CHOLANGIO CARCINOMA

Presenter : Georvin Marco

Supervisor:Dr.Mwanga
 introduction
• Introduction
• Objectives
• Pathogenesis of cholangiocarcinoma
• Classification of cholangiocarcinoma
• Diagnosis of cholangiocarcinoma
• Management of cholangiocarcinoma
 objectives
• At the end of session we should be able to
• define cholarngiocarcinoma.
• explain the risk factors and pathophysiology
of cholangiocarcinoma.
• Classify cholarngiocarcinoma.
• Explain diagnostic and metastatic work up for
cholarngiocarcinoma.
• Explain management of cholangiocarcinoma.
 Introduction
• Cholangiocarcinomas arise from the epithelial cells
of the biliary truct (intra or extra hepatic biliary duct).

• they are highly lethal because most are locally

advanced at presentation and un resectable tumor at
time of diagnosis

• Most of them involve vessel , lymph node , and

adjucent stricture as the result of curative surgical
resection is imposible
 Epidemiology
• the incidence of biliary tract cancers increases with age typical
ranging between 50 and 70 years of age.
• However, CC arising from primary sclerosing cholangitis (psc)
and t choledochal cysts present nearly two decades earlier.
• The incidence of CC is slightly higher in men may be due to
higher incidence of PSC in men, contraly to gall badder tumor
where is predominant female gender.
• From data of 2001 to 2015 suggest an incidence of 1.26 cases
of CC per 100,000 people per year, and that 2/3 two-thirds of
cases are intrahepatic CC.
 Cont…
• In the United States, an estimated 41,260 primary liver and
intrahepatic bile duct cancers are diagnosed annually and
about 15 % of these are IHCC.

• 12,130 cases of extrahepatic biliary tract cancers are

diagnosed annually and 2/3 are gallbladder cancers. About
3000 cases per year, are EHCC.

• Internationally, the incidence of CC varies significantly,

While the incidence is low in high-income countries.
• in endemic regions of Thailand and China, the incidence is up
to 40-fold higher,most likely due to chronic infection with
hepatobiliary flukes.

• In africa ,CCA is more predominant in male gender and

median age was approximatelly 52.5 and 61 years .
 Pathogenesis of cholangiocarcinoma
• The epithelium of the biliary tract under chronic irritation and inflammation
goes through hyperplasia to metaplasia and dysplasia, finally to carcinoma,
which involves mutations in different oncogenes and tumor suppressor
genes.

• Proinflammatory cytokines IL-6 activate inducible nitric oxide synthase

resulting in excess nitric oxide that mediates oxidative DNA-damage,
inhibition of DNA repair enzymes and expression of cyclooxygenase 2 (COX-
2). cyclooxygenase 2 cause inhibition of apoptosis and growth stimulation.

• Proinflammatory pathways downregulate hepatobiliary transporters,

thereby, contributing to cholestasis.
• Bile acids and oxysterols activate epidermal growth factor receptor (EGFR)
and enhance COX-2 expression.
 Cont..
• intrahepatic bile duct tumors
• 20% of Isocitrate dehydrogenase (IDH) genes – IDH1 ,IDH2
and 13 to 17% of Fibroblast growth factor receptor (FGFR)
• The tumor suppressor gene Tumor protein 53 (Tp53)
mutation, has been found to occur in about 40% of perihilar
(pCCA) and distal (CCA) and 25% of ICCA.
• Alteration in the proto-oncogene KRAS is more prevalence
extra hepatic CCA 42% compared to ICCA 22% .
• epidermal growth factor receptor (EGFR) more prevalent in
IHCCA 11-27% as compared to distal and perihilar type 5-
19%.
Risk factors for cholangiocarcinoma
main risk factors are
• primary sclerosing cholangitis (PSC) and fibropolycystic liver
disease (carolidisease and choledochal cyst.
• chronic intrahepatic stone disease (hepatolithiasis)
• Chronic liver disease (cirrhosis and viral infection) chronic
infection with liver fluke is the driving risk factor.
• genetic conditions, Lynch syndrome, BRCA-associated
protein-1 (BAP1) tumor predisposition syndrome, cystic
fibrosis and biliary papillomatosis, appear to increase the risk
for cholangiocarcinoma.
Anatomical classification
 Cont..
• Anatomically classified as intra hepatic and extrahepatic
CCA
• Intrahepatic CCA originate from small ductules (peripheral
cca) or large intrahepatic ducts proximal to the bifurcation
of the right and left hepatic ducts.
• The extrahepatic bile ducts are divided into perihilar and
distal segments, with the transition occurring at the point
where the common bile duct lies posterior to the
duodenum, proximal to the insertion of the cystic duct into
the common bile duct
 Cont..
• perihilar cca 50 %

