Liver Metastases of Intrahepatic Cholangiocarcinoma: Implications for an Updated Staging System

Abstract

Background and aims: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases is perceived to have a poor prognosis, but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread.

Approach and results: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCC v.7) data were eligible. Modified staging was used (mAJCC v.7): group A: stages I-III (excluding T2bN0); group B: stage IVa (excluding T2bN1M0); group C: liver metastases (T2bN0/1); and group D: stage IVb (extrahepatic metastases). Survival analysis (Kaplan-Meier and Cox regression) was performed in an ENS-CCA training cohort (TC) and findings internally (ENS-CCA iVC) and externally (SEER) validated. The aim was to assess whether liver metastases (group C) had a shorter survival compared to other early stages (group A) to propose a modified version of AJCC v.8 (mAJCC v.8). A total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into group C, respectively. In the ENS-CCA TC, multivariable Cox regression was adjusted for obesity (p = 0.026) and performance status (P < 0.001); patients in group C (HR, 2.53; 95% CI, 1.18-5.42; P = 0.017) had a higher risk of death (vs. group A). Findings were validated in the ENS-CCA iVC (HR, 2.93; 95% CI, 2.04-4.19; P < 0.001) and in the SEER registry (HR, 1.88; 95% CI, 1.68-2.09; P < 0.001).

Conclusions: iCCA with liver metastases has a worse outcome than other early stages of iCCA. Given that AJCC v.8 does not take this into consideration, a modification of AJCC v.8 (mAJCC v.8), including "liver metastases: multiple liver lesions, with or without vascular invasion" as an "M1a stage," is suggested.

FIG. 1

Patient flow. N refers to number of patients. (A) Patient flow for patients included in the ENS‐CCA registry. (B) Patient flow for patients included in the SEER registry.

FIG. 2

OS for each stage groups. (A) Kaplan‐Meier for the ENS‐CCA cohort using AJCC v.7 is shown; multivariable Cox regression HRs are shown for the stage variable (with stage I as the reference category); the multivariable HR for obesity was 0.79 (95% CI, 0.62‐1.03; P = 0.083), and the multivariable HR for ECOG‐PS (continuous variable) was 1.69 (95% CI, 1.51‐1.89; P < 0.001). (B) Kaplan‐Meier for the ENS‐CCA cohort using mAJCC v.7 is shown; multivariable Cox regression HRs are shown for the stage variable (separately for analysis with stage I and group C as reference categories); the multivariable HR for obesity was 0.81 (95% CI, 0.63‐1.05; P = 0.113), and the multivariable HR for ECOG‐PS (continuous variable) was 1.68 (95% CI, 1.49‐1.89; P < 0.001). (C) Kaplan‐Meier for the SEER cohort using mAJCC v.7 is shown; univariate Cox regression HRs are shown for the stage variable (separately for analysis with stage I and group C as reference categories). Abbreviations: excl, excluding; incl, including; mts, metastases; Tis: tumour in situ (1 case only).

FIG. 3

OS for each stage groups: ENS‐CCA and SEER joined data. Using the proposed updated staging system, mAJCCv.8, provided a slightly higher Harrell’s C index (mAJCC v.8 (FIG. 3.B); C index, 0.624) compared to the AJCC v.7 (FIG. 3.A); C index, 0.614). In addition, the mAJCC v.8 allowed for a more clinically relevant separation of survival curves (while there was significant overlapping in AJCC v.7). (A) Kaplan‐Meier for the ENS‐CCA and SEER joined cohort using the proposed AJCC v.7 is shown; univariate Cox regression HRs are shown for the stage variable (with stage I as the reference category). (B) Kaplan‐Meier for the ENS‐CCA and SEER joined cohort using the proposed updated mAJCC v.8 is shown; univariate Cox regression HRs are shown for the stage variable (separately for analysis with stage I and stage IVa [liver metastases] as reference categories). Of the 820, 755, and 1,614 patients with stage III, IVa, and IVb disease, 418 (50.1%), 194 (25.7%), and 671 (41.6%), respectively, were N1. Abbreviations: excl, excluding; incl, including; mts, metastases; Tis, tumor in situ (1 case only).