Annals of Hepatology 27 (2022) 100737

Contents lists available at ScienceDirect

Annals of Hepatology
journal homepage: www.elsevier.es/annalsofhepatology

Concise review

Clinical treatment of cholangiocarcinoma: an updated comprehensive

review
Alessandra Elvevia, Alice Laffusaa, Miki Scaravaglioa, Roberta Elisa Rossib, Raffaella Longarinic,
Anna Maria Stagnoc, Laura Cristoferia, Antonio Ciaccioa, Diego Luigi Cortinovisc,
Pietro Invernizzia,*, Sara Massironia
a
Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery,
University of Milano-Bicocca, Monza, Italy
b
Gastroenterology and Endoscopy Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
c
Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy

A R T I C L E I N F O A B S T R A C T

Article History: Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the sec-
Received 6 June 2022 ond most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholan-
Accepted 25 June 2022 giocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar
Available online 7 July 2022
cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA).
The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epi-
Keywords:
thelium and bile stasis represent the main risk factors shared by all CCA sub-types.
Primary liver cancers
When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with
Cholangiocarcinoma
Biliary tract neoplasm
capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral cen-
Therapies ters only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting,
Treatment systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prog-
nosis remains poor.
In order to ameliorate patients’ survival, new drugs have been studied in the last few years. Target therapies
are directed against different molecules, which are altered in CCA cells. These therapies have been studied as
second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune check-
points inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-
lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy
(ACT). These experimental treatments showed promising results and have been proposed as second- or
third-line treatment, alone or in combination with chemotherapy or target therapies.
© 2022 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Abbreviations: CCA, Cholangiocarcinoma; HCC, Hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; eCCA, extrahepatic cholangiocarcinoma; pCCA, perihilar cholan-
giocarcinoma; dCCA, distal cholangiocarcinoma; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease; ICD, classification of diseases; ICD-O, classification for diseases for
oncology; PSC, primary sclerosing cholangitis; IBD, inflammatory bowel disease; OR, Odds Ratio; IARC, International Agency Research on Cancer; HBV, hepatitis B virus; NASH, non-
alcoholic steatohepatitis; GBC, gall bladder cancer; BTC, biliary tract cancer; GBD, gall bladder disease; GWAS, Genome-wide Association Study; FLR, future liver remnant; ALPPS,
associating liver partition and portal vein ligation; OS, overall survival; PBD, preoperative biliary drainage; PTBD, percutaneous transhepatic biliary drainage; EBD, endoscopic biliary
drainage; LT, liver transplantation; DFS, disease-free survival; HZ, hazard ratio; DCR, disease control rate; PDL-1, programmed death-ligand1; PFS, progression-free survival; ORR,
objective response rate; PS, performance status; EGFR, epidermal growth factor receptor; HER2, epidermal growth factor receptor 2; IDH1/2, isocitrate dehydrogenase 1 and 2; FGF,
fibroblast growth factor; FGFR, fibroblast growth factor receptor; PR, partial response; SD, stable disease; RPED, retinal pigment epithelial detachment; CSR, central serous retinopa-
thy; MAPK, mitogen-activated protein kinases; TRK, tyrosine receptor kinase; NCCN, National Comprehensive Cancer Network; NK, natural killer; EMT, epithelial to mesenchymal
transition; TGF, tumor growth factor; PD, programmed death; CTLA-4, cytotoxic T-lymphocyte antigen-4; ACT, adoptive cell therapy; MMR, mismatch repair; MSI-H, microsatellite
instability-high; dMMR, deficient mismatch repair; MSS, microsatellite stable; TKI, tyrosine kinase inhibitors; TILs, tumor-infiltrating lymphocytes; Tregs, regulatory T; VEGFR, vas-
cular endothelial growth factor receptor; VEGF, vascular endothelial growth factor; IDO1, indoleamine 2,3 dioxygenase; PARPi, poly ADP-ribose polymerase inhibitors; CAR, chime-
ric antigen receptor; TCR, T-cell receptors; WT1, Wilms Tumor 1; MUC1, Mucin1; CDCA1, cell division cycle-associated 1; CDH3, cadherin3
* Corresponding author.
E-mail address: [email protected] (P. Invernizzi).

https://doi.org/10.1016/j.aohep.2022.100737
1665-2681/© 2022 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

1. Introduction true iCCAs, while 92% of those that were truly pCCAs were coded as
iCCAs [10]. This miscoding of the perihepatic form might make the
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms rising rate of iCCA merely apparent.
of the bile ducts [1] and represents the second most common hepatic Regardless of methodological issues in retrieving and elaborating
cancer after hepatocellular carcinoma (HCC). It has been reported as data, the global incidence of CCA has increased worldwide in recent
a rare disease in Western countries, accounting for less than 1% of all decades (0.3-6 per 100,000 population per year), according to statis-
human cancers, and around 10−15% of all primary liver cancers, and tics available through 2020 [7].
it is mostly diagnosed in the seventh decade with a small male pre- This trend may also be explained by improved diagnostic techni-
dominance (male:female ratio of 1.2—1.5:1.0) [2]; however, over the ques (radiological, endoscopic, and histological), increased disease
past few decades, its overall incidence has increased worldwide and awareness among physicians of this malignancy, and wider accep-
in the last 10 years, the incidence rate of intrahepatic CCA increased tance by the patients of liver biopsy, all of which contribute to achiev-
rapidly by 109%, from 0.67 per 100 000 in 2007 to 1.40 per 100 000 ing a diagnostic confirmation of primary liver lesions [7].
in 2016 [3]. However, epidemiologic data should not be based solely on
CCA is classified as intrahepatic cholangiocarcinoma (iCCA), origi- biopsy-proven cases, as there is substantial variation in the histologic
nating from the intra-hepatic biliary tree and accounting for 10% or cytologic diagnosis rates of CCA cases reported in international
−20% of cases, and extrahepatic cholangiocarcinoma (eCCA), outside registries. Of note, Thailand has one of the lowest rates of microscopic
the liver parenchyma, the latter comprising both perihilar cholangio- diagnosis for CCA and liver disease in general, despite its very high
carcinoma (pCCA or Klatskin tumor), the most frequent type, incidence of CCA. Finally, it should be noted that even in countries
accounting for 50% of cases, and distal cholangiocarcinoma (dCCA) with larger histology-driven diagnoses, sampling issues occurring for
observed in 30%−40% [4]. many cases and the lack of specific radiological diagnostic criteria are
This neoplasm still shows a high mortality rate due to its aggres- possible explanations for underestimating the incidence of CCA.
siveness, late diagnosis, and immunoregulation capacity [5]. It is CCA mortality has also increased worldwide, according to 2020
rarely diagnosed at an early stage owing to its silent clinical course, data: 1-6 per 100,00 inhabitants per year, without taking into
lack of biomarkers, difficult-to-access anatomical location, and highly account the Asian regions with the highest incidence (> 6 per
desmoplastic and paucicellular nature. Therefore, in only about a 100,000 inhabitants per year) [7].
third of cases, the tumor can be completely removed by surgery, Mortality data also differ among subtypes: a 2019 study (limited
while in other cases, systemic chemotherapy is usually the first-line by using only the classification into eCCA and iCCA) showed an
treatment option. However, new emerging therapies are under eval- increase in mortality for iCCA and a decrease for eCCA, considering
uation for unresectable advanced disease. In fact, the molecular char- countries with acceptable data. Regarding mortality, confounding
acterization and immunological analysis of these neoplasms, as well factors, such as misdiagnosis between iCCA and HCC in cirrhotic
as the identification of the possible crucial role of intestinal micro- patients who do not always undergo a biopsy, should be considered
biota, may open other horizons for novel therapeutic strategies, such [8]. In addition, the reduction in eCCA mortality could be partly
as immunotherapy, to enhance the overall survival of these patients, explained by the increase in the number of cholecystectomies that
for whom the late diagnosis often results in limited therapeutical are now performed laparoscopically, assuming that gallstones repre-
options and poor clinical outcomes and survival rates. sent an important risk factor for eCCA [11]. Therefore, in the coming
years, new ICD classifications and an increasing understanding of risk
2. Epidemiology factors will enable us to obtain more accurate epidemiological data
for this cancer, which will be extremely useful in better understand-
Disease incidence and prevalence, as described by epidemiology, ing its etiopathogenesis and improving diagnostic and therapeutic
reflect population risk factors in different geographical areas. As for strategies.
other diseases, the epidemiology of CCA is closely linked to natural
and human environment changes, thus helping understand a disease 3. Established and emerging risk factors for CCA
about which little is known.
CCA is an emerging cancer worldwide, presenting some challeng- The considerable geographical and overtime variation in the epi-
ing issues and potential biases in defining its epidemiology and risk demiology of CCA reflects a complex landscape of multiple and evolv-
factors, with consequences on understanding etiopathogenesis and ing risk factors driving cholangiocarcinogenesis.
public health policy [6]. Although some risk factors are shared by all forms of CCA, others
Defining CCA epidemiology is even more complex when consider- seem to be more specific to distinct subtypes and more important in
ing its three subtypes , each exhibiting different risk factors and prev- certain regions. A commonly shared characteristic among risk factors
alence rates [7]. It has been observed that in recent years iCCA has is the chronic inflammation of the biliary epithelium and bile stasis
shown a stable rate in Countries where a reduction in alcohol-related [7]. The trigger of chronic biliary inflammation varies across different
chronic liver disease and cirrhosis is observed. In contrast, the same geographic areas in which viral and parasite infections and predis-
form of CCA showed an increasing rate in European and American posing environmental conditions show different prevalence rates.
countries that experienced an increase in alcohol consumption, Hep- Despite this, most cases are sporadic and occur without any accepted
atitis C Virus (HCV) infections, obesity, and non-alcoholic fatty liver or known risk factors. Thus, the adoption of a surveillance protocol is
disease (NAFLD) [8]. limited, and early diagnosis remains a challenge [12].
The latest age-standardized incidence shows an increase in iCCA
and a decrease in eCCA [7], not discriminating in the last group 3.1. Chronic biliary diseases
between pCCA and dCCA forms. Indeed, the International Classifica-
tion of Diseases (ICD) has long lacked a separate code for pCCA, and In Western countries, Primary Sclerosing Cholangitis (PSC) is one
the previous version of the ICD for Oncology (ICD-O) identified pCCA of the most well-known risk factors for CCA [13]. PSC is a rare
as an intrahepatic subtype. Only classifications that came into effect immune-mediated disease of the biliary tree leading to a fibroinflam-
in 2021 for ICD-11 and ICDO-4 provide separate codes for iCCA, pCCA matory obstruction of bile ducts, chronic cholestasis, and progressive
and dCCA [9]. A recent retrospective review of 625 hepatobiliary can- liver failure. Previous studies have reported an up to 400 fold higher
cers from three regional centers in the United Kingdom shows that risk for CCA in PSC patients compared to the general population with
only 43% of CCAs coded as intrahepatic, according to ICD-10, were the co-existence of inflammatory bowel disease (IBD) further
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A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