• distal cca 40 %

• intrahepatic tcca less han 10 % of

cholangiocarcinoma cases .
 Histological classification
• The American Joint Committee for Cancer (AJCC) modified this
classification from simply well-differentiated to poorly
differentiated carcinoma on the histological basis to:
• Adenocarcinoma
• Intraductal papillary neoplasm without any invasive
characteristics
• Mucinous cystic neoplasm with an associated invasive carcinoma
• Adenosquamous carcinoma
• Squamous cell carcinoma
• Poorly differentiated neuroendocrine carcinoma
• Mixed adenoneuroendocrine carcinoma and undifferentiated
carcinoma.
 Histologically classsification
• The majority of CCA more than 90% are
adenocarcinomas
• squamous cell carcinoma being responsible for
most of the remaining cases , adenosquamous
cancers are rare.
• CCA are graded as well, moderately, or poorly
differentiated.
• These Histologic findings and immunohistochemical
stains that can assist in the differential diagnosis of
CCA from other malignancies, particularly those
that arise in liver.
 Morphological classification
• Morphologically, both intra and extra hepatic biliary CCA can
be sclerosing, nodular, and papillary
• Sclerosing (scirrhous),have extensive fibrosis that makes
preoperative diagnosis by biopsy and cytology more difficult
than for other tumors ,
• they invade the bile duct wall early that leads to low
resectability and cure rates. Intraductal spread may mimic PSC
on cholangiographic studies, complicating the radiographic
diagnosis.
• Most CCA are of this type in one report, 94% of perihilar, 79 of
80 distal tumors and all nine intrahepatic CCA tumors were
sclerotic adenocarcinomas,
 Morphological cont..
• Nodular CCA present as a constricting annular lesion of the
bile duct. These are highly invasive tumors, and most patients
have advanced disease at the time of diagnosis; thus, the
resectability and cure rates are very low .
• Papillary CCA are the rarest form of CCA, These usually
present as bulky masses in the common bile duct lumen,
which cause biliary obstruction early in the course of the
disease. For this reason, they have the highest resectability
and cure rates
• At the large intrahepatic bile ducts, papillary growth and
periductal infiltration is typical, while tumors arising from
ductules share a similar phenotype with hepatocellular
carcinoma (HCC).
 Immunohistochemistry
• There are no known proteins that are differentially expressed
by normal or malignant epithelial thereby no pathognomonic
immunohistochemical test. that can be used to confirm the
cell type of origin.
• However, immunohistochemical staining with cytokeratin C7
positive may be used to support a diagnosis of malignant
biliary epithelium with biriary origin. metastatic cancers of
the lung and breast are also CK7 positive, and the diagnosis of
a CCA is frequently a diagnosis of exclusion.CK 19 and ck 20
 Cont..
• Combined hepatocellular CCA also referred to as primary
liver carcinoma with biphenotypic differentiation or
hepatocholangiocarcinoma, is now acknowledged as a distinct
subtype of cholangiocarcinoma
• These tumors consist of intimately admixed elements of both
HCC and cholangiocarcinoma. They are distinguished from
separate HCC and cholangiocarcinomas arising in the same
liver lobe (which may be separated or intermixed "collision"
tumors). These tumors are staged as intrahepatic
cholangiocarcinomas and not HCCs.
 Clinical presentation

