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Cholangiocarcinoma

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Dr. Thakur Prashant Singh

This document provides information on cholangiocarcinoma (CCA), a malignant tumor of the bile ducts. It discusses the epidemiology, risk factors, classification, molecular pathogenesis, clinical features, diagnosis and imaging of CCA. CCA can be intrahepatic, perihilar or distal. Risk factors include primary sclerosing cholangitis, hepatolithiasis, liver fluke infections and bile duct cysts. Diagnosis involves tumor markers like CA19-9 and imaging modalities like ultrasound, CT and MRI to detect lesions. Molecular testing helps characterize mutations in genes like KRAS, TP53 and IDH1/2 involved in CCA pathogenesis.

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CHOLANGIOCARCINOMA PRESENTOR – Dr Jairaj V Bomman
Introduction • Cholangiocarcinoma is an epithelial carcinoma with differentiated features of biliary epithelium that arises from the intra- and extrahepatic biliary tract. • It is the most common bile duct tumor and second most common primary hepatic malignancy (after HCC). • Ninth most common GI malignancy.
Epidemology • Global incidence rates for cholangiocarcinoma are heterogeneous. • Highest incidence in Southeast Asia, with age-adjusted incidence rates up to 113 per 100,000 population, and the lowest incidence is observed in Australia, with rates as low as 0.1 per 100,000 population. • Rates are higher for males than females ( 1.2-1.5:1 ). • Average age at diagnosis is around 50 years.
Cholangiocarcinoma
Classification Biliary malignancies are divided into 3 categories: 1. carcinomas of the intra- and extrahepatic bile ducts (cholangiocarcinomas) 2. carcinoma of the gallbladder, and 3. carcinoma of the ampulla of Vater
Cholangiocarcinoma Anatomic classification Intrahepatic cholangiocarcinoma 20% Perihilar or Hilar cholangiocarcinoma 50-60% KLATSKIN TUMORS Bismuth Corlette classification Type I Type II Type IIIa Type IIIb Type IV Distal cholangiocarcinoma 20-30%
Anatomic classification • iCCA – Above 2nd segment of bile duct • pCCA – Between 2nd segment of bile duct and insertion of cystic duct • dCCA – between cystic duct insertion and ampulla of Vater (not including).
Bismuth Corlette classification
Pathological Classification
iCCA mass forming MC 80% periductal intradctal pCCA Periductal MC nodular intraductal
• Mass forming invades the liver parenchyma via lymphatics. • Periductal invades the GLISSON’S CAPSULE via lymphatics. • Intraductal spreads along the superficial mucosa without infiltrating the fibromuscular wall. • Intraductal spread is commonly associated with Hilar and Peri pancreatic LN metastasis.
Etiology • In the majority of cases, the etiology of cholangiocarcinoma is unknown • Most cases are sporadic and occur in the absence of several known risk factors • The risk factors are characterized by their association with inflammation and cholestasis
DEFINITE • Caroli disease • Choledochal cyst • Hepatolithiasis • Opisthorchis viverrini infection • PSC • Thorotrast • Hepatitis C • NAFLD PROBABLE • Biliary-enteric drainage procedures • Cirrhosis • Clonorchis sinensis infection • Heavy alcohol consumption • Toxins (dioxins, polyvinyl chloride)
• Odds ratios of 22.92 [95% confidence interval (CI): 18.24–28.79] for cirrhosis, • hepatitis C with OR of 4.84 (95% CI: 2.41– 9.71) and • hepatitis B with OR of 5.10 (95% CI: 2.91–8.95). Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012; 57: 69–76.
• Hepatolithiasis has been defined as a well-known risk factor for iCCA (upto 20%) in Asian countries but not in Western countries*. • Opisthorchis viverrini infection and Clonorchis sinensis infection accounts for iCCA with a OR of 27%** *Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011;54:173–84. **Shin HR, Lee CU, Park HJ, Seol SY, Chung JM, Choi HC, et al. Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea. Int J Epidemiol 1996;25:933–940.
• Choledochal cystic diseases, such as Caroli’s disease, are uncommon inherited abnormalities of the pancreatobiliary ducts which result in reflux of pancreatic enzymes, cholestasis, and biliary inflammation. • Strongly associated with CCA, with an overall lifetime risk ranging from 5% to 30%. • Caroli’s disease Types I (solitary, extrahepatic) and IV (intra- plus extrahepatic) bile-duct cysts have the greatest predisposition to CCA. • CCA incidence increases with age, the average age at CCA diagnosis is 32 years. • More common in Asian than Western countries. Soreide K, Korner H, Havnen J, Soreide JA. Bile duct cysts in adults. Br J Surg 2004;91:1538–1548.
