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Intrahepatic Cholangiocarcinoma
Tumors Harboring Targetable Mutations
IDH1 mutations are seen in up to 30% of intrahepatic cholangiocarcinoma (Lowery et al. 2018), and trial data suggests a
small survival benefit with IDH inhibitors. The phase III double-blind placebo-controlled ClarIDHy tria randomized 185
patients with previously treated advanced IDH-1 mutant
cholangiocarcinoma to ivosedinib or placebo. 57% of patients
in the placebo group crossed over to ivosedinib. Median PFS
was 2.7 months (95% CI 1.6–4.2) compared to 1.4 months
(95% CI 1.4–1.6) for placebo (HR 0.37; 95% CI 0.25–0.54).
Median OS in the ITT population was 10.8 months (95% CI
7.7–17.6) for the ivosidenib group versus 9.7 months (4.8–
12.1) for placebo.
Fibroblast growth factor receptors (FGFR) regulate cell pro-
liferation, survival, migration, and angiogenesis, and aberrations are associated with oncogenesis (Javle et al. 2016). FGFR
fusions and rearrangements are present in 13–17% of intrahepatic cholangiocarcinoma butrare in extrahepatic cholangiocarcinoma. The selective FGFR1-3 inhibitor pemigatinib has
been approved in the US based on the phase II single arm
FIGHT-202 trial which demonstrated activity in patients with
pre-treated FGFR2 mutant cholangiocarcinoma. 37% of 108
patients achieved a response and had a longer OS of 30.1
months (95% CI 21.5-NE) compared to 13.7 months (95% CI
9.6–16.1) for non-responders. There were no responses in
patients with other or no FGFR aberrations. Hyperphosphatemia,
alopecia, diarrhea, and fatigue were most the most common
adverse events (Abou-Alfa et al. 2020; Abou-Alfa et al. 2021).
Other potential targetable mutations include BRAF, HER2
amplification (Javle et al. 2015; Subbiah et al. 2020).
Immunotherapy
Patients with MSI-H cholangiocarcinoma may respond well to
checkpoint inhibitor immunotherapy. 22 patients with previously treated cholangiocarcinoma were included in the
KEYNOTE-158 trial and treated with pembrolizumab with an
ORR of 40.9% and a median PFS of 4.2 months (Range 2.1-NR)
and OS of 24.3 months (Range 6.5-NR). Grade 3–5 adverse
events occurred in 14.6% overall (Piha-Paul et al. 2020;
Marabelle et al. 2020).
Doublet anti-PD-1 and anti-CTLA4 therapy may overcome
immunotherapy resistance in microsatellite stable intrahepatic
carcinomas. In the biliary tract cancer subgroup analysis of the
CA2090-538 trial, 5 of 16 patients with MSS intrahepatic cholangiocarcinoma experienced tumor response for a duration of
3–14.8 months. Grade 3 to 4 immune mediated adverse events
occurred in 15% of the cohort. No patients with extrahepatic
cholangiocarcinoma responded (Klein et al. 2020).
Extrahepatic Cholangiocarcinoma
There are fewer data for targeted therapies in extrahepatic cholangiocarcinoma. The potential targets KRAS and HER2
amplification are more common than in intrahepatic carcinoma, and are associated with poorer survival on chemotherapy hence these patients may benefit from trial referral
(Javle et al. 2016; Montal et al. 2020; Fernandes et al. 2015).
Conclusion
Chemotherapy is currently the standard therapy for advanced
cholangiocarcinoma, and some patients will benefit from this.
It is important patients who have MSI-H cholangiocarcinoma
or targetable mutations as they may respond better to alternate
treatments, especially beyond the first-line setting. While these
advances are promising, molecular testing and matching agents
(including those mentioned above) are often difficult to access
outside of a trial.
Key Take Home Messages
1 Outcomes are poor with curative resection alone.
2 Hence adjuvant chemo(radiotherapy) should be considered in all
appropriate patients with R1 or node positive disease, but the data
is not robust.
Chemotherapy is currently the standard of care for unresectable/meta-
3
static disease.
4 Patients with MSI-H disease or targetable mutations may benefit from
immunotherapy and targeted therapy.
5 Access to molecular testing, and access to immunotherapy and tar-
geted therapy is a significant barrier.