• Extrahepatic duct CCA usually become symptomatic when the

tumor obstructs the biliary drainage system,
• jaundice, pruritus, clay-colored stools, and dark urine.
abdominal pain dull persistent (30 to 50 %) weight loss (30
%to 50 %), and fever 20 % , Malaise, fatigue, and night sweats
may be present
• intrahepatic ducts CCA may present differently Affected
patients are less likely to be jaundiced. Instead,
• they usually have a history of dull right upper quadrant pain,
weight loss,
• However classical presentation of CCA , jaundice , weight loss
and right upper abdominal pain
 Clinical present…
• Physical examination examination, patients with
• extrahepatic CCA may have jaundice 90%, hepatomegaly 25% -
40 %, a right upper quadrant mass 10 %, or fever 2 -14 % and
palpable gallbladder occurs rarely
• A palpable gallbladder in a jaundiced patient (Courvoisier sign
or Courvoisier sign of maliginancy.
• Exceptions to this rule in chronic pancreatitis, parasitic biliary
obstruction, congenital choledochal cyst, common hepatic duct
obstruction proximal to the takeoff of the cystic duct.
• intrahepatic CCA may include right upper quadrant tenderness,
signs of weight loss,
Diagnosis and assement of resectability
• The tumor markers
• CA-125 and CEA , non specific ,
• CA 19-9 in CCA ,in PSC are ST 79% and SP 98%, at a cutoff
value of 129 U/mL.
• A change from baseline of >63 U/L has a ST of 90% and SP of
98% for CCA.
• In patients without PSC, its ST 53% at a cutoff of >100 U/mL
and its NPV is 76% to 92%

• For ca 19.9 > 1000u/ml associated with unresectable tumor,

advanced tumor wc peritoneal involvement.
• AFP ( intrahepatic icc vs HCC ,mixed ICC) ,IgG4 (PSC).
Diagnosis and assement of resectability

• Ultrasound, (obstruction detection and site localization)

• Limited detecting distal cca,
• adjunct on vascular involvement (encasement or compression,
thrombosis or occlusion)
• Different finding depend on type of cca
• MDCT, (obstruction , dilation , vascular involvement , but
limitation on nodal involvement to the hepatodeudenal
ligament)
• MDCT help on differentiating intra icc and hcc, and mixed
cca
Diagnosis and assement of resectability
• MRI/MRCP info on intra ,etra hepatic duct and pancreatic
duct , vascular stutus
• Chorangiography (ERCP or PTC)
• FNAC ,or brush cytology (30% of cca positive), combination
of positive cytology plus abnormal CA 199 has ST 88 and SP
94 and therapeutic stenting or dranage , stone extraction.
• (fish as role in cca)
ERCP
CHORANGIOSCOPEVS MRCP
Diagnosis and assement of resectability
• Endoscopic uss, local extent of the tumor, regional node( most
ST method) and biopsy of L node
• Detection of cca (endosc uss ST 96%, uss 81%, ct 86%)
• Cholangioscopy, visualize biliary tree, extent of tumor , take
biopsy.

• PET scan / FDG PT detecting occult metastatsis , follow up on

recurrence

• Diagnostic laparoscopy
 Creteria for resectability
• The traditional guidelines for resectability of cholangiocarcinoma in the
United States include:

• Absence of retropancreatic and paraceliac nodal metastases or distant

liver metastases

• Absence of invasion of the portal vein or main hepatic artery (although

some centers support en bloc resection with vascular reconstruction in
such cases)

• Absence of extrahepatic adjacent organ invasion

• Absence of disseminated disease.

 Criteria for resection
• Addition creteria for perihilar icca local unresectability
tumors include
• bilateral hepatic duct involvement up to secondary radicles
bilaterally, encasement or occlusion of the main portal vein
proximal to its bifurcation,

• atrophy of one liver lobe with encasement of the contralateral

portal vein branch,
• atrophy of one liver lobe with contralateral secondary biliary
radicle involvement, or nvolvement of bilateral hepatic
arteries
 Creteria for resection
• However, as a general rule, true resectability is ultimately
determined at surgery, particularly with perihilar tumors. Due to
their location within the upper hepatoduodenal ligament, these
tumors often extend into the liver and major vascular structures,
and preoperative evaluation of resectability is often difficult. Thus,
surgical exploration is the appropriate .