• A recent Korean case-control study confirmed a strong association between bile duct cysts and iCCA, with an OR of 10.7 * • A US SEER-based study reported strong associations between bile duct cysts and increased risk of iCCA (OR 36.9) and extrahepatic CCA (OR 47.1)** *Lee TY, Lee SS, Jung SW, Jeon SH, Yun SC, Oh HC, et al. Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case-control study. Am J Gastroenterol 2008;103:1716–1720. **Welzel TM, Mellemkjaer L, Gloria G, Sakoda LC, Hsing AW, El Ghormli L, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007;120: 638–641.
Cholangiocarcinoma
Cholangiocarcinoma
Cholangiocarcinoma
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Cholangiocarcinoma and PSC • Accounts for 10% CCA • Annual incidence is 0.6-1.5% • 27-37% patient’s develop CCA within a year of PSC diagnosis.
Intrahepatic Cholangiocarcinoma (iCCA) • Least common subtype. • Multiple cells of origin – • Biliary epithelial cells • Intrahepatic biliary tract • Hepatic bipotent progenitor cells • Mature hepatocytes • Differentiated hepatocyte and cholangiocytes in adults maintain the cell turn over.
Cholangiocarcinoma
INJURY Canal of hering carrying bipotent cells Increase in hepatocytes and cholangiocytes carcinoma Adult hepatocytes dedifferentiate into bipotent cells Increase in hepatocytes and cholangiocytes carcinoma
Molecular pathogenesis Mutations – • KRAS, one of the most frequent genetic mutations found in iCCA (5–54%). • KRAS is a bonafide oncogene inducing iCCA in genetically engineered mouse models. • Loss-of-function mutations of TP53 occur in 20% of cases. • BRAF, NRAS, PI3K, EGFR, and MET mutations are rare events involving <5% of cases. • Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) have been identified in 10–23%. • These mutations cooccurred with TP53 mutations and were associated with DNA hypermethylation.
Copy number variations - Chromosomal gains on 8q, 17q, and 20q and deletions on 3p (60%), 4q, 9p,and 17p. High level amplifications (e.g., 1p31, 11q13) and focal deletions (e.g.,9p21, 14q22) in 4–12% of cases. Protein fusions - Fusions including the kinase domain of FGFR2. Seen in 8-14%. Epigenome changes - Hypermethylation of p16INK4A in 18–83% of cases [82], SOCS-3 in 88% [83], RASSF1A in 49% [75], and p14ARF in 25%.
Signaling pathways activated in iCCA – IL6-STAT3 pathway – JAK/STAT signaling activation occurs in 50% of iCCA, and may affect more than 70% of the iCCA inflammation subclass. IL-6 promotes growth of malignant cholangiocytes, and its over- expression is due to silencing of SOCS-3 (the inhibitor of IL-6 cytokine signaling).
EGFR signaling - Over-expression of EGFR (10–32%) and HER-2/neu have been reported in iCCA patients. Aberrant EGFR phosphorylation activates MAPK/ERK and p38, which in turn increases COX-2. Hepatocyte growth factor/Met signaling - C-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF) is over-expressed in iCCA (12–58%).
• The NOTCH signaling pathway is known to play an important role during embryonic development and is essential for a proper maturation of the liver architecture. • NOTCH pathway deregulation has been implicated in induction of inflammation and the development and progression of iCCA. • In human CCAs, upregulation of NOTCH1 and NOTCH4 has been reported in 82.9% and 56.1%, respectively. • The inhibition of NOTCH2 reduced tumor burden, NOTCH1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CCA-like tumors.
• The WNT signaling pathway is highly activated in the tumor epithelium of human CCAs and is often characterized by overexpression of the ligands WNT7B and WNT10A along with several target gene. • The WNT pathway was progressively activated during the course of iCCA development, and treatment invitro and in vivo with WNT inhibitors (ICG001 and C59) successfully inhibited tumor growth.
Clinical features and Diagnosis • Diagnosis of cholangiocarcinoma is challenging due to insidious presentation , and results of diagnostic studies are frequently nonspecific. • Biliary tract obstruction occurs infrequently with iCCA • Patients with early stage disease are usually asymptomatic.
• At more advanced stages, patients may present with weight loss, malaise, abdominal discomfort, jaundice, hepatomegaly, or a palpable abdominal mass, fever with night sweats. • A multidisciplinary approach including clinical evaluation and laboratory, endoscopic, and imaging studies is required.
• CCA should be considered in patients with underlying hepatolithiasis or PSC with worsening performance status, unexplained loss of weight, or failure to thrive.