increasing the risk of malignancies with a significant impact on the 3.3. Lifestyle and professional exposure
patient’s prognosis [14,15]. While several recommendations have
been published for surveillance of CCA in PSC, there is no common Alcohol consumption is a well-known risk factor for HCC [31];
consensus on the best prevention strategy, even if performing sched- conversely, its association with CCA has been less investigated. A
uled imaging techniques is associated with better survival [16−18]. recent large metanalysis using data from 15 and 11 case-control stud-
Choledochal cysts are a rare congenital disorder characterized by ies comprising 13,986 and 8,293 cases, respectively for iCCA and
the development of cystic dilatation of the biliary tree. The correla- eCCA showed an increased risk of development in alcohol consumers
tion between bile duct cysts and CCA is well established with an over- that was higher for iCCA with respect to eCCA (OR 3.15 (95% CI 2.24
all increased risk for both iCCA and eCCA with an estimated Odds −4.41) and 1.75 (95% CI 1.20−2.55), respectively) [12]. Similarly,
Ratio (OR) of 26.71 (15.80−45.16) and 34.94 (24.36−50.12), respec- smoking habits have been associated both with iCCA and eCCA (OR
tively [12]. Caroli's disease is the choledochal cyst phenotype more 1.25 (1.05−1.49) and 1.69 (1.28−2.22), respectively) [12]. The carci-
frequently complicated by CCA, with a 38 fold higher risk for the nogenic effect may be secondary to the excretion of the metabolized
iCCA and a 97 fold higher risk for the eCCA subtype [19]. In addition, carcinogenic compounds (e.g., benzopyrene, formaldehyde, benzene
when the risk factor is congenital, the development of CCA can occur and chromium) by hepatic microsomes to the bile.
even in the first decades of life, with its onset at a mean age of Given the increasing prevalence of obesity and cardiovascular dis-
32 years [20]. ease in Western countries, their putative role as a predisposing factor
The most prevalent risk factor for the development of CCA in East of CCA has been hypothesized. However, neither hypertension nor
Asia involves parasitic infection, specifically with Opisthorchis viver- obesity has shown a statistically significant association with iCCA (OR
rini or Clonorchis sinensis (also called liver flukes) [21], which have 1.1, 95% CI 0.89−13.7 and OR 1.14, 95% CI 0.93−1.39, respectively) or
been listed as group 1 biological carcinogens by the International eCCA, (OR 1.21, 95% CI 0.77−1.90 and OR 1.20, 95% CI 0.84− 1.70,
Agency Research on Cancer (IARC) [22]. respectively) [12].
Liver fluke infections are associated with an up to the 5-fold risk of Based on the evidence of the female predominance of gall bladder
CCA development in endemic areas [23]. Despite anti helminthic cancer (GBC) compared to other biliary tract cancers (BTCs) with a
effective treatment, chronic infections, and possible re-infections male predominance, the role of sex hormones has been suggested to
after consumption of undercooked freshwater fish carrying the larval be involved in cholangiocarcinogenesis. Indeed a recent case-control
parasite lead to the development of CCA in up to 10% of people [24]. study reported an increased risk of gall bladder disease (GBD) associ-
While the association of intrahepatic biliary lithiasis (or hepatoli- ated with the use of orally-administered combined menopausal hor-
thiasis) with a higher risk of iCCA has been well documented, espe- mone therapy particularly [32].
cially in East Asia cohorts [25], the risk of CCA related to cholelithiasis Recently, a link between asbestos exposure and CCA has been pro-
and choledocholithiasis is more controversial. However, a recent vided in two different case-control studies. These findings have been
meta-analysis confirms a significant association of these conditions confirmed in a population based case-control study on the Nordic
with eCCA with a pooled OR of 18.58 (95%CI 11.07-31.18) and 2.11 Occupational Cancer cohort, where an increased risk of iCCA, but not
(95%CI 1.64-2.73) for choledocholithiasis and cholelithiasis respec- of eCCA, was observed by cumulative exposure to asbestos [33,34].
tively [12].
3.4. Genetic factors