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Radiation Therapy
Natalie Collier
Unresectable Intrahepatic
Cholangiocarcinoma (Icca)
Up to 70% of patients with non-metastatic unresectable iCCA
experience first progression in the primary tumour despite palliative chemotherapy, and overall survival remains poor. Only
recently, external beam radiation therapy (EBRT) has been recommended in guidelines for unresectable iCCA after induction
chemotherapy; or alone for those unsuitable for induction chemotherapy (Apisarnthanarax et al. 2022). EBRT may reduce the
occurrence of liver failure and death, current recommendations
for definitive RT are based on retrospective and phase I/II data.
Dose Escalation
There has been a strong signal from retrospective and prospective studies, that a relationship exists between RT dose
and increasing iCCA tumour control (Hong et al. 2016; Tao
et al. 2016). Tao et al. (2016) demonstrated that dose escalation to ablative doses compared to lower doses resulted in
improved local control (78% vs 45%, P=0.04) and overall
survival (73% vs 38%, P=0.017) at 3 years. (Hong et al. 2016;
Tao et al. 2016) reported a high 2-year local control rate of
94.1%, with local recurrences occurring solely in the lower
radiation dose group.
A Biological Equivalent Dose (BED) > 80.5Gy appears to be
ablative for iCCA and can be achieved with various regimens
(Table 6). There is no randomised data comparing prescription
doses and fractionation schedules, and therefore selection
should be based on risk of toxicity to organs-at-risk (OARs),
and available techniques (discussed below).
Table 6 Radiotherapy regimens with ablative potential in iCCA treatment1.
Type of fractionation regimen
Conventional fractionation
(CFx)
Moderate hypofractionation
(MHFx)
Ultra-hypofractionation
(UHFx)
Stereotactic Body Radiation Therapy (SBRT) >5 ≤5 45-50Gy/5#
1
Biological Equivalent Dose (BED) > 80.5Gy.
Dose per fraction
(Gy/#)
1.8–2 25–30 n/a
3–5 12–20 58–67.5Gy/15# (4.5Gy per #)
>5 ≤10 51Gy/6#
Typical number
of fractions
Example of regimen with ablative
potential
Non-ablative CFx regimen = 50Gy/25#
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Radiotherapy Technique
Large targets, and those adjacent to critical normal structures
are challenging to treat. Modern techniques incorporating
highly conformal radiotherapy, patient immobilisation,
assessment/management of tumour motion and image
guidance during treatment delivery are important and are
incorporated in prospective trial protocols (NCT02200042
(NRG Oncology 2017)).
Options for precise radiotherapy delivery, include megavoltage photons or charged particles (e.g. protons), and choice of
technology is largely dependent on availability. Protons have a
unique advantage, which may correlate to a clinical benefit by
enabling dose escalation and OAR-sparing, with no exiting
dose. Delivery of internal radiotherapy with brachytherapy has
also be utilised in a number of settings to dose-escalate (discussed previously).
A phase II study (Hong et al. 2016) for unresectable or locally
recurrent iCCA with a median tumour size of 6cm (range 2.2–
10.9cm), used protons to deliver 58.05–67.5Gy/15#, with an
excellent 2-year local control and overall survival rates of 94.1%
and 46.5%, with 7.7% of patients experiencing grade 3 toxicity.
Hepatobiliary Toxicity (HBT)
Caution has been exerted for many years over radiation to the
liver. Through increasing awareness of liver tolerance to RT,
reducing low-moderate doses to normal liver and using
modern RT techniques, the risk of radiation-induced liver
disease (RILD) can be minimised. Other factors which may
increase the risk of RILD include underlying cirrhosis, liver
impairment, prior/concurrent systemic therapy, and tumour
size (Pan et al. 2010).
A Phase I Stereotactic Body Radiation Therapy (SBRT) study
(Tse et al. 2008) first reported acute temporary biliary obstruction, in 2 out of 10 patients with iCCA; likely from tumour
oedema due to ultra-hypofractionation. (Osmundson et al.
2015) defined factors that predicted HBT after SBRT for primary and metastatic liver tumours. There was a significant
relationship between grade ≥3 toxicity and dose to the central
hepatobiliary tract, and recommended dose constraints have
since been published (Toesca et al. 2017).
