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Della Corte et al. Hepatoma Res 2022;8:5 https://dx.doi.org/10.20517/2394-5079.2021.103 Page 11 of 15

not responding to the previously mentioned therapies or systemic therapy.

COMBINED THERAPIES
[90]
Koch et al. showed that combination of TACE and chemotherapy doubled median OS compared to
TACE alone (26.3 months). Recently, Mosconi et al. showed that TARE combined with chemotherapy
[91]
had a median OS of 17.9 months (95%CI: 14.3-21.4 months) with significantly better median survival in the
treatment-naive patients (52 months vs. 16 months). A phase II clinical trial evaluating TARE plus
[92]
chemotherapy as first-line for locally advanced ICC in 41 patients, demonstrated a mean OS of 22 months.
Interestingly, 9 patients were downstaged to surgery; of these, 8 received resection with R0 margins and 6
were still disease-free at 24 months follow-up. In this study, grade 3-4 hematologic toxicity was observed in
70% of patients, similarly to the toxicity observed in the ABC-02 trial [93,94] , possibly due to
gemcitabine/oxaliplatin more than due to addition of TARE. Looking at liver-specific toxicity, among
patients with liver cirrhosis (n = 12), 9 had hepatic failure; of the 9 patients, 5 had undergone bilobar TARE.

HAIC with floxuridine was studied in combination with systemic gemcitabine and oxaliplatin in patients
[95]
with unresectable ICC in a phase 2 clinical trial on 38 patients, with a mean OS of 25 months; 4 patients
were downstaged to surgery. Liver-specific toxicity leading to discontinuation was observed in 4 patients;
47% received full-dose of floxuridine at 6 months.

CONCLUSION
The frequency of ICCs, in particular due to its presence in the aging population, is becoming increasingly
relevant. Its dismal prognosis, especially in non-resectable disease, makes the role of diagnostic radiology
crucial; disease diagnosis at an early stage and the most detailed prognostic information derived from
imaging may change the approach and final outcome of patients. As the knowledge of this disease advances,
so do treatment strategies, with continuously evolving techniques and indications. In this setting,
combination therapies, with the apparent ability to effectively downstage the disease to resectability, seem
promising due to a critical improvement compared to both loco-regional treatments alone and to
[17]
[94]
systemic therapy . Future perspectives include the introduction of novel systemic agents (i.e.,
immunotherapeutic regimens and molecular targeted therapy with TACE or TARE). For both the
diagnostic and the interventional setting, the multidisciplinary approach, including but not limited to,
pathologists, oncologists, and surgeons, is fundamental to achieve a better characterization of the vast CC
disease spectrum and identify the best personalized care possible.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design, data analysis, and interpretation: Della Corte A,
Di Gaeta E, Steidler S, De Cobelli F

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declare that there are no conflicts of interest.