Information on the predisposing genetic risk factors causing CCA

3.2. Chronic liver diseases is currently scarce [7]. The available data are mostly available from
the Genome-wide Association Study (GWAS) of patient cohorts diag-
iCCA is a primary liver cancer and shares several similar underly- nosed with PSC, which have an increased risk of CCA [35,36]. A
ing risk factors with HCC. Cirrhosis is a well established risk factor detailed genetic signature investigated by genome sequencing has
for HCC, with >90% of HCCs developing in cirrhotic patients [26]. In a been found in CCAs caused by liver fluke infection. These tumors
meta analysis of fourteen case control studies, cirrhosis was also showed an overall higher mutational rate (median 4,700 versus
identified as a strong risk factor for iCCA (OR 15.32 (95%CI 9.33- 3,143 somatic mutations per tumor) with prevalent mutations
25.15) [12]. Also, chronic viral infections such as chronic hepatitis B in SMAD4 and TP53 as well as ERBB2 amplifications [37]. Addition-
virus (HBV) and HCV infection may also represent a risk factor for ally, the fact that all CCA cases cannot be explained by the currently
CCA development, with a stronger association for iCCA (OR 4.57 (95% identifiable and established risk factors may mean a significant
CI 3.43−6.09) and OR 4.28 (95% CI 2.98−6.16) respectively) [12]. genetic component to CCA pathogenesis, which will require identifi-
Notably, the increased risk of CCA among HBV and HCV patients cation via whole-genome sequencing [38].
likely relies not only on the presence of cirrhosis but also on a direct
carcinogenic effect of these viruses on target cells [27]; moreover, 4. Surgical treatment
chronic liver inflammation resulting from virus infection triggers cel-
lular proliferation, thus increasing the risk of malignant transforma- The standard treatment for CCA is liver resection. Hepatobiliary
tion [27]. resection is, in fact, indicated whenever it is feasible and is reserved
NAFLD encompasses a spectrum of liver diseases ranging from for iCCA and pCCA [39], while the diagnostic work-up and treatment
steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. While of dCCA are more similar to cancer of the head of the pancreas. The
NAFLD/NASH has been identified as a risk factor for HCC, a positive goal of the surgery is to achieve a radical (R0) resection while pre-
association between NAFLD and CCA has also been suggested, espe- serving an adequate function of the future liver remnant (FLR). Surgi-
cially for iCCA [28]. Indeed, in the last years, epidemiological studies cal resection is the only potentially curative option for CCA. Survival
have provided evidence that some metabolic disorders may predis- after resection ranges between 25%−40% at 5 years [40]. An impor-
pose to primary liver cancers [29]. tant aspect to keep in mind is that it might be difficult to accurately
A positive association between type II diabetes and both CCA can- assess resectability preoperatively as conventional radiology can
cer types, especially iCCA, has also been reported (OR of 1.73 (95% CI underestimate the actual extent of the disease, and the definitive
1.47−2.04) [12]. Moreover, a potential protective role of metformin decision to resect or not is generally made at surgical exploration. A
for the development of CCA has been found with an OR of 0.4 (95% CI staging laparoscopy to rule out undetected liver or peritoneal metas-
0.2 0.9) in patients under treatment [30]. tases is clearly recommended with a reported yield above 20% [41].
3
A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

Resectability depends on two main variables: the location of the obstruction, resection of the biliary confluence is indicated, followed
tumor lesion, including its relationship with intrahepatic vascular by a roux Y hepaticojejunostomy.
and biliary structures, and the amount and quality of the liver paren- Some patients might require neoadjuvant chemotherapy,
chyma remaining after tumor resection. In terms of the type of surgi- although the actual benefit of preoperative chemotherapy is still
cal intervention, an R0 surgery for pCCA consists of an extended unclear. According to the preliminary findings of the phase II trial of
hemi hepatectomy with resection of the extrahepatic bile duct, the NACRAC study [52], in 24 patients with borderline or unresect-
which is considered a major surgery and requires a good perfor- able pCCA, pre-operative chemotherapy might enhance R0 resection,
mance status of the patient together with a proper pre-operative while it is still to be clarified whether it also improves survival. On
evaluation of the volume and function of the FLR. The majority of the other hand, no randomized controlled trials are available regard-
patients with iCCA have a single large tumor that requires, similarly ing the role of preoperative systemic chemotherapy for patients with
to pCCA, an extended hemi-hepatectomy. Conversely, the results of a resectable or unresectable iCCA and, according to some studies, pre-
minimal invasive resection for CCA are generally disappointing [42]. operative chemotherapy does not affect OS when compared with
In the presence of nodal involvement beyond the hepatoduodenal patients undergoing upfront surgery [53]. However, the administra-
and gastrohepatic ligament, the benefit of surgery decreases, due to a tion of chemotherapy in the pre-surgical setting might allow the
reported high recurrence rate [43], even though controlling disease downstaging from unresectable to resectable forms in selected cases.
in the liver also with a no curative surgery can improve survival, as Regarding the role of systemic chemotherapy with gemcitabine
many patients risk to die of liver insufficiency [39]. and cisplatin in the adjuvant setting, there are inconsistent findings
In patients with normal liver parenchyma, a “safe” liver resection so far. According to a large Japanese randomized controlled trial [54]
should leave an FLR of at least 25%, while a FLR of at least 30% to 40% including a total of 508 patients with pancreaticobiliary tumors of
needs to be considered in livers affected by steatosis, chronic chole- whom 118 with CCA, adjuvant chemotherapy did not improve OS.
stasis, cirrhosis or treated with chemotherapy [44]. FLR function can The BILCAP trial [55] included 447 patients with biliary cancer, of
be assessed with the indocyanine green test together with the hepa- whom 84 with iCCA, compared adjuvant capecitabine with observa-
tobiliary scintigraphy. In those cases where the FLR is insufficient, tion and found a median OS of 51 months with capecitabine versus
strategies to increase the FLR should be considered in order to avoid 36 months with observation (P = 0.097). Conversely, the Prodige-11
post hepatectomy liver failure and these include portal vein emboli- trial [56], which compared adjuvant gemcitabine plus oxaliplatin ver-
zation, generally indicated when the FLR is below 30% 40% [45] and sus observation after resection of biliary cancer, found no survival
associating liver partition and portal vein ligation (ALPPS) for staged benefit. A benefit in survival for patients treated with adjuvant che-
hepatectomy; in detail, during the first procedure of ALPPS, the liver motherapy has been reported in the presence of positive lymph
parenchyma is transected with portal vein ligation of the liver with nodes and/or R1 resection [57−59]. However, based on available
the tumor and in the second stage, after the FLR has become hyper- studies, it is still not possible to make a clear-cut, evidence-based rec-
trophic, involves the resection [46,47]. ommendation, also considering that the majority of trials include all
It is worth mentioning that lymphadenectomy of locoregional patients with biliary tumors [39].
lymph nodes in the hepatoduodenal ligament is generally recom-
mended and at least six locoregional lymph nodes should be sam- 4.1. Liver transplant
pled [48]. Lymph node metastases can be found at clinical
diagnosis in up to 45%-65% of patients with iCCA, significantly A specific mention needs to be made regarding the role of liver
impacting survival: 5-year overall survival (OS) is approximately transplantation (LT) for pCCA and iCCA, which should be reserved for
0%-20% in pN1 patients versus 35-50% in pN0 patients [49]. How- unresectable CCA with no evidence of extrahepatic disease. The ratio-
ever, no solid evidence exists on the survival benefit provided by a nale of LT in this setting is, indeed, to avoid an R1 resection and an
systematic lymphadenectomy, and available studies in this regard inadequate FLR. In addition, LT allows removing of underlying liver
are retrospective and mostly unmatched [50]. According to the disease including liver cirrhosis and PSC. iCCA has been a recognized
available series, an aggressive surgical treatment including contraindication for LT due to very poor initial results with a 2-year
extended lymphadenectomy might improve survival despite the survival of around 30% [60−62].
presence of lymph node metastases. Conversely, whether adequate The concept of LT for CCA has started to change since specific
lymphadenectomy might be beneficial in the absence of lymph selection criteria, as well as neoadjuvant chemo-radiation protocols,
node metastases is still a matter of debate; as no clear-cut data have been introduced with promising survival outcomes [63].
suggests that lymphadenectomy could prevent local nodal recur- According to retrospective studies, LT may offer satisfying out-
rences and considering the related morbidity, each case should be comes for patients with unresectable very-early iCCA (i.e., ≤ 2 cm)
discussed by a hepato-biliary multidisciplinary team with specific [40]. Sapisochin et al. [64], in their cohort of 2301 patients trans-
attention to more fragile patients (i.e., cirrhotic patients). planted for end-stage liver disease or HCC, had twenty-three patients
Some procedures might be necessary before surgery. First, diagnosed with an iCCA on pathology examination; they reported a
obstructive cholangitis is an absolute indication of preoperative bili- 5-year OS of 45% with far better results for very early iCCA (namely
ary drainage (PBD) with approximately 15% of iCCA showing biliary single tumor ≤ 2 cm) than multifocal and larger tumors in terms of 5-
obstruction requiring PBD. As liver resection in jaundiced patients is year risk of recurrence (18% versus 65%, P = 0.01) and 5-year OS (65%
considered to be at higher surgical risk, PBD in jaundiced CCA versus 45%, P = 0.02). These promising results for early stages tumors
patients is generally performed [51]. However, PBD is often associ- were then confirmed in an international collaborative study contain-
ated with infectious complications, and cholangitis is an independent ing 48 patients [64]. In order to obtain more solid evidence, a multi-
prognostic factor for post-operative mortality [51]; thus, the decision centric single-arm clinical trial (NCT02878473) is ongoing to confirm
on making PBD should be carefully balanced. As in patients with an the effectiveness of LT for very early iCCA.
insufficient FLR (i.e., below 40%), biliary obstruction impairs liver On the other hand, a recent study [63] enrolled patients with iCCA
regeneration, PBD of the FLR is generally suggested before portal vein >2 cm but with favorable tumor biology (i.e., no evidence of extrahe-
embolization. Percutaneous transhepatic biliary drainage (PTBD) and patic disease, vascular invasion, and lymph node spread). All the
endoscopic biliary drainage (EBD) are the two available procedures patients underwent at least 6 months of chemotherapy with gemcita-
to drain the bile ducts, but in the absence of large randomized con- bine and cisplatin in order to get a sustained response. Out of 21
trolled trials, there is no definitive evidence to recommend one pro- patients, 6 underwent LT and 1 liver resection, followed by adjuvant
cedure over the other [39]. Furthermore, in patients with biliary chemotherapy. The authors reported promising outcomes in terms of
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A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