• For more proximal tumors that will require liver resection,

drainage of the future liver remnant is widely accepted. The best
method (endoscopic versus percutaneous transhepatic) by which to
perform preoperative biliary drainage is also debated.
 Intrahepatic cholangio carcinoma
• CCA is a CCA subtype that arises from the
intrahepatic biliary tract.
• Patients with iCCA often present with an
intrahepatic mass lesion.
• Based on macroscopic growth patterns, mass-
forming subtype is the most common and
spreads via venous and lymphatic vessels.
 Dx of icc
• Dx of icca , CT and MRI help in diagnosis of CCA
• Multidetector CT is more accurate than MRI in predicting
resectability, with an accuracy of 85% to 100%.

• iCCA takes up contrast agent progressively during the arterial

and venous phases of studies especially if the lesion is larger
than 20 mm

• iCCAs with extensive desmoplasia take up the contrast agent

more ,In contrast, HCCs take up contrast agent rapidly during
the arterial phase, and quickly wash out the contrast during the
venous phase of the study.
 Dx of icca
• (CA19-9) have 62% sensitivity and 63% specificity for
detecting icca.
• For pt without Psc the cut-off value is set at 100 U/Ml
and 129u/ml for with PSC , however,the Levels of
CA19-9 of 1000 U/mL or greater have been associated
strongly with unresectable disease.
• In mixed tumors, analysis for cytokeratins (CKs) 19 and
7. Tumors positive for CK19 and CK7 can be considered
mixed HCC.
• AFP use to differentiate HCC and icca
 Management of icc
• Usually treated by hepatic resection to achieve negative
resection margins.
• But they a/c high rates of tumor recurrence and short survival
times.

• the median survival time is 36 month after resection recurrence

rate of 62.2% after 2 yrs follow up.

• 60% undergo curative resection ( R0) survive for 5 years,

• Factors reduced survival time positive tumor margins lymph
node metastases and Cirrhosis
• absolutely contra indication
• distant metastatic disease or lymph node
disease beyond the porta hepatis,
• relatively contraindications for resection
• patients with cirrhosis is child purg b/c ,portal
hypertension
• Multifocal tumors have high rates of recurrence
(>90%) and usually preclude curative
resection(study)
 Intrahepatic cont….

• Although it is clear that lymph node involvement have poor prognostic

factor, lymphadenectomy does not appear to provide proven therapeutic
benefit, no consensus as to whether or not it should be routinely
performed
• The risk of performing portal lymph node dissection such as common
bile duct devascularization should be weighed against the perceived
benefit.
• we suggest selective aproach for portal lymphydenectomy
• For a peripheral localized tumor, portal lymph node dissection is not
routinely done.
• For more centrally located tumors in which an extrahepatic bile duct
resection is required to maximize the width of the resection margin, we
recommend portal lymphadenectomy at the same time.
• liver transplants , 5 yrs recurrence > 70%, and
the median time of disease-free survival is
only 8 months,
• neoadjuvant therapy for mixed type is of
paramount important thus biopsy is
mandatory before liver transplant.for icca with
atypical lesion for HCC.
• Un resctable icca
• The Advanced Biliary Cancer (ABC)-02 study showed that
systemic chemotherapy with a combination of gemcitabine
and cisplatin prolonged survival times of patients with
inoperable CCA, making it a treatment standard
• A recent meta-analysis supports adjuvant therapy for patients
with lymph node–positive disease.
• Targeted therapies also are being investigated
• for inoperable iCCA without extrahepatic metastases
• include transarterial chemoembolization, radiofrequency
ablation, and transarterial radioembolization.

• Patients who receive transarterial chemoembolization or

transarterial radioembolization had median survival times of
20 and 43.7 months, respectively, after diagnosis.