Diagnostic tools TUMOUR MARKERS – • CA 19-9, has a sensitivity of 62 % and specificity of 63%. - > 100 U/ml ; worse recurrence free survival. - increased in bile duct obstruction and cholangitis. - HALF LIFE of 1-3 days, to be repeated after 3 days post biliary drainage and/or intervention. NOTE - absence of Lewis antigen expression on red blood cells or in body fluids (approximately 5% to 10% of the general population) have undetectable serum CA 19-9 level.
• CK 7 and CK 20, specific for biliary origin, helpful in mixed HCC-iCCA. • Newer markers Cytokeratin-19 fragment (CYFRA 21-1) and CA-242, have higher specificity, still under trail.
Imaging modalities • USG, shows hypoechoic mass, with peripheral ductal dilatation (non sp). • CONTRAST USG, Hyperenhancement (non sp).
• CT ABDOMEN, - Unenhanced phase → hypodense mass with irregular margins - Arterial phase → Peripheral rim enhancement - Venous phase and → Progressive hyperattenuation delayed phase
Cholangiocarcinoma
Cholangiocarcinoma
• ADVANTAGES – • CT can also detect the level of biliary obstruction, capsular retraction or hepatic atrophy. • Dynamic CT scanning can help distinguish between iCCA and HCC. • LIMITATION – • Cannot detect small mass • Cannot differentiate HCC and iCCA if fibrosis or cirrhosis co exist. • Cannot differentiate Distant Adeno Mets in liver with iCCA
“POOLING OF CONTRAST ON A DELAYED PHASE IMAGES IS INDICATIVE OF FIBROSIS / iCCA”
• MRI ABDOMEN – T1-weighted - iCCA appear hypointense T2-weighted – hyperintense, may also show central hypointensity corresponding to areas of fibrosis. Dynamic images show peripheral enhancement in the arterial phase followed by progressive and concentric filling-in of the tumor with contrast material.
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Cholangiocarcinoma
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• MRCP – MRI with cholangiopancreatography (MRI/MRCP) can be helpful to visualize the ductal system and vascular structures and thereby to determine the anatomic extent of tumor.
Cholangiocarcinoma
• PET CT – • There is limited clinical utility of CT/PET for diagnosis of iCCA in the liver when CT or MRI imaging has been performed as it doesn’t differentiate between types (HCC, iCCA or distant Mets). • Doesn’t provide extent of biliary duct infiltration. • Mass forming iCCA as small as 1 cm can be detected with a reported sensitivity of 85–95%. • However FDG-PET is less useful for infiltrating tumors.
Cholangiocarcinoma
To assess extent of disease/tumour • Radiological studies are necessary for assessment of the extent of local-regional, or distant spread, staging, and resectability. • Invasion into the portal vein or hepatic artery, and volumetric assessment of uninvolved liver are important determinants of resectability.
• Color Doppler duplex US - can identify vascular invasion, encasement, or occlusion of the portal vein and the hepatic artery. • Preoperative US detected 13 of 16 cases of liver tumors involving the hepatic vein with 81% sensitivity and 97% specificity, and an 87% positive predictive value. • In another study, preoperative US detected 38 of 41 patients with CCA and portal vein involvement at surgery, with 93% sensitivity, 99% specificity, and 97% and 98% positive and negative predictive values, respectively. • Angiography with computed tomographic arterial portography 90% sensitivity, 99% specificity, 95% positive predictive value, and 97% negative predictive value.
Staging Three staging systems are used – 1. AJCC/UICC TNM Staging 2. Liver Cancer Study Group of Japan Staging System 3. National Cancer Centre of Japan Staging System
Cholangiocarcinoma
• Out of three staging system only the TNM staging has shown correlation between staging and survival. • Limitation – requires tissue diagnosis for Tis and T4 stage.
Liver Cancer Study Group of Japan Staging System
Liver Cancer Study Group of Japan Staging System • TNM Classification – 1. Tumour 2 cms or less 2. Single nodule 3. No serosal or vascular membrane invasion T 1 1+2+3 T 2 any 2/3 T 3 any 1/3 T 4 None N 0 No LN N 1 any group lymph nodes M 0 No metastasis M 1 distant metastasis Stage 1 T1N0M0 Stage 2 T2N0M0 Stage 3 T3N0M0 Stage IVa T4N0M0 or Any T N1M0 Stage IVb any T, any N with M1
NATIONAL CANCER CENTRE OF JAPAN STAGING SYSTEM T1 Solitary tumour without vascular invasion T2 Solitary tumour with vascular invasion T3 Multiple tumours with or without vascular invasion N0 No regional lymph node N1 Regional lymph node metastasis M0 No distant metastasis M1 Distant metastasis
Treatment • Surgery • Locoregional therapy • Systemic therapy • Liver transplantation
Surgery • Surgical resection (segmental) is the mainstay for treatment of iCCA. • Goal is to remove all the disease with negative microscopic (R0) margins while preserving an adequate remnant liver volume. • Removal of clinically suspicious nodal disease is mandatory, the role of routine lymphadenectomy is less defined but • portal lymphadenectomy helps in accurate staging and hence is recommended.