5-year OS rate (i.e., 83%) with a recurrence rate of 50% despite the rel- confirmed the benefit of adjuvant chemotherapy and chemoradio-
evant tumor burden. therapy, in particular in the group with node-positive and surgical
Given high recurrence and unacceptably low survival, LT was ini- positive margin [58].
tially contraindicated also in patients with pCCA [65−67]. However, These data were confirmed by another meta-analysis of 30 studies
according to a large multicenter retrospective study including 216 confirming a definitive benefit in terms of reduction of the risk of
patients with early-stage [68] unresectable pCCA treated with neoad- death with post-surgery chemotherapy [71].
juvant chemoradiotherapy followed by LT, 5-year disease-free sur- Three randomized phase-III studies were published focusing on
vival (DFS) rates of 65% have been reported. In a direct comparison the adjuvant setting. In the PRODIGE12-ACCORD18 study, 193
between LT and resection, patients resected for pCCA and meeting patients were randomized to the observation or GEMOX scheme
transplantation criteria had a significantly worse 5-year survival (gemcitabine plus oxaliplatin) after surgery, with no significant dif-
compared to transplanted patients (18% vs. 64%), and the survival ferences in terms of relapse-free survival [72]. Another negative
benefit of LT versus resection was also maintained when considering phase III study in which gemcitabine was used was the BCAT study
only CCA < than 3 cm with no lymph nodal involvement. [69]. [73].
In summary, also considering the well-known organ shortage and The first positive, large, randomized phase III trial was the BILCAP-
the still limited evidence on the actual benefit of LT for CCA, LT for study, which compared 8 cycles of capecitabine to surveillance: the
CCA should be considered only in referral centers; in patients with median OS was 36.4 months for the control group and 51.1 months
very early iCCA (single tumor ≤2 cm) upfront LT might be of benefit, in the experimental arm (Hazard Ration (HR) 0.81 95% CI 0.63-1.04
whereas those with advanced unresectable iCCA or pCCA neoadju- p=0.097), reaching the statistical significance after the correction for
vant chemoradiation needs to be administered within specific proto- prognostic factors [55].
cols [64]. Based on these data, capecitabine at the moment is considered the
standard of care after curative resection of BTC.
5. Chemotherapy To improve the benefit of capecitabine as an adjuvant treatment is
currently recruiting the phase III trial ACTICCA-1, which compares
5.1. Adjuvant chemotherapy capecitabine (control arm) with cisplatin/gemcitabine as the experi-
mental arm. In addition, patients with R1 resection are randomized
After the radical surgical approach, the available treatments for between chemotherapy (capecitabine or cisplatin plus gemcitabine)
BTC are chemotherapy and radiotherapy, or a combination of the and the same regimens followed by chemoradiation with capecita-
two. In particular, the role of post-operative chemotherapy was quite bine (NCT02170090) [74].
recently defined due to the conflicting or few specific data on the
topic. 5.2. Chemotherapy for metastatic disease: first and later lines
The first study, published in 2002, demonstrated the benefit of
chemotherapy over observation in the post-operative setting for GBC Several pivotal trials for metastatic setting in biliary disease are
[54]. ongoing Figure 1. The AC-02 trial, in which the combination of gemci-
The ESPAC-3 trial explored the efficacy of 5-Fluoruracile or gemci- tabine and cisplatin is compared with gemcitabine alone, demon-
tabine compared to observation in periampullary carcinoma [70]. strated a higher median OS (11.7 vs. 8.1 months, respectively; HR
A significant point was reached by the meta-analysis by Horgan 0.64; 95% CI 0.52-0.8; p< 0.001) and better disease control rate (DCR)
et al, which evaluated data from more than 6000 patients who for the combo [75]; the results were confirmed in the Japanese phase
underwent different types of post-surgical treatments: the analysis II BT22 trial [76]. In the recent ASCO-Gastrointestinal Cancer

Figure 1. Treatment strategies for unresectable CCA. First line treatment for unresectable CCA is chemotherapy (CT), with gemcitabine and cisplatin; different agents have been
proposed as second line chemotherapy and a clinical trial with FOLFOX is still ongoing in this setting. Target therapies against different molecular targets and immunotherapy have
been proposed in the last few years as second and third line of treatment, alone or in combination (i.e. chemotherapy and target therapies, chemotherapy and immunotherapy, tar-
get and immunotherapy together). FGFR, fibroblast growth factor receptors; IDH, Isocitrate Dehydrogenase 1 and 2; ERBB2, HER familiy receptors; MAPK, Mitogen-Activated Protein
Kinases; TRK, Tyrosine receptor kinase.