• Patients with tumors smaller than 3 cm who were treated with

radiofrequency ablation had an overall median survival time
of 38.5 months.
INTRAHEPATIC CCA
 PERIHILAR CHOLANGIOCARCINOMA
• PerihilarCCAs develop anywhere from the second-order
biliary ducts to above the site of cystic duct origin;
• Periductal infiltrating ( sclerosing subtype) is most common
morphological type

• PCCA spread by perineural invasion and lymphatic metastasis

 Bismuth-Corlette classification
• Type I- Tumors below the confluence of the left and
right hepatic ducts
• Type II -Tumors reaching the confluence
• Types IIIa and IIIb -Tumors occluding the common
hepatic duct and either the right or left hepatic duct (
respectively)
• Type IV -Tumors that are multicentric, or that involve
the confluence and both the right or left hepatic duct
Copyrights apply
 Management of perihilar
cholangiocarcinoma
Indications
No peritoneal metastasis no metastasis , no
distant lymnode metastatsa
 Peri hilar cholangiocarcinoma

For type I and II lesions, the procedure

• is en bloc resection of the extrahepatic bile ducts and gallbladder
with 5 to 10 mm bile duct margins and a regional
lymphadenectomy with Roux-en-Y hepaticojejunostomy
reconstruction
• The addition of an en bloc hepatic lobectomy or trisectionectomy
is usually required to achieve adequate negative bile duct margins
(5 to 10 mm).
• For type II tumors, the caudate branches are often involved, and
the caudate lobe must be resected. Clinically, it is often difficult to
distinguish between types I and II. Most surgeons recommend
treating unclear cases as a type II tumor.
• type III tumors usually require hepatic lobectomy or
trisectionectomy, Since type II and III lesions often
involve the ducts of the caudate lobe, many surgeons
recommend routine caudate lobectomy.
• Type III and type IV tumors are amenable to potentially
curative resection in centers with expertise in these
procedures. Aggressive techniques such as multiple
hepatic segment resection with portal vein resection
(hilar en bloc resection) to achieve negative margins
should not be a contraindication to resection
 Cont..
• extended right or left hemihepatectomy, involving half
of the liver, the inferior part of segment IV or V, most of
the caudate lobe, the hilar plate, the extrahepatic bile
duct, and regional lymphadenectomy, is regarded as the
standard radical operation for perihilar CCA
• Even for patients with Bismuth and Corlette types I or II
• extended hemihepatectomy is warranted to ensure
negative margins and improve survival among patients
suitable for surgery.
• Highly selected patients with type II, III, and IV
tumors that are not resectable due to vascular
invasion or primary sclerosing cholangitis may
be candidates for liver transplantation
 DISTAL CHOLANGIOCARCINOMA
• dCCA develops anywhere between the cystic duct origin
and the ampulla of Vater (without its involvement).
• dCCA arises from the precursor lesions intraductal
papillary neoplasm or biliary intraepithelial neoplasia.
• Well-to-moderately differentiated adenocarcinoma is the
most common histologic subtype.
• It is difficult to distinguish dCCA from early cancer of the
head of the pancreas. However, dCCA is less aggressive
than pancreatic cancer and merits more aggressive
surgical intervention.
 Distal cholangiocarcinoma
• Blood tests reveled rised cholestatic parameters
• cross-sectional studies show thickening and/ stricture of the
extrahepatic bile duct with proximal bile duct dilatation, and,
more rarely than for pancreatic cancer, an associated mass
• MRI with MRCP and CT can help to detect hepatic artery and
portal vein involvement and the extension into the pancreas.
• ERCP is an important diagnostic and therapeutic tool, but
intraductal ultrasonography also is helpful in diagnosis
• EUS with FNA can aid in evaluation of lymph node metastases
and status of the vascular structures.
• The role of direct intraductal visualization with cholangioscopy
for diagnosis of dCCA i
 Management of distal CCA
• Surgery for dCCA usually requires a Whipple procedure.
• When surgery is performed, positive lymph nodes are
identified in 68% of patients with distal common bile duct
tumors,
• compared with 28% and 29% for perihilar and intrahepatic
CCAs, respectively for positive lymnode identification.
• The overall 5-year survival rate of patients with dCCA after R0
resection is 27%, with a median survival time of 25 months
• Negative tumor margins are the most important predictor of
patient survival.
• When R0 resection is not achievable, patients are given a
combination of chemotherapy and relief of biliary obstruction.
 NEOADJUVANT APPROACHES

• Neoadjuvant therapy has gained favor in the treatment of

CCA.
• Theoretical benefits include
• Downstaging / downsizing unresectable disease to rectable
disease.

