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Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83 Page 5 of 19

elucidate best practice, but the low incidence of CCA and the heterogeneous pathophysiology makes these
studies difficult to perform.

An adequate future liver remnant (FLR) requires at least two continuous segments with adequate perfusion,
venous outflow, and biliary drainage. The degree of underlying liver disease (e.g., steatohepatitis, cirrhosis,
chemotherapy-associated liver injury, etc.) influences the amount of FLR needed to prevent postoperative
hepatic complications. For patients undergoing major hepatectomy, surgeons should consider CT or MRI
volumetry and liver function assessment with indocyanine green clearance testing to determine the
[70]
maximum extent of major hepatic resection that will not lead to postoperative liver complications . In
situations when complete surgical resection will create an inadequate FLR, alternative approaches are
needed. Historically, surgeons performed a 2-stage hepatectomy to induce liver regeneration after the first
[71]
resection . However, liver regeneration could be slow, and many patients never received the second stage
of the procedure . In turn, a novel 2-stage liver resection called associating liver partition and portal vein
[72]
ligation for staged hepatectomy (ALPPS) procedure was proposed. This procedure combines portal vein
ligation with transection of the liver along the FLR. After adequate liver hypertrophy approximately 1-2
weeks later, the surgeon completes the hepatectomy by transecting the right hepatic artery, the biliary duct,
and the hepatic vein(s) during the second stage of the procedure . ALPPS induced greater liver
[73]
hypertrophy, and patients had a higher rate of stage 2 hepatectomy completion compared with historical
[74]
staged hepatectomy; however, high morbidity and mortality have prevented broader adoption of ALPPS .
Portal vein embolization (PVE) is another option to increase the FLR. The initial PVE approach through an
ileocolic venous branch is a surgical procedure requiring general anesthesia and has fallen out of favor of
minimally invasive approaches performed by interventional radiology . In appropriately selected patients,
[75]
PVE induces liver hypertrophy leading to high rates of planned hepatectomy and low rates of postoperative
liver failure .
[76]

NEOADJUVANT THERAPY
Neoadjuvant therapy has gained favor in the treatment of CCA. Theoretical benefits include downstaging
unresectable disease, early treatment of potential micro-metastatic disease, and allowing time to evaluate the
aggressiveness of the tumor biology as disease progression on neoadjuvant therapy is a poor prognostic
[77]
indicator . Limited studies have revealed no improvement in OS among patients who underwent surgical
resection after neoadjuvant chemotherapy compared with patients who underwent upfront surgery [78,79] .
With multiple neoadjuvant chemotherapy trails currently recruiting, the role of neoadjuvant chemotherapy
[80]
for patients with CCA will be better defined in the future .
Patients with unresectable CCA may benefit from liver-directed therapies such as transarterial
radioembolization (TARE), transarterial chemoembolization (TACE), transarterial bland embolization
(TAE), yttrium-90 (Y-90) radioembolization, as well as hepatic artery infusion (HAI) therapy. In HAI
therapy, a surgically placed pump into the gastroduodenal artery delivers high-dose chemotherapy directly
to the liver with few systemic side effects . A retrospective review and follow-up phase 2 clinical trial
[81]
demonstrated improved OS for CCA patients with unresectable disease that received combined HAI
therapy and systemic chemotherapy even when patients had positive lymph nodes [81,82] . These therapies are
discussed in greater detail in the Locoregional Options section of this review.

APPROACH TO RESECTION
Current best evidence to guide the surgical management of CCA comes from observational studies.
Complete surgical resection with negative margins remains the only chance for cure from CCA. Improved
surgical techniques, regionalization of care to high-volume centers, and appropriate application of