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A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

Symposium was presented the TOPAZ-1 study, the first phase III trial alterations was higher in patients with BTC than in the MOSCATO
that demonstrated positive results with the addition of an immune trial overall, suggesting that BTC may comprise target-rich tumors.
checkpoint inhibitor to the standard of care in an unselected popula- Moreover, molecular target-directed allocation to appropriate tar-
tion [77,78]. In 685 previously untreated patients, treatment with geted therapies significantly increased PFS when compared with
durvalumab, a programmed death-ligand1 (PD-L1) inhibitor, plus cis- patients with BTC not allocated to a targeted therapy trial, confirming
platin and gemcitabine, conferred a 20% reduction in the risk of death the benefit of precision medicine for BTC.
compared with cisplatin and gemcitabine alone (HR 0.80, 95% CI In the last years, lots of basic studies identify many molecular tar-
[0.66,0.97] p=0.021); also progression-free survival (PFS) and objec- gets potentially useful as target-directed therapies, i.e. fibroblast
tive response rate (ORR) were better in the chemo-immunotherapy growth factor receptor (FGFR), epidermal growth factor receptor
arm. Due to these results, the association cisplatin plus gemcitabine (EGFR), human epidermal growth factor receptor 2 (HER2), metabolic
plus durvalumab is likely to become the new standard of care for regulators as isocitrate dehydrogenase 1 and 2 (IDH1/2), BRAF, tyro-
advanced biliary cancer in the first-line setting. sine kinase receptors inhibitors, transcription factor FOSL1 [90−95].
In a metastatic setting, the combination of gemcitabine with oxa- Among them, different target therapies have been studied in clini-
liplatin was also investigated: the overall response rate varies from cal trials during the last few years.
15% to 50%, while oxaliplatin exhibits more favorable toxicity profile
compared with cisplatin [79]. Furthermore, fluoropyrimidine-based 6.1. FGFR Antagonists
chemotherapy has shown efficacy in advanced biliary tract cancers
[80]. Fibroblast growth factors (FGFs) signaling has a role in cell devel-
Although combination treatment has to be preferred in advanced opment and angiogenesis; they are moreover largely expressed in
disease, due to the prognostic relevance of performance status (PS) different cell types; these are the reasons why FGFs and their associ-
ECOG in this disease [81], in PS 2 patients, monotherapy remains the ated fibroblast growth factor receptors (FGFRs) have been studied
best choice. extensively, with a focus to exploit the therapeutic potential of FGF-
Unanswered questions in advanced biliary disease comprise FGFR signaling [96]. FGFRs comprise a family of receptor tyrosine kin-
whether more intensive treatment is superior to a two-drug s stan- ases (FGFR1−4). FGF-FGFR signaling is triggered by the ligand-depen-
dard combo. Some interesting trials addressed this issue, such as the dent receptor dimerization following the binding of FGF at the cell
aBTCs trial, a phase II trial focused on triplet therapy cisplatin, gemci- surface. This leads to intracellular phosphorylation of receptor kinase
tabine, and nab-paclitaxel [82], as well as the phase III trial of cis- domains, a cascade of intracellular signaling, and gene transcription
platin, gemcitabine plus S1 [83]. that activates a number of intracellular survival and proliferative
Another question is about the possibility of increasing the activity pathways [97]. In detail, the binding of FGFR by its ligand results in
of chemotherapy by overcoming the mechanisms of resistance. Ace- multiple downstream signaling pathways activation, including JAK-
larin (NUC-1031) is a first-class nucleotide analog that presents a STAT, RAS−BRAF− MEK−ERK, and PI3K−AKT−mTOR, leading to cell
good safety profile in association with cisplatin for the first-line treat- proliferation, differentiation, and survival [98].
ment in the phase Ib trial ABC-08 [84] at the recommended dose of Alterations in FGFR genes, including activating mutations, chro-
725 mg/m2 NUC-1031 is under evaluation in phase III trial NuTide- mosomal translocations, gene fusions, and gene amplifications, can
121. result in ligand-independent signaling, which, in turn, leads to consti-
Regarding patients who fail first-line chemotherapy, a good PS tutive receptor activation [99] and pathologic cell proliferation.
ECOG is the most important selection factor for the activation of sec- Several FGFR inhibitors have been developed and studied in clini-
ond-line therapy [85]. cal trials. Both reversible ATP-competitive FGFR inhibitors (eg, dera-
A systematic review of several phase II or retrospective trials was zantinib [ARQ 087], infigratinib [Truseltiq], erdafitinib [JNJ-
published by Lamarca et al. in 2014. In this analysis, the treatment 42756493], and pemigatinib [Pemazyre]) and irreversible non-ATP-
regimens included fluoropyrimidine, irinotecan, docetaxel, gemcita- competitive FGFR inhibitors (eg, futibatinib [TAS-120]) have shown
bine, and platinum compounds. The calculated median OS in these promising clinical activity [2].
trials ranged between 6.6 and 7.7 months, while the median PFS was
2.8 months and the median response rate was only 7.7% [86].
6.1.1. Derazantinib
By the same Author is the publication of the first randomized
Derazantinib is an oral ATP-competitive, pan-FGFR inhibitor with
phase III study ABC-06 in the second-line setting. There were 162
strong activity against FGFR1−3 kinases. It also inhibits a number of
patients randomized to receive active symptom control (i.e., antibi-
other kinases, including RET, DDR2, VEGFR1, and KIT [100].
otic therapy, corticorticosteroid therapy, biliary drainage) versus FOL-
A multicenter, phase I/II, open-label study (NCT01752920)
FOX regimen (oxaliplatin/fluorouracil) after cisplatin-gemcitabine
enrolled 29 adult patients with unresectable iCCA with an FGFR2
failure. Although the reported median survival benefit of the FOLFOX
fusion, who progressed on, were intolerant to, or not eligible for first-
regimen over active symptom control was small (6.2 versus 5.3
line chemotherapy; Derazantinib provided an overall response rate
months, adjusted HR 0.69), the FOLFOX regimen obtained a more sig-
of 20.7% and the DCR was 82.8% with a median PFS of 5.7 months
nificant survival rate at 6 (50.6% versus 35.5%) and 12 months (25.9%
[101].
versus 11.4%) [87]; the regimen is now considered the reference sec-
ond-line treatment.
Other trials are focusing on second-line chemotherapy, such as 6.1.2. Infigratinib
the recently closed recruitment NALIRICC, in which nal-IRI (liposomal Infigratinib (BGJ398, Novartis AG) is an oral, ATP-competitive pan-
irinotecan) is compared to fluorouracil (NCT03043547). FGFR inhibitor. Infigratinib efficacy was assessed in a phase II trial in
patients with different FGFR alterations [FGFR2 fusions (n = 48),
6. Target therapies FGFR2 mutations (n = 8), FGFR2 amplification (n = 3)] after first-line
chemotherapy. The overall response rate was 14.8%, almost all with
MOSCATO-01 trial by Massard C et al. [88] firstly showed, in a FGFR2 fusions, and median PFS was 5.8 months, and interestingly
largescale evaluation of hard-to-treat cancers, that molecular altera- DCR was 75.4%; however, the durability of response was limited
tions could be matched to appropriate targeted molecular therapy [102,103].
[89] . This trial included 43 BTC cases (29 iCCA, 10 eCCA, 4 gallbladder PROOF 301 (NCT03773302), a phase III multicenter, open-label,
cancer) and showed that the proportion of patients with actionable randomized trial of infigratinib in comparison to standard of care
6
A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