Cholangiocarcinoma
Recurrence has been reported to occur in up to 50–60% of patients with a median-disease free survival of 26 months. Liver is the most common site of recurrence (e.g., 50–60%), and recurrence in regional lymph nodes or the peritoneum is (20–25%). Five-year survival and overall survival after surgical resection of iCCA ranges from 15% to 40% in most series. Metastatic nodal disease is one of the most powerful, independent determinants of survival.
The presence of either intrahepatic metastasis or major vascular invasion similarly have a 5-year survival in the range of 20% or less with the vast majority of patients experiencing a recurrence. Relatively strong contraindications to surgical resection. For those patients undergoing resection – especially those with N1 disease – adjuvant therapy should be strongly considered.
• RIBERO et al, - Ro resection showed 5 year survival 39.8% v/s 4.7% - Recurrence rates 53.9% v/s 73.6% - Resected margin width was not a consideration • FARGES et al, Ro resection is matter only when No, if N+, Ro doesn’t make difference.
Loco regional therapy • Loco-regional therapies for patients with unresectable iCCA include 1. radiation therapy (RT), 2. transarterial chemoembolization (TACE), 3. transarterial chemoinfusion (TACI)/ Hepatic Arterial Infusion (HAI), 4. radioembolization and 5. radiofrequency ablation (RFA). • Provides symptomatic relief, and might have a positive effect on survival.
RADIATION THERAPY (RT) – (i) external-beam RT (EBRT), including three dimensional-conformal RT (3D-CRT), intensity-modulated RT (IMRT) and stereotactic body radiotherapy (SBRT), (ii) brachytherapy, and (iii) proton therapy. To date, no prospective randomized studies have shown that EBRT benefits.
• EBRT in form of either 3D-CRT or IMRT. • DOSAGE – 45 Gy at 1.8 Gy/fraction OR 50 to 60 Gy at 1.8 to 2.0 Gy/fraction to tumour bed.
• A single institute prospective study including 79 patients, CRT at high doses with photons or protons showed 3 year benefit of OS (73% vs 38% respectively, p=0.017), and local control (78% vs 48% respectively, p=0.04) compared to lower doses. Tao R, Krishnan S, Bhosale PR, et al. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis [published correction appears in J Clin Oncol. 2019 Apr 10;37(11):942]. J Clin Oncol. 2016;34(3):219-226. doi:10.1200/JCO.2015.61.3778
Transarterial chemoembolization (TACE), transarterial chemoinfusion (TACI), and transarterial radioembolization (TARE) A single-center, retrospective cohort study of 155 patients with iCCA reported a median overall survival that was significantly longer in the patients treated with cTACE group (12.2 months) than in the non-TACE treated cohort (3.3 months), and that the tumor control rate in the former group was 89%, including partial responses in 23% and stable disease in 66%. Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP. Transarterial chemoembolization vs. supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin Radiol 2011;66: 322–328.
• HAI, has shown better OS and tumour response, with Median tumour response of 57% compared to TACE, DEB-TACE and TARE. • HAI plus chemotherapy with (gemcitabine, irinitectan or 5-FU) had OS greater than chemotherapy alone, 30.8 months to 18.4 months respectively, p < o.oo1. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer. 2016;122(5):758-765. doi:10.1002/cncr.29824
• A recent meta-analysis of 14 trials of transarterial therapies in patients with unresectable cholangiocarcinoma found that the calculated weighted cumulative median overall survival from date of diagnosis was 15.6 ± 1.1 months; 49.8% of all patients had stable disease by Response Criteria in Solid Tumors (RECIST) criteria. Edwards A, Ray JC. Transarterial therapies for unresectable cholangiocarcinoma: a meta-analysis. J Vasc Interv Radiol 2012;23:S101.
Radiofrequency Ablation • Rates of primary technical effectiveness and early necrosis of small (roughly 3.0 cm) tumors were reported to be 90–100%. • Median overall survival ranged from 33 to 38.5 months, one-year survival rates from 84.6% to 100%, and three-year survival rates from 43.3% to 83.3%. • In patients with local recurrence or residual tumor after surgery with curative intent, RFA resulted in a median overall survival of 27.4 to 51 months.