Clearly ablative doses for disease control need to be balanced
with the risk of HBT, and some trials have adopted a modified
dose based on tumour location. A phase II study prescribed
67.5Gy/15# for peripheral tumours, and 58.05Gy/15# to tumours
<2cm from the porta hepatis, resulting in acceptable rates of
grade 3 toxicity for patients with iCCA (7.7%) and no grade 4/5
events.
Randomised Phase III Trials
The NRG-GI001 Randomised phase III attempted to randomised 146 patients with unresectable localised iCCA and no
tumour progression following induction gemcitabine/cisplatin
chemotherapy, to either radiation therapy or observation (see
Table 7 for eligibility criteria) (NRG Oncology 2017). Use of
Table 7 Eligibility criteria for the NRG-GI001 randomised phase III study of focal radiation therapy for unresectable localised iCCA (NCT02200042).
Criteria
1 Pathological diagnosis of iCCA without distant extrahepatic metastasis.
2 Single lesion with a maximum axial diameter of 12cm at the time of study entry. Up to 3 satellite lesions (less than 2 cm that are within 1 cm of
the periphery of the dominant lesion) are permitted. Clinically positive regional porta hepatis lymph nodes are permitted.
3 CT scan chest/abdomen/pelvis with multiphasic liver CT scan within 30 days prior to study entry (or CT chest without contrast plus MRI of
abdomen/pelvis)
4 Zubrod Performance Status 0–1
5 Age ≥ 18;
6 Adequate bone marrow and organ function:
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm;
• Platelets ≥ 75,000 cells/mm
• AST and ALT < 5.0 X institutional upper limit of normal;
• Albumin ≥ 2.5mg/dl;
• Creatinine within normal institutional limits or creatinine clearance ≥ 60mL/min/1.73 m2
• Hemoglobin ≥ 9.0 g/dl.
7 Must have received 6 months of Gemcitabine/Cisplatin chemotherapy without progression (or at least 4 months if toxicity precludes 6 months).
3
; Total bilirubin < 2.5mg/dl;
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image-guidance and real-time RT quality assurance was mandated, and the highest dose deliverable in 15# was 67.5Gy;
modified to prioritise the mean dose constraint to the liver and
GI luminal structures. Unfortunately, the study closed early
due to unmet accrual goals, and no outcome data is expected.
A second randomised trial (NCT02773485) comparing 52.560Gy/25# using modern RT with weekly gemcitabine and 8
cycles of cisplatin and gemcitabine, to 8 cycles of chemotherapy
alone for non-metastatic unresectable CCA (iCCA and eCCA),
has an estimated completion in mid-2022.
Concurrent Chemotherapy with
Denitive RT
There are potential advantages of using radio-sensitising chemotherapy with radiotherapy, particularly if ablative doses
cannot be achieved, although there is no standard regimen or
recommendation for use. The choice of agent should be based
on individual patient factors.
Conventionally fractionated radiotherapy to a dose of
50-60Gy with fluoropyrimidine-based chemotherapy is
included in recent guidelines (NCCN 2022). Concurrent chemotherapy with ultra-hypofractionation/SBRT is not considered common or safe practice and is not included in guideline
recommendations.
ABC-07 phase II trial (ISRCTN10639376) continues to recruit
and deliver moderately or ultra-hypofractionated radiotherapy
to unresectable eCCA or iCCA following chemotherapy.
Palliative Radiotherapy Following
Biliary Stenting
(Shinohara et al. 2009) concluded that patients who received
palliative RT in the SEER database, had an improved survival
compared to no RT or surgery, though this was a heterogenous
group with no information about biliary stenting. Approaches
to delay tumour progression causing biliary stent re-occlusion,
aside from EBRT, have included intra-luminal brachytherapy
(ILBT) or radioactive stents (see earlier section).
Those who survive long enough, remain at risk of toxicity
from high radiation doses, and the optimal RT schedule, when
the primary goal is to palliate symptoms and prevent stent reocclusion, is not defined. Several recent series have reported
safety and efficacy of EBRT following stent insertion, including
a retrospective comparison of 25 patients who received
37–40.7Gy/10–11# after percutaneous biliary stenting (PBS),
to 13 patients with PBS alone. There were significant improvements in median stent patency (326d vs 196d) and median
overall survival (12.2m vs 8.9m), with no difference in early
complication rates (Tan et al. 2015).