gemcitabine and cisplatin in advanced/metastatic cholangiocarci- Nail toxicities also occur on FGFR inhibitors, especially with the
noma with FGFR2 translocations is still ongoing [104,105]. increased duration of treatment; most are grade 1 and 2, and grade 3
nail toxicity rarely occurs. Onycholysis, the painless detachment of
6.1.3. Erdafitinib the nail from the nail bed, occurs in 5−7% of patients. Paronychia, an
Erdafitinib (JNJ-42756493, Jansenn) is a pan-FGFR small molecule often tender bacterial or fungal infection that develops at the nailbed,
kinase inhibitor being tested in clinical trials. In a phase I study Erda- occurs in 5−7% of patients. Other nail toxicities include nail discolor-
fitinib was tested in different advanced solid tumors; CCA was mostly ation, nail disorder, nail dystrophy, nail hypertrophy, nail infection,
responsive to erdafitinib, with ORR of 27.3% (3/11). All patients with onychalgia, and paronychia [102,108].
cholangiocarcinoma who responded to erdafitinib carried FGFR
mutations or fusions. The median response duration was 11.4 months 6.2. Inhibitors of IDH1/2 mutant
for cholangiocarcinoma [106].
An interim analysis of an open-label phase II, a study conducted in IDH catalyzes decarboxylation of isocitrate to a-ketoglutarate.
China, Korea, and Taiwan (NCT02699606), conducted on adults with Mutated IDH converts a-ketoglutarate to 2-hydroxyglutarate, an
advanced CCA containing FGFR alterations who had failed at least oncometabolite. The accumulation of 2-hydroxyglutarate leads to
one prior systemic treatment, showed that 15 of the 17 treated epigenetic changes, impaired DNA repair, and aberrant cell metabo-
patients had an evaluable response: 7 (46.7%) achieved partial lism, promoting tumourigenesis [114].
response (PR); 5 (33.3%) had stable disease (SD); and progression dis- Several inhibitors of mutant IDH1 protein have been developed
ease was seen in 3 (20.0%) patients. The ORR was 7/15 (47%) and the and evaluated in clinical trials. Most notably, ivosidenib (AG-120), an
DCR was 12/15 (80%) [107]. oral, targeted, small-molecule inhibitor of IDH1-mutant, was studied
in a phase 1 trial of 73 previously treated patients with IDH1-mutant
6.1.4. Pemigatinib CCA, showing a median PFS 3.8 months (95% CI 3.6−7.3) and median
Pemigatinib (Pemazyre) is an oral selective inhibitor of FGFR1−3. OS of 13.8 months (95% CI 11.1−29.3) [115,116]. In the follow-up
In FIGHT-202, 146 enrolled patients were assigned to one of three phase 3 ClarIDHy trial [117], patients with advanced, unresectable
cohorts: patients with FGFR2 fusions or rearrangements (N = 107), IDH1-mutant CCA, who had one to two previous lines of therapy,
patients with other FGF/FGFR alterations (N = 20), or patients with no were randomized to ivosidenib versus placebo. The ORR with ivosi-
FGF/FGFR alterations (N = 18). The primary endpoint was centrally- denib was 2.4%, the DCR was 50.8%. Median PFS was longer with ivo-
assessed ORR among those with FGFR2 fusions or rearrangements. sidenib (2.7 months) versus placebo (1.4 months; HR 0.37 [95% CI
After a median follow-up of 17.8 months, 38 (35.5%) of patients with 0.25−0.54]; p<0.0001). Median OS was 10.3 months for ivosidenib
FGFR2 fusions or rearrangements achieved an objective response (3 versus 7.5 months for placebo (p=0.093), which included 70% of
had complete responses, 35 had PRs). The median duration of patients who crossed over from placebo. Although the clinical activity
response was 7.5 months [108]. According to these data, in April of ivosidenib has been encouraging, the challenge of acquired resis-
2020, the US FDA approved pemigatinib as the first targeted drug for tance has been reported [115]. The treatment appeared to be well tol-
patients with advanced refractory CCA with an FGFR2 fusion or rear- erated, the most common treatment-related adverse events being
rangement. nausea (38%), diarrhea (32%), and fatigue (28%).
In addition to ivosidenib, many other IDH mutant inhibitors and
6.1.5. Futinatinib IDH pathway target therapy are under evaluation in clinical trials (i.e.
Futibatinib is an oral, highly selective, irreversible FGFR1-4 inhibi- NCT02381886, NCT02481154, NCT03684811) [114].
tor [109] that showed promising results in phase I trial (FOENIX-101;
NCT02052778): among patients treated with futinatinib, 5.8 achieved
PRs and 46% achieved SD. Responses were rapid (mostly occurring 6.3. Agents Targeting HER Family (ERBB2) Receptors
within 3 months) and lasted for >12 months in 2 of the 5 responders,
indicating durable clinical benefit [110]. The HER family includes 4 members: epidermal growth factor
These promising results led to FOENIX-CCA2, an open-label, mul- receptor (EGFR/HER1), HER2, HER3, and HER4; they are type I trans-
ticenter phase II registrational trial in patients with iCCA harboring membrane growth factor receptors that function to activate intracel-
FGFR2 gene fusions or other rearrangements (NCT02052778). Interim lular signaling pathways in response to extracellular signals; HER2
results from the FOENIX-CCA2 study (NCT02052778) were reported overexpression has a well-demonstrated tumorigenic potential
after the enrolment of 103 patients, who had progressed on previous [118].
standard therapies, or for whom standard therapy was not tolerated. The combination of pertuzumab and trastuzumab was investi-
Among the 67 patients having ≥ 6 months of follow-up included in gated in 11 patients with previously treated BTC, with HER2 amplifi-
this analysis for efficacy and safety, the ORR was 37.3% and the DCR cation or HER2 mutations; ORRs of 7.5% and 33.3% were reported,
was 82.1% [111]. respectively [119]. Targeting gene mutations rather than amplifica-
While other molecules are under investigation in phase III clinical tions may also have potential (e.g., neratinib [120]. An ORR of 10%
trial, FGFR-inhibitors' adverse events are reported to be similar and was reported in the biliary subgroup (20 patients) of the SUMMIT
they are, as a class, very well tolerated. The most common adverse clinical trial exploring the role of neratinib in patients whose tumors
events are hyperphosphatemia (55-81% of patients), which is second- harbored HER2 mutations [121].
ary to inhibition of FGF23, and determines inhibition of phosphate Altogether, HER represents the most frequent targetable aberra-
absorption in the intestine and reducing phosphate reabsorption in tion for CCA and GBC, but only a few data exist regarding their utility
the kidney [112,113]. as treatment of BTC; work is still needed for this target to be ready
Ophthalmologic toxicity: retinal toxicities such as retinal pigment for prime time use in clinical practice.
epithelial detachment (RPED) and central serous retinopathy (CSR)
may cause symptoms such as blurred vision, visual floaters, or pho- 6.4. MAPK (Mitogen-Activated Protein Kinases) Pathway Inhibitors
topsia. RPED and CSR occur in around 4% and 9%, respectively, of
patients with CCA treated with FGFR inhibitors, and these are gener- BRAF is a serine/threonine protein kinase activating the MAP
ally of grade 1 or 2 [108,111]. Other FGFR toxicities are blepharitis, kinase/ERK-signaling pathway, leading to cell proliferation, differen-
cataract development, increased lacrimation, trichiasis, trichomegaly, tiation, and survival mutational activation of BRAF favors its hyper-
and blurred vision. activation, which promotes cell proliferation, differentiation, and
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A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