• Early treatment of potential micro-metastatic disease or

reduce the micrometastasis .

• allowing time to evaluate the aggressiveness of the tumor

biology as disease progression on neoadjuvant therapy is a
poor prognostic indicator..
 NEOADJUVANT APPROACHES

• Indications
• patients with large, locally advanced unresectable
intrahepatic cholangiocarcinomas. Have potential for
conversion to resectable.

• Orthotopic liver transplantation (OLT) might be

considered for highly selected patients with early stage
cholangiocarcinoma arising in the setting of primary
sclerosing cholangitis (PSC) or those with small (<3 cm)
 Criteria for neoadjuvant therapy and liver transplantation

• Diagnosis of cholangiocarcinoma ,CA 19-9 >100 mg/mL or

mass on cross-sectional imaging with a malignant-appearing
stricture on cholangiography or biliary ploidy by fluorescence
in situ hybridization [FISH] with a malignant-appearing
stricture on cholangiography)
• Unresectable tumor above the cystic duct
• resectable cholangiocarcinoma arising in a patient with PSC)
• Radial tumor diameter ≤3 cm
• Absence of intra- and extrahepatic metastases
• Candidate for liver transplantation
 Adjuvant chemotherapy
• Indications
• for all patients following resection, consistent with clinical
practice guidelines from the American Society of Clinical
Oncology (ASCO)
• Following complete surgical resection, the most common
relapse pattern for distal and perihilar cholangiocarcinomas is
local and distant metastasis rare.
• 60% distant metastases following a microscopically complete
(R0) of hilar cca
 Adjvunant cont..
Choice of regimen
• chemoradiotherapy (CRT) plus chemotherapy
• for patients with margin-positive or node-positive
extrahepatic CCA and for margin-positive intrahepatic CCA
• chemoradiotherapy
• Concurrent radiotherapy (RT) plus infusional FU (NCCN)
• Four cycles of capecitabine plus gemicitabine followed by
concurrent RT plus oral capecitabine in Southwest
Oncology Group (SWOG).
 Adjuvant cont..
Chemotherapy

• Capecitabine alone, as was used in the BILCAP trial

• Single-agent gemcitabine, as was used in the European Study

Group for Pancreatic Cancer (ESPAC)-3 trial .
 Cont…

The National Comprehensive Cancer Network (NCCN) suggests

the following
• Extrahepatic cholangiocarcinoma,

• pt with margin-negative extra hep CCA, and negative regional

nodes, fluoropyrimidine or gemcitabine-based chemotherapy, or
fluoropyrimidine-based CRT are acceptable options.

• Pt positive margins or positive regional lymph nodes, options

include fluoropyrimidine- or gemcitabine-based chemotherapy,
fluoropyrimidine-based CRT, or a combined approach.
 Cont…

The National Comprehensive Cancer Network (NCCN) suggests

the following
For Intrahepatic cholangiocarcinoma,
• pt with no residual local disease, options include observation or
fluoropyrimidine- or gemcitabine-based chemotherapy alone.

• For patients with positive margins or positive regional nodes,

options include fluoropyrimidine- or gemcitabine-based
chemotherapy, fluoropyrimidine-based CRT, or a combined
approach.

• On the other hand, surgical resection margins are often adequate

for intrahepatic cholangiocarcinomas,
 Management of locally advanced cca
Creteria for patient to fit for locally advanced.
• unresectable, nonmetastatic disease, which may present as an
isolated intrahepatic mass with imaging characteristics
consistent with malignancy but not hepatocellular cancer,

• an apparent mass lesion with a malignant biliary stricture,

often with jaundice.

• Microscopically or macroscopic residual disease following

resection of either an intrahepatic or an extrahepatic
cholangiocarcinoma.
 Management of locally advanced cca
• Systemic chemotherapy plus followed by FU based CRT
rather than local regionaltherapy
• Combination systemmic therapy
• gemicitabine plus ciplastin (superior than single therapy )
• Capecitabine plus gemicitabine
• Also biopsy is recommended so as to targeted therapy like
pembrolizumab,
• Mass lesion on liver(either CRT with FU based
chemoradioherapy wc biological equivalentdose>80.5, hepatic
artery embolization or ablation (RFA,
• ).
• Extra hepatic lesion (systemic therapy plus
low dose radiochemotherapy
 Systemic management of
cholangiocarcinoma.
• Systemic chemotherapy is increasingly being applied in cases
of advanced cholangiocarcinoma.