• Primary treatment care for unresectable patients include – 1. Clinical trail 2. systemic therapy 3. best supportive care
systemic therapy Intra CCA Ro resection Observation alone Fluropyridimine therapy Gemcitabine alone R1 Resection Fluropyrmidine chemotherapy Fluropyrimmidine based CRth Gemcitabine based chemothrapy
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Liver transplantation for iCCA and mixed HCC- iCCA – • Liver transplantation (LT) for iCCA is highly controversial. • LT is not recommended for iCCA (3 yr survival 50-60 % not definite) or mixed HCC-iCCA (5 yr recurrence 65%) as results are well below those published for standard indications (cirrhosis 5 yr survival 75%). • LT should only be offered in centers with designed clinical research protocols employing adjuvant or neoadjuvant therapy.
• Seven predictive features were identified – multifocality, perineural invasion, infiltrative pattern of tumor growth, lack of adjuvant or neoadjuvant anti-cancer therapy, lymphovascular invasion, and history of PSC. • The UCLA group, patients without adverse prognostic factors received adjuvant and neoadjuvant therapy and they had excellent long-term survival. • The iCCA and pCCA were grouped together, hence it is difficult to dissect the prognostic index to iCCA.
PROGNOSIS • Five year survival rate was higher for patients who lacked multiple lesions, vascular lesions and N1 lesion and was 38.3%, 27.3% and 18.1% respectively. • EGD and Colonoscopy should be part of diagnostic procedures to rule out primary adenocarcinoma, and the mass in liver to be metastatic. • IDH1 mutation is associated with poor outcome. • FGFR mutation has favourable outcome.
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• Extra hepatic biliary cancer • diagnosis • staging • treatment • Advanced biliary tract cancer • Adjuvant chemotherapy and chemoradiotherapy • Targeted therapy
• The Hippo–YAP signalling pathway regulates organ size and cell proliferation, among other functions. • YAP is a transcriptional co- activator that is usually inhibited by Hippo (MST1 or MST2), but can be activated by Hippo- independent signals, such as inflammation and changes in ECM composition and stiffness. • Several groups have reported increased nuclear expression of YAP in CCA specimens and correlation with a worse prognosis. • In vitro studies on CCA cell lines have shown that YAP can be activated by IL-6, PDGF and fibroblast growth factor
Perihilar and Distal Cholangiocarcioma • Most cases manifest with painless jaundice secondary to malignant biliary obstruction • In 10% of patients, bacterial cholangitis is the initial presenting symptom • An “atrophy-hypertrophy” complex can be documented by physical examination as palpable hypertrophy of the contralateral, unaffected lobe of the liver, with atrophy of the affected lobe as a result of vascular encasement and bile ductal obstruction
Diagnostic tools TUMOUR MARKER – • With PSC, the sensitivity and specificity of CA 19-9 for the diagnosis of cholangiocarcinoma are 79% and 98%, respectively, with the cutoff value of 129 U/mL. • In patients without PSC, the sensitivity is 53% with a cutoff value of 100 U/mL. • High levels of CA 19-9 levels (>1000 U/mL) have been associated with metastatic cholangiocarcinoma.
• IgG4 levels should be done in patients with doubtful Extrahepatic CCA to rule out IgG4 Cholangiopathy, as this too causes biliary strictures and jaundice and to avoid resection.
• FISH Fluorescence in situ hybridization (FISH) increases the sensitivity and specificity of cytology for diagnosing cholangiocarcinoma in patients with and without PSC. • Assesses chromosomal aneusomy (gains or losses of chromosomes targeting the 1q21, 7p12, 8q24, 9p21 loci) via the use of fluorescently labeled DNA probes. • Sensitivity of 93% and specificity 100%, for the detection of pancreaticobiliary malignancies
Imaging Modalities CECT ABDOMEN vascular invasion, surrounding structure association, intra and extra hepatic mets MRI/MRCP biliary invasion and extent, guide for intervention. SUPERIOR TO CT in assessing intrabiliary extension ERCP OR THC biliary invasion and extent, guide/ simultaneous intervention and TISUUE SAMPLING PET sens 63% spec 67%, LN positivity in 3-38%. FALSE POSITIVE PET (d/t inflammation) EUS SUPERIOR OF ALL. SAMPLES ONLY FROM LN
Imaging modalities • CT ABDOMEN – gives vascular invasion, relation to other surrounding structures. • cross sectional imaging is must before going for MRI/MRCP, helps in guiding biliