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Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79 Page 5 of 23

Prognostication
Reliable prognostic/predictive biomarkers to assist the therapeutic decision making in patients with aBTCs
are still lacking. To date, only clinical prognostic factors independently associated with OS have been
suggested, including Eastern Cooperative Oncology Group (ECOG) performance status (PS), blood tests
(white blood cells and neutrophil count, haemoglobin and bilirubin levels), disease status, and gender, from
the post-hoc analysis of CisGem pivotal trials [7,26,40] ; and ECOG PS, prior resection, tumour grading, baseline
carcinoembryonic antigen and carbohydrate antigen 19.9 (CA19-9), from the Italian Group of
[36]
Cholangiocarcinoma, G.I.Co .

Recently, a prognostic score was derived by baseline neutrophil count, lymphocytes-monocytes ratio,
neutrophil-lymphocytes ratio and albumin: the A.L.A.N. score. This prognostication has been shown to
correlate with OS in a cohort of 123 aBTCs patients undergoing first-line chemotherapy. A.L.A.N. score was
able to identify three classes of patients with significantly different OS (high-risk: median OS, 5 months;
[14]
intermediate-risk: median OS, 12 months and low-risk: median OS, 22 months; P < 0.001) . Many other
clinical prognostic scores have been proposed, however, no standard currently exists [41-45] .

The post-hoc analysis of ABC-01/02/03 trials of CisGem has also indicated a more favourable prognosis of
iCCA and iCCA with liver-only disease. iCCA had a longer OS compared with other non-iCCA biliary tract
cancers (HR = 0.58; 95%CI: 0.35-0.95; P = 0.03); liver-only iCCA patients also showed longer OS even
though findings did not reach statistical significance (HR = 0.65; 95%CI: 0.36-1.19; P = 0.16) .
[40]

Despite being informative, evidence is yet to be confirmed in large, prospective, clinical studies, but until
then, the optimal prognostication to adopt in the therapeutic decision of aBTCs remains uncertain.

To summarise, CisGem is the regimen of choice in the frontline, while FOLFOX is the standard after first-
line progression in unselected patients [Figure 1]. Other options (i.e., single agents) may be carefully
considered when the standard treatment is contraindicated or due to patient’s preferences. Several novel
combinations are currently under clinical investigation. A selection of the most relevant ongoing clinical
trials based on cytotoxic chemotherapy are shown in Table 2.

The allocation of locoregional strategies, complementary to chemotherapy, should be considered in the
context of clinical studies.

Reliable prognostic and predictive biomarkers are still lacking and desirable, particularly in the second-line
setting.

PRECISION MEDICINE: BIOLOGICAL RATIONALE AND THERAPEUTIC STRATEGIES
Advances in Next-Generation Sequencing technologies and large-scale initiatives from cooperative groups
such as The Cancer Genome Atlas, the International Cancer Genome Consortium and others have allowed
the characterisation of the molecular landscape of BTCs over the last decade, resulting in the identification
of key actionable oncogenic drivers and signalling networks [46-54] . Firstly, biological differences according to
anatomic location (iCCAs vs. eCCA), geographical location (Eastern vs. Western), and etiology (Hepatitis B,
fluke, other causes) have been identified. Secondly, somatic - potentially targetable - alterations have been
described in up half of patients with BTC [55-58] .