• A benefit for first-line chemotherapy over best supportive care

alone was suggested in a randomized trial , fluorouracil-based
systemic chemotherapy or best supportive care alone (median
survival 6 versus 2.5 months, respectively) .
 FIRST-LINE CHEMOTHERAPY
• Gemicitabine combination chemotherapy as standard first line.

• Gemicitabine based combination vs gemicitabine alone(GE is

combinationation is superior to gemi alone low response 7-27% ,
low survavival rate not more 8 months)

• Gemicitabine based vs non gemicitabine based (gemicitabine is

being termed as standard but trial not proven if any is superior to
one onother .
• except for patient with with good performance status and
hyperbilrubinemia we prefer non gemicitabine regime
(FOLFOX)
 First line cont..
• Gemicitabine plus ciplacitin (for the pt with good perfomance
status)

• Gemicitabine plus oxaliplatin(GEMOX)(is well tolarated)

• Gemicitabine plus ciplastin is prefered because , it provide

room for short-term infusional FU plus LV
and oxaliplatin (FOLFOX) as a second-line regimen,

• Which we would not use if the patient had initially received

GEMOX.
 Cont…
• 'Borderline performance status, monotherapy is ideal such as

• leucovorin (LV)modulated fluorouracil (FU), FU lone have

low response rate compared to combination with LV.

• capecitabine monotherapy

• S-1 alone (where available) .

 second-line chemotherapy
• second-line chemotherapy is not established.
• Three independent studies suggest that patients who have a
good performance status (0 or 1 ), disease control with first-
line chemotherapy, a relatively low carbohydrate antigen 19-9
(CA 19-9) level, an absence of peritoneal carcinomatosis, and
possibly, previous surgery on their primary tumor have the
longest survival with second-line chemotherapy
 Cont…
• most patients who have disease progression while
receiving gemcitabine plus cisplatin and who retain an
adequate performance status, in the absence of potentially
actionable molecular targets, (FOLFOX) is recommended.
• After failure of GEMOX,
• gemcitabine plus capecitabine
• capecitabine plus cisplatin,
• short-term infusional FU plus LV and irinotecan (FOLFIRI)
• second-line molecularly targeted therapy using erlotinib plus
bevacizumab may be considered; however, this regimen is
highly costly.
 Molecularly targeted therapy
• As many as 68 percent of advanced cholangiocarcinomas
may harbor a molecular alteration for which a targeted
treatment might be imployed.

• For individuals who did not receive frontline durvalumab

immunotherapy using a checkpoint inhibitor in the setting of
deficient DNA mismatch repair (dMMR),

• overexpression of programmed cell death ligand 1 (PD-L1),

or high levels of tumor mutational burden (TMB)
• fibroblast growth factor receptor 2 (FGFR2) gene
alterations.(Pemigatinib infigratinib or futibatinib)
• Ivosidenib for isocitrate dehydrogenase (IDH) mutations.
• A tropomyosin receptor kinase (TRK) inhibitor for those
with TRK fusion-positive cancers.
• RET fusion-positive cancer. (Selpercatinib)
• BRAF V600E mutations.
• HER2-targeted therapy for individuals with HER2
overexpression or amplification.(tratzumamb
 references
• Hewitt DB, Brown ZJ, Pawlik TM. Surgical management of
cholangiocarcinoma. Hepatoma Res 2021;7:75.
http://dx.doi.org/10.20517/2394-5079.2021.83
• Sharma M, Somani P, Rameshbabu CS, Sunkara T, Rai P. Stepwise evaluation of liver
sectors and liver segments by endoscopic ultrasound. World J Gastrointest Endosc.
2018 Nov 16;10(11):326-339. doi: 10.4253/wjge.v10.i11.326. PMID: 30487943;
PMCID: PMC6247100
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