Unresectable Extrahepatic
Cholangiocarcinoma
Radiotherapy fields for eCCA are more likely to abut or overlap
sensitive OARs and there are valid concerns about the use of
ablative doses in this location. In the absence of safety data to
support the use of dose-escalation or moderate/ultra-hypofractionation for extrahepatic tumours, conventionally fractionated radiotherapy up to 60Gy with fluoropyrimidine-based
chemotherapy is considered acceptable (NCCN 2022).
A randomised phase 2 trial by (Phelip et al. 2014) closed
early due to slow recruitment, and although no significant conclusions were made, the results suggest that PFS and OS with
CRT (50Gy with 5-FU and cisplatin) alone may not be adequate without additional standard chemotherapy. However, the
rate of biliary complications appeared less frequent on the CRT
arm compared to 6 months of CT alone (28% vs 44% (risk ratio
(RR): 1.60 [0.65–3.92])). The results of the recruiting phase III
study (NCT02773485) for unresectable CCA (including eCCA)
discussed in the randomised trials section, are anticipated
(CRT 60Gy/25# + CT, compared to CT alone).
The outcomes of phase I/II trials investigating dose-escalation
are awaited. The STRONG phase I trial (n=6) (NCT03307538),
completed in January 2021, used risk-adapted doses up to
67.5Gy/15# for peri-hilar tumours using stereotactic techniques,
following standard chemotherapy (Koedijk et al. 2018). The UK
Adjuvant Chemoradiotherapy
Multi-disciplinary discussion around reducing the risk of recurrence is recommended, particularly for patients with high risk
features including positive surgical margin (R1) and lymph node
positivity. Despite the increasing use of liver radiotherapy, there is
still no standard adjuvant approach for resected CCA (Table 8).
Resected eCCA
Non-randomised phase 2 trials and meta-analyses support the
efficacy of adjuvant CRT, with the most benefit seen in LN
positive and R1 resections. The SWOG S0809 phase 2 trial for
resected T2-4 R0, R1 or pN+ eCCA and GBC reported promising 2-year OS outcomes of 76% for R0 and 60% for R1 resections, with adjuvant capecitabine and gemcitabine, followed by
CRT (45–59.4Gy/25# with capecitabine). Some retrospective
studies have escalated doses by using either intra-operative
radiotherapy (IORT) or brachytherapy, though the benefit in
this cohort is not clear.
A sub-study of the currently recruiting randomised phase 3
ACTICCA-1 study (NCT02170090), randomises eligible patients
with R1 resected iCCA, eCCA or pCCA between gemcitabine/
cisplatin or capecitabine for 24 weeks, or 18 weeks followed by
concurrent CRT with capecitabine. Lymph node positive R0
resections are excluded.
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Table 8 Meta-analyses on adjuvant radiotherapy in eCCA.
Study Patient cohort Comparison No. studies Outcome Other
(Beltrán et
al., 2012)
(Horgan et
al. 2012)
(Ren et al.
2020)
eCCA: extra-hepatic cholangiocarcinoma, GBC: gall bladder cancer, OS: overall survival, GIB: gastrointestinal bleed, LN: lymph node, R1: positive
resection margin.
Resected iCCA
Retrospective data suggests a benefit to post-operative radiotherapy for lymph node positive and R1 resections, though higher
quality data is awaited (see previous). Retrospective evaluation of
definitive iCCA treatment in the SEER database (Shinohara et al.
2008), revealed that surgery and adjuvant RT conferred a
significant benefit on OS compared to surgery alone. The retrospective nature, lack of concurrent/adjuvant chemotherapy
information, and absence of patient specific limits this analysis.
In an evaluation of 70 patients with iCCA adherent to major
vessels, the outcomes of patients with narrow margin resection
(70%), defined as <1.0cm (47–51% R1), were compared to
margins of ≥1.0cm (Zheng et al. 2018). In the narrow-margin
group, 50% received adjuvant radiotherapy (no CT), with
3-year OS/PFS rates similar to wide-margin resections, compared to poorer outcomes for narrow-margins. Furthermore, a
review of 137 patients (58% iCCA, 25% LN+) who received
surgery ± adjuvant therapy (53%) with CT, CRT or RT, demonstrated that adjuvant CRT (10%) was seen to improve RFS compared to surgery alone (Kim et al. 2017).