survival [122,123]. Mutations of BRAF are described in iCCA, with a microenvironment encourages the immune escape and inhibition of
prevalence of 1−3% [124]. immune response [134].
BRAF mutations at codon 600, mostly V600E, are of interest In this context, the immune checkpoints inhibitors, targeting pro-
because they are potentially targetable with BRAF inhibitors. Unfor- grammed death 1 (PD-1), PD-L1, cytotoxic T-lymphocyte antigen-4
tunately, single-agent BRAF inhibitors seemed to have limited activ- (CTLA-4), and novel therapeutic approaches like cancer vaccines and
ity in CCA, and it could be due to feedback EGFR activation as in adoptive cell therapy (ACT), can empower antitumor activity.
colorectal cancer. The inhibition of MEK could be an alternative strat-
egy to target MAPK [2]. 7.1. Immune checkpoint inhibitors
The dual inhibition of BRAF and MEK is an alternative and poten-
tially more efficient strategy to target the RAS-ERK pathway. In two PD-1, PD-L1, and CTLA-4 are immune checkpoints expressed by
independent reports, the combination of Dabrafenib and Trametinib activated T cells: they dampen the immune response downregulating
showed durable clinical responses [125,126]. Finally, the preliminary the function of activated T cells and the tumor cells enhance their
results of a basket trial involving patients with BRAF mutation survival. In this contest, the immune checkpoint inhibitors targeting
showed, in a cohort of pretreated BTC, a response rate of 42% with a PD-1, PD-L1, and CTLA-4 block this pathway in order to maintain the
median OS of 11.7 months [127] immunologic balance [135].
At present, the data on immunotherapy in the BTC is limited, but
6.5. Tyrosine receptor kinase (TRK) inhibitors several trials are currently investigating the role of anti-CTLA-4 (such
as ipilimumab or tremelimumab), anti-PD-1 (such as pembrolizumab
There are three TRK tyrosine kinase receptors, TRKA, TRKB, and or nivolumab) and anti-PD-L1 (such as durvalumab) [136,137].
TRKC. These are encoded by the genes NTRK1, NTRK2, and NTRK3, PD-L1 expression has been detected in 10-70% of patients with
respectively. Neurotrophin ligand binding and TRK activation result BTC, a wide range depending on different factors [138−140] . Patients
in homodimerization of the receptor, followed by transactivation of with a high expression of PD-L1 have a poor prognosis but can better
the intracellular domains, and recruitment of cytoplasmic adaptors. respond to immune checkpoint inhibitors [140].
These adaptors, in turn, activate downstream signaling via the MAPK, PD-L1 positive tumors are linked with: microsatellite instability
PI3K, and/or PKC pathways, involved in cycle cell progression, cell increased tumor mutational burden, and expression of biomarkers,
proliferation, and cell survival [128]. e.g. BRCA2, TP53, BRAF, RNF43, TOP2A mutations [141]. In addition,
Actionable oncogenic TRK activation is primarily mediated by in particular in GBC, there is an association between the expression
NTRK gene fusion. The NTRK inhibitors larotrectinib (VITRAKVI; Loxo of ERBB2/ERBB3 mutants and the PD-L1 expression [142].
Oncology Inc, San Francisco, CA, USA) and entrectinib (Rozlytrek; Monotherapy with PD1/PD-L1 inhibitors does not obtain satisfac-
Hoffmann-La Roche, Basel, Switzerland) have shown high response tory results in unselected patients with BTC.
rates and durable responses in early phase trials of NTRK-fusion-posi- Pembrolizumab is a highly selective, humanized monoclonal anti-
tive advanced solid tumors, which included patients with CCA. Laro- body against PD-1 which has been designed to block the interaction
trectinib yielded an ORR of 75% and a median duration of response of between PD-1 and its ligands, PD-L1, and PD-L2. It was approved by
10 months. Entrectinib showed an ORR of 57% with a median dura- FDA for DNA mismatch repair (MMR) deficiency and/or microsatellite
tion of response not reached [129,130]. Both larotrectinib and entrec- instability-high (MSI-H) advanced solid tumors, thus including biliary
tinib have been approved by the US FDA for patients with NTRK- tract cancers. Of note, MMR deficiency has been reported to occur in
fusion-positive solid tumors who have no alternative treatment or 5% to 10% of BTC [143]. We can consider MSI-H and deficient mis-
progressed after treatment. The National Comprehensive Cancer Net- match repair (dMMR) as predictive biomarkers of immunoresponse
work (NCCN) guidelines also recommend NTRK inhibitor as first or like PD-L1 tumor expression [144−146].
subsequent-line therapy in NTRK-fusion-positive biliary tract cancer. KEYNOTE-028 was a phase Ib trial testing the activity of pembroli-
zumab in heavily treated BTC patients [147].
In the phase II trial KEYNOTE-158 pembrolizumab obtained an
6.6. Further perspectives ORR has been 5.8% (6/104, 95% CI: 2.1%-12.1%), the median OS of
7.4 months (95% CI: 5.5-9.6) and the median PFS of 2 months (95%CI:
Signaling pathways involved in CCA development and progression 1.9-2.1). All responders had microsatellite stable (MSS) tumors [147].
are still under investigation, i.e., transcription regulators as NOTCH Nivolumab is a monoclonal antibody that binds to the PD-1 recep-
genes and FOSL1; their inhibition showed in vitro promising results tor and blocks its interaction with PD-L1 and PD-L2. It has been eval-
[131,132]. Tumor microenvironment role is under investigation as a uated in a phase II trial single-arm [148]. With the ORR was 22%, the
promising target for future therapies development; it is constituted median OS was 14.24 months (95% CI: 5.98 months to not reached)
by CCA stroma, made by cancer-associated endothelial cells, inflam- and the median PFS was 3.68 months (95% CI: 2.30-5.69 months). All
matory cells (macrophages, neutrophils, natural killer (NK), and T the responder patients had MSS tumors. Moreover, there was a corre-
cells), cancers associated fibroblasts and extensive network of pro- lation between PD-L1 expression and better PFS but no correlation
teins such as collagens, laminin, and fibronectin [7]. with OS.
Epithelial to mesenchymal transition (EMT) is a cell plasticity-pro- Due to unsatisfactory results of monotherapy, recent strategies
moting phenomenon initially reported to occur during embryogene- include the combination of checkpoint inhibitors with different
sis, but that also takes place in cancer, enabling epithelial cancer cells checkpoint inhibitors, anti-angiogenic therapies, multi-target tyro-
to acquire mesenchymal features with invasive properties that lead sine kinase inhibitors (TKI), poly ADP-ribose polymerase inhibitors,
to metastatic colonization. The prototype inducer of EMT is the tumor and chemotherapy (Table 1).
growth factor-b (TGFb)-dependent pathway and is under investiga-
tion to become a target for new drugs fibronectin [7].
7.1.1. Anti PD1/PD-L1 combinations with CTLA-4 inhibitors
7. Immunotherapy for metastatic biliary tract cancer The combinations of PD-1 and CTLA-4 blockade have shown good
results in several tumor types [118,149,150] due to synergistic effects
Recent advances in immunotherapy have changed the therapeutic resulting in increased numbers of Tumor-infiltrating lymphocytes
chances in BTC, which are considered ‘immune-cold’ due to low- (TILs), decreased regulatory T (Tregs) cells, and overall improved
moderate tumor mutational burden [7,133]; moreover, the tumor inhibition of tumor growth [151,152].
8
A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

Table 1
Some of the many clinical trials of combination therapies

Trial name Agent Target Setting Outcomes

NCT04211168 [176] Toripalimab PD-1 2° Line and subsequent ORR

Lenvatinib TKI
NCT04010071 [177] Toripalimab PD-1 2° Line and subsequent PFS
Axitinib TKI ORR
NCT03684811 [178] FT-2102 IDH1 2° line in IDH1 mutated Safety
Nivolumab or GEMCIS PD-1 ORR
CT
NCT04895046 [179] Dostarlimab PD-1 Maintenaince after 1° line platinum based therapy PFS
Niraparib PARPi
NCT03639935 [180] Nivolumab PD-1 Maintenaince after 1° line platinum based therapy PFS
Rucaparib PARPi
NCT03991832 [181] Durvalumab PD-L1 IDH1 mutated and pretreated tumors ORR
Olaparib PARPi Overal disease control rate
PD-1: programmed death 1; PD-L1: programmed death ligand 1; PFS: median progression free survival; ORR: overall response rate; TKI: Tyrosine
kinase inhibitors; PARPi: Poly (ADP-ribose) polymerase inhibitor; CT: chemotherapy; IDH1: Isocitrate dehydrogenase 1.

