ¹⁸University of Virginia, Charlottesville, VA; ¹⁹University of Colorado Denver, Denver, CO

Introduction: Liver resection for multifocal intrahepatic cholangiocarcinoma (ICC) remains controversial, largely due to its aggressive tumor biology. In turn, rigorous selection of patients for resection is crucial to achieve optimal outcomes. We sought to evaluate surgical outcomes after resection of multifocal ICC and identify patient subgroups most likely to benefit from operative management.
Methods: Patients who underwent upfront curative-intent hepatectomy for ICC were identified from an international multi-institutional database. Among patients with multifocal ICC, overall survival (OS) was analyzed using multivariable Cox regression to identify prognostic factors. Tumor burden score (TBS), which combines tumor size and number, was used to stratify patients based on an optimal cutoff determined using restricted cubic spline (RCS) analysis. OS in TBS-based subgroups of patients with multifocal versus solitary ICC was compared.
Results: Among 1,502 patients, 208 (13.8%) had multifocal ICC. Patients with multifocal versus solitary ICC had a markedly worse OS (3-year OS: 27.1% vs. 57.1%, respectively; p<0.001). Multivariable analysis identified TBS (HR 1.09, 95% CI 1.04-1.14), American society of Anesthesiologists physical status classification > 2 (HR 1.48, 95%CI 1.03-2.12), liver cirrhosis (HR 2.05, 95% CI 1.24-3.38), and periductal infiltrating or mass-forming plus periductal infiltrating type (HR 1.58, 95% CI 1.03-2.41) as independent predictors of worse OS. Receipt of adjuvant chemotherapy was associated with improved prognosis (HR 0.59, 95% CI 0.41-0.86). RCS analysis demonstrated that TBS > 7 was associated with poor prognosis. Based on this cutoff, patients with multifocal ICC were stratified into low-TBS (TBS < 7; n=75, 36.1%, 3-year OS: 43.6%) and high-TBS (TBS ? 7; n=133, 63.9%, 3-year OS: 17.8%) cohorts (p<0.001). In the entire cohort, OS was further analyzed based on tumor burden (Figure). Notably, multifocal ICC patients with low TBS demonstrated comparable 3-year OS to patients with solitary ICC who had AJCC stage II/III disease. In contrast, patients with high TBS and multifocal ICC had the worst prognosis (3-year OS: stage I & solitary 67.1%, stage II/III & solitary 43.2%, low-TBS & multifocal 43.4%, high-TBS & multifocal 17.8%, p<0.001) (Figure).
Conclusion: While patients with high-TBS multifocal ICC had a poor prognosis, individuals with low-TBS multifocal ICC demonstrated survival outcomes comparable to patients with solitary ICC patients. These findings emphasize the importance of stratifying patients by tumor burden to guide surgical decision-making and optimize treatment strategies for multifocal ICC.

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