Key Take Home Messages
1 Definitive EBRT for inoperable localised cholangiocarcinoma (CCA) ±
induction chemotherapy may reduce liver failure and death
Conventionally fractionated regimens (e.g. 50.4Gy/28#) ± concurrent
2
chemotherapy appear to be well-tolerated
3 EBRT alone to “ablative doses” for intrahepatic CCA can be achieved
with modern techniques and hypofractionation (> 2Gy/fraction),
with high local control rates
4
Multi-disciplinary discussion around reducing recurrence after surgery
should include chemoradiotherapy, particularly for high risk patients
(R1, lymph node positive)
Liver radiation therapy should always be balanced with the risk of
5
toxicity and the goals of care
6 High-level evidence to support RT for CCA is not yet available, and
randomised studies are awaited
eCCA, GBC and
ampullary cancer
CCA and GBC
(25%)
eCCA and GBC Adjuvant RT or CRT
Adjuvant RT or CRT
with 5FU vs
surgery alone
Adjuvant CT, RT or
CRT vs surgery
alone
vs surgery alone
10 Improved OS (HR 0.62, 95% CI:
0.48–0.78)
20 Improved OS with CT (OR 0.39, 95%
CI: 0.23–0.66) and CRT (OR 0.61,
95% CI: 0.38–0.99) but not RT alone
21 Improved 5-year OS rate (OR
CI: 0.50–0.81),
0.63, 95%
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location and whether treatment is with palliative or curative
intent. This creates a complicated set of decision permutations
which outlined below and in Table 9.
Distal Biliary Strictures
Drainage of dCCA strictures is by stent placement at ERCP
(Scatimburgo et al. 2021). If ERCP is unsuccessful or infeasible,
alternative approaches including percutaneous or EUS-guided
drainage may be employed (Hayat et al. 2022).
Advantages and disadvantages of different stent types are
well addressed in the pancreatic cancer literature (Nehme and
Lee 2022). Usually at the index procedure, a pathological diagnosis of malignancy has not yet been made. To allow neoadjuvant chemotherapy or as a “bridge-to-surgery”, removable
plastic or fully-covered self-expanding metal stent (SEMS) are
preferred. The role for perioperative biliary drainage is
addressed above. Definitive palliative stenting is best performed with uncovered SEMS, which do not require routine
replacement, and have a low risk of stent migration. Tumour
ingrowth may occur, hence the use in certain situations of
covered or partially-covered SEMS, which carry the potential
higher risk of cholecystitis (Scatimburgo et al. 2021; Yamashita
et al. 2022).
Other Therapies
Nicholas Holt & Philip I. Craig
Biliary Drainage for
Cholangiocarcinoma
In the setting of malignant biliary obstruction, drainage
improves mortality (Liang et al. 2021). The strategy for drainage in malignant biliary obstruction depends on both stricture
Table 9 Biliary drainage options in the setting of cholangiocarcinoma.
Management Intent
Curative Palliative
Location of
obstruction
Hilar Plastic biliary stent(s) placed at ERCP, draining future liver remnant as a bridge to
surgery
Distal Either
• Surgery as primary drainage procedure
• Endoscopically placed plastic or removeable metal stent as bridge to surgery
Hilar Strictures
Hilar strictures present further challenges, and the management
strategy is also dependent on patient and disease factors.
Strictures more advanced than Bismuth I preclude complete
hepatic drainage with a single stent. In addition, ERCP
management of hilar strictures is more technically challenging
than distal strictures, meaning some centres favour percutaneous transhepatic biliary drainage (PTBD) depending on
local expertise. Care should be taken to not inject contrast into
ducts which are not planned for drainage, to reduce the risk of
cholangitis. If a definitive diagnosis of malignancy is not made
prior to ERCP then removable plastic stents are placed. Covered
SEMS are not used for hilar strictures due to the risk of
Either endoscopic or percutaneous
drainage of at least 30–50% of
liver using metal stents
Endoscopic drainage, ideally with
metal stents
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blocking intra-hepatic ductal side branches. For palliative biliary drainage, uncovered SEMS offer the best long-term drainage option. Three randomised controlled trials have shown a
lower rate of stent failure and re-intervention compared with
plastic stents; one also showing an improvement in survival
(H.J. Mukai et al. 2013; Sangchan et al. 2012; Wagner et al.
1993).
Choosing single versus multiple biliary SEMS to improve the
volume of liver drained is controversial. Pre-procedural
cross-sectional imaging, particularly MRCP, is useful to assess
the feasibility of draining multiple biliary segments. The
proportion of the liver that needs to be drained to achieve
“effective drainage” – defined by resolution of jaundice, has
been assessed in uncontrolled (Hintze et al. 2001) and retrospective (Bulajic et al. 2012; Takahashi et al. 2015; Vienne et al.
2010) studies. These suggest that drainage of 33% may be ade-
quate to palliate jaundice, however often 50% is required.
Achieving drainage of multiple biliary segments with multiple
stents is procedurally more challenging. Several meta-analyses
using retrospective data and including other causes of hilar
malignant biliary obstruction (MBO), provide disparate conclusions concerning placement of single versus multiple stents.
Advocates of bilateral drainage, cite prolonged stent patency
and lower rates of reintervention (Ashat et al. 2019; F. Yang
et al. 2021). Other studies suggest no difference in effective
drainage, with increased complications when multiple SEMS
were utilised (Fu et al. 2021; Meybodi et al. 2020). Overall however, in the setting of more complex Bismuth strictures, if preceding cross-sectional imaging confirms multiple SEMS can
achieve drainage of the majority of the liver then our group will
usually endeavour to place at least two SEMS.
EUS Guided Biliary Drainage
EUS-guided biliary drainage has recently evolved in settings
where ERCP has been unsuccessful. In these studies dCCA has
been grouped with other causes of distal MBO. The technique
involves biliary puncture under EUS guidance, with subsequent
placement of a lumen-apposing metal stent creating a choledochoduodenostomy (EUS-CD). Clinical success appears to be
equivalent with lower rates of complications compared with
PTBD, for patients with distal MBO and failed ERCP (Hayat
et al. 2022). Studies have also assessed EUS-CD as the initial
procedure as an alternative to ERCP, showing no difference
between technical and clinical success, and overall adverse
events (Lyu et al. 2021) . A similar technique, EUS-guided
hepaticogastrostomy (EUS-HG), has been employed to drain
hilar strictures using a trans-gastric approach to puncture the
intrahepatic biliary tree and place a stent. EUS-HG and PTBD
each share the potential for peritoneal seeding and difficulties
in placing multiple stents to achieve adequate liver drainage
particularly in the setting of more complex Bismuth strictures.
Furthermore, EUS-HG has a higher risk of complications compared to EUS-CD (J. Li et al. 2022).
Intrahepatic Cholangiocarcinoma –
Locoregional Therapies
There are limited data concerning the role of locoregional therapies to manage iCCA. Data is usually combined with other
intra-hepatic tumours (including hepatocellular carcinoma
and metastatic adenocarcinoma). There are no comparative
randomised data available. Substantial retrospective data suggest improved overall survival with these approaches compared
with historical controls. In these studies, locoregional therapies
are used to achieve local control in patients with non-resectable
disease, or to treat post-surgical recurrence. Radiofrequency
ablation (RFA) and microwave ablation seem to be effective for
local control of lesions usually smaller than 3cm (G.H. Kim
et al. 2022). Trans-arterial chemoembolization (TACE) and
brachytherapy have also been used, but only a few retrospective
studies report benefit (Jonczyk et al. 2018; Liu et al. 2020).
Many patients receiving locoregional therapies receive additional chemotherapy. Irreversible electroporation has recently
been assessed in small pilot studies but remain confined to subspecialist centres.
Endobiliary Radiofrequency Ablation
RFA is a relatively new technique to treat ductal biliary tumours.
Tissue necrosis is induced by delivery of thermal energy to
tumours either at ERCP (Figure 10) or PTBD. RFA is used in
combination with palliative biliary stenting. RFA has also been
used in neoadjuvant settings to manage eCCA (E.J. Kim et al.
2018) and for therapy of tumour ingrowth causing occlusion to
existing biliary stents (So et al. 2021). To date, six prospective
randomised controlled RFA trials have been published. Survival
was improved by 4.1–4.9 months in three of the four studies
designed to detect this difference (Gao et al. 2021; J. Yang et al.
2018; Hu et al. 2016). The complication rate from RFA, is up to
19% (Alvarez-Sánchez and Napoléon 2016). Most are mild, and
take the form of typical ERCP-related complications, however
cholecystitis, haemobilia and other vascular complications are
more common.