The phase II trial, CA209-538, has investigated the combination of 11.9 months (95% CI: 6.2-NA), respectively. It is interesting to note
anti-CTLA-4 ipilimumab with nivolumab [153]. ORR has been how, on tumor biopsies, high baseline levels of PD-L1 and indole-
reported at 23% with a DCR of 44%. The median PFS was 2.9 months amine 2,3 dioxygenase 1 (IDO1), which is an enzyme that plays a cru-
(95% CI: 2.2-4.6 months) while the median OS was 5.7 months (95% cial role in modulating the tumor microenvironment were associated
CI: 2.7-11.9 months). All patients who responded to treatment had with improved outcomes. Further studies should investigate in a
MSS tumors. Treatment has been well tolerated (only 15% of patients selected population (high PD-L1 and/or high IDO1 expression).
reported adverse events > grade 2). Only 1-7% of BTC are BRCA1-2 mutated, but DNA damage repair
A phase II study has evaluated the efficacy of PD-L1 durvalumab mutation occurs in 60% of this type of cancer [164]. This genetic alter-
alone or in combination with anti CTLA-4 remelimuab in 42 pre- ation seems to be sensible to poly ADP-ribose polymerase inhibitors
treated patients [154]. In the monotherapy arm, the ORR was 4.8%, (PARPi). Prior studies suggest that PARPi may promote responsive-
the median PFS was 2 months and the median OS was 8.1 months. ness to immune checkpoint inhibitors by increasing neoantigens and
The median OS for the combination was 10.1 months (95% CI: 6.2- tumor mutational burden, recruiting T cells through particular path-
11.4 months) versus 8.1 months with durvalumab in monotherapy, ways and upregulating PD-L1 expression [165]. There are several
the median duration of response was 8.5 months, and the ORR was ongoing clinical trials that are evaluating different combinations of
10.8%. PARPi and anti-PD-1 like nivolumab plus rucaparib (NCT03639935)
The association of double immunotherapy did not show favorable or dostarlimab ant-PD-1 plus niraparib (NCT04895046).
results.
7.2. Adoptive immunotherapy
7.1.2. Other combinatory strategies
Anti-angiogenetic therapies inhibit tumor growth and have an Adoptive immunotherapies with chimeric antigen receptor (CAR)
immune-modulatory role [155−157]. T-cells [166,167] have found a rationale in the treatment of BTC due
The combination of anti-vascular endothelial growth factor recep- to its harsh tumor immune microenvironment.
tor 2 (VEGFR2) ramucirumab with pembrolizumab failed in a phase I This immunotherapeutic strategy provides T cells genetically
study that enrolled patients with advanced BTC showing an ORR of modified to express CAR or tumor antigen-specific T cell receptors
4%, median PFS and OS of 1.6 months, and 6.4 months respectively (TCR) in order to enhance their ability to recognize and kill cancer
[158,159]. cells.
Pembrolizumab has been assessed with an anti-angiogenic multiki- The use of the adoptive transfer of ex-vivo-expanded tumor-reac-
nase inhibitor lenvatinib in phase II study LEAP-005 on 31 pretreated tive T cells has created a challenge in the development of a novel
patients with BTC [160]. The ORR was 10%, and the median PFS and therapy. Injecting a specific population of T cells, which have an affin-
OS were 6.1 months and 8.6 months, respectively. The most observed ity for patients’ cancer cells helps to contrast the immune inhibitory
adverse events have been hypertension, dysphonia, and diarrhea. At tumor microenvironment. Anti-CD133 CAR T-cells have shown effi-
present, an ongoing phase II study is investigating the association cacy in ex-vivo tissue models [168]. Over 50% of biliary tracts express
pembrolizumab/levantinib in 100 patients (NCT03797326). CD133. Feng et al., have tested in a patient with metastatic BTC CAR-
Another combination study was toripalimab and levatinib with T targeting CD133 and EGFR with PR of 8.5 months with CAR-T EGFR
gemcitabine and oxaliplatin in 30 patients at the first line in meta- therapy and a PR of 4.5 months with CAR-T 133 treatment [169].
static iCCA. In a follow-up of 16.6 months, the study showed an ORR Moreover, a phase I clinical study (NCT01869166) studied CAR-T cells
of 80%, (with one complete response), a median PFS of 10 months, in EGFR-positive metastatic BTC. The study has shown 5.8% of com-
while the median OS was not reached. Expression tumor of PD-L1 plete responses and 58.8% (10/17) of SD [170]. The ongoing trial
was associated with significant responses [161]. (NCT04660929) is necessary for validating the activity and the safety
The IMbrave 151 trial has involved 150 patients with biliary tract of CAR-T cells. Moreover, several studies have suggested that the
cancers at first or following lines of therapy treating with gemcita- addition of PD-1/PD-L1 blockade could improve the anti-tumor effi-
bine plus cisplatin with or without bevacizumab (anti- vascular endo- cacy of CAR T cells in solid tumors, representing another potential
thelial growth factor (VEGF)). The trial is still ongoing [162] and the strategy that warrants further evaluation [171].
results are awaited.
In a single-arm, multicentre phase II trial, the antitumor activity of 7.3. Tumor vaccines
regorafenib (anti-VEGF) in combination with avelumab (anti-PD-L1)
has been assessed in 34 pretreated patients with metastatic BTC The use of tumor vaccines in BTC is an attractive therapeutic
[163]. The median PFS and OS were 2.5 months (95% CI: 1.9-5.5) and approach as they can introduce antigens capable of activating the
9
A. Elvevi, A. Laffusa, M. Scaravaglio et al. Annals of Hepatology 27 (2022) 100737

immune system, promoting the proliferation of memory T cells, and in the concept, design, analysis, writing, or revision of the manu-
enhancing the immune response. Single peptide-based vaccines can script. All the authors gave their final approval of the version to be
induce an immune response to Wilms Tumor 1 (WT1) and Mucin 1 published, and agreement to be accountable for all aspects of the
(MUC1) which are overexpressed cell surface molecules in BTC. A work in ensuring that questions related to the accuracy or integrity
study has combined gemcitabine with WT1 peptide vaccine in 16 of any part of the article are appropriately investigated and resolved.
patients with advanced BTC reporting a DCR of 50% and a median OS A.E. and S.M. gave substantial contributions to the conception and
of 9.5 months [172] . In a phase I study MUC1 vaccine in 3 patients design and had a main role in drafting the article. A.L, M.S., R.L., A.M.
with BTC proved to be safe and well-tolerated, but 2 of 3 patients had S., L.C, and A.C revised the literature and contributed to drafting and
PD [173]. editing the article. D.C., P.I., and S.M critically revised the manuscript
Multiple peptide-based vaccines improved the efficacy in patients for important intellectual content.
with biliary tract cancers. A study has shown in 9 patients the use of
peptide vaccines for cell division cycle-associated 1 (CDCA1), cad- Data availability statement
herin 3 (CDH3), and kinesin family member 20A [174].The results
registered stable disease in 5 patients and a median OS of 9.7 months. Data sharing is not applicable to this article as no new data were
In a clinical trial (UMIN000005820) dendritic cell vaccines have been created or analyzed in this study.
combined with adoptive cellular therapy in patients with BTC in
post-operative [175]. The median OS for surgery plus immunother-
apy was 31.9 months versus 17.4 months for only surgery. Several Declaration of interest
ongoing studies (NCT04853017, NCT03942328) are necessary to
improve responses with tumor vaccines in BTC. Pietro Invernizzi and Sara Massironi are members of the European
The role of immunotherapy in the treatment of BTC is under Reference Network on Hepatological Diseases (ERN RARE LIVER), and
investigation. Although immunotherapies have demonstrated limited they thank AMAF Monza ONLUS and AIRCS for the unrestricted
efficacy in the unselected population, the combination of new thera- research funding. The remaining authors have no conflicts of interest
peutic strategies could be the next therapeutic frontier. Further trans- to declare.
lational studies are needed to define more specific biomarkers
predictors of tumor response. References

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