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Page 4 of 8 Gavriilidis et al. Hepatoma Res 2023;9:23 https://dx.doi.org/10.20517/2394-5079.2023.26

Figure 2. Patterns of lymphatic spread for right and left iCCA. Tumors of the left hemi-liver drain to lymph nodes near the left and
common hepatic artery lymph nodes and then toward the celiac axis. Right hemi-liver tumors drain to hepatoduodenal ligament and
then peri-pancreatic and aortocaval lymph nodes. Adapted from Compton CC et al. [37] .

gained from LND and was initially described among patients undergoing surgery for gastric cancer [19,20] . To
determine the therapeutic index, LNM frequency in a certain patient group is multiplied by the 3-year
cancer-specific survival (CSS) of patients with LNM in that subgroup . Recently, Sahara et al. utilized a
[20]
multicenter institutional database to apply the concept of therapeutic index to iCCA . In this study,
[20]
roughly one-half (43.5%) of the 471 included patients had positive lymph nodes; the median counts of
removed and metastatic lymph nodes were 4 and 0, respectively. The 3-year CSS was 29.9%, with a
therapeutic index of 13.0. Of note, patients who had iCCA with major vascular invasion, CEA greater than
5.0, and LNM within nodal basins outside of the HDL had lower therapeutic indices, suggesting these
patients may not draw a survival benefit from LND. In turn, while LND may provide prognostic
information, LND in patients with high-risk features (i.e., major vascular invasion, high CEA, etc.) may not
provide a therapeutic benefit given the high likelihood of systemic disease spread. Of note, patients who had
seven or more lymph nodes resected had the greatest therapeutic value in patients with positive lymph
nodes, suggesting that assessment of more lymph nodes leads to more accurate staging . Interestingly, the
[20]
presence or absence of LNM may also impact the relative prognostic importance of other modifiable
surgical factors such as margin status. For example, Farges et al. reported data from the AFC-IHCC-
2009 study group and noted no survival differences among patients with margin negative versus margin
positive hepatic resection among patients who had LNM . A summary of current consensus guidelines
[21]
on LND is presented in Figure 3.

PRODIGE 12-ACCORD 18 trial
In addition to helping stratify patients relative to long-term prognosis, data derived from LND may help
guide the use of adjuvant therapy. The PRODIGE 12-ACCORD 18 Trial was a multicenter prospective
randomized controlled trial that included 196 patients who underwent an R0/R1 resection of a biliary tract
[22]
cancer . There were 86 (43.9%) patients with iCCA included in the cohort. Patients were randomized to
either adjuvant doublet gemcitabine-oxaliplatin (GEMOX), which had been standard of care for advanced
biliary tract cancers, or standard surveillance. The primary endpoints were relapse-free survival (RFS) and
health-related quality of life (HRQOL). Of note, median RFS (GEMOX 30.4 months vs. surveillance 18.5
months, P = 0.48), 3-year RFS (47% vs. 43%), or OS (75.8 months vs. 50.8 months, P = 0.74), or HRQOL
were not significantly different among groups [Figure 4]. Consequently, adjuvant GEMOX was not
recommended for use in biliary tract cancers including iCCA.