Photodynamic Therapy
Photodynamic therapy (PDT) relies on preferential accumulation
of a parenterally administered photosensitising agent (e.g. porfimer sodium or hematoporphyrin) in tumour cells. When light
of a specified wavelength is applied, it generates oxygen radicals,
ultimately resulting in tumour cell death. PDT has mostly been
used in the palliative setting for patients with unresectable biliary
malignancy. There are also several studies in the neoadjuvant (A.
434 3 HEPATOBILIARY AND PANCREAS CANCER
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Figure 10 Endobiliary RFA for distal cholangiocarcinoma; fluoroscopy (left), endoscopy (right) demonstrating the RFA probe being
inserted into the bile duct.
Wagner et al. 2015), pre-transplant (Cosgrove et al. 2014) and
post-surgical recurrence settings (Z. Li et al. 2021).
Several small randomised controlled trials and retrospective
analyses assessing PDT in the palliative setting have been
reported. Meta-analysis level data suggest that PDT may
improve survival, biliary drainage, and performance status
(P. Chen et al. 2022). Two RCTs comparing PDT to stenting
alone, demonstrated improved survival from 98 to 493 days
and 7 to 21 months, respectively (Ortner et al. 2003; Zoepf et al.
2005). The largest and most recent randomised control trial
however, was abandoned after it showed overall worse survival
in the PDT group – it was not included in the aforementioned
meta-analyses. Importantly, PDT has not been widely adopted
because it induces cutaneous photosensitivity requiring most
patients to avoid direct sunlight for at least 6 weeks.
Brachytherapy
Brachytherapy involves the direct application of a radiation emitting radioisotope to tumours. Rapid dose attenuation results in
delivery of high doses of ionising radiation to target CCA, with
little exposure of surrounding tissues. High dose rate (HDR)
brachytherapy applications involve relatively higher doses
administered over short time periods. HDR theoretically has less
potential for locoregional toxicities (Mukewar et al. 2015) .
For extrahepatic CCA, HDR brachytherapy with iridium-192
wires has been available for several decades. Its role has been
predominantly in the setting of unresectable disease, often
administered in parallel with external beam radiotherapy, chemotherapy or other locoregional therapies (Autorino et al.
2020; Bisello et al. 2019). It has also been incorporated into pretransplant regimens (Mukewar et al. 2015). Delivery is via
PTBD or ERCP and modest survival benefits have been
observed in retrospective studies (Taggar et al. 2021) and a
single randomised controlled trial (Válek et al. 2007).
Complications appear to be predominantly related to biliary
intervention rather than radiation, however gastroduodenal
ulceration and strictures and biliary fistulae, have been reported
(Takamura et al. 2003). Delivery of brachytherapy is difficult
and, it is not widely used outside the setting of liver transplant.
Low dose rate brachytherapy with iodine-125 “seeds” incorporated into SEMS has been recently studied. Stent placement
has usually been via PTBD. In this regard, several randomised
controlled trials from China compared conventional SEMS
with “radioactive stents”. The patient populations included heterogeneous groups with a variety of tumours including small
numbers of CCA subjects (Y. Chen et al. 2012; W. Chen et al.
2018; Hasimu et al. 2017; Jiao et al. 2017; Zhu et al. 2012, 2018).
These preliminary data were combined in a meta-analysis of all
types of malignant biliary obstruction, both distal and hilar,
suggesting modest survival benefits (HR 1.6) and stent patency
compared with biliary drainage alone (Sha et al. 2021).
Complications do not appear increased with brachytherapy
seeds compared to conventional SEMS.
Drug-eluting (gemcitabine and cisplatin) stents have also
been developed with several small trials and a meta-analysis
assessing their use in malignant distal biliary strictures. These
studies showed no improvement in either stent patency or
patient survival but were associated with increased rates of
cholangitis (Yuan et al. 2019).
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 435
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Key Take Home Messages
1 The majority of eCCA patients with biliary obstruction have unresect-
able disease and benefit from palliative stenting with a SEMS
2 Technical factors around optimal biliary drainage are complex and
often best decided with expert input in a MDT setting
3 In eCCA, endobiliary RFA, and brachytherapy in specific clinical set-
tings are useful adjuncts to biliary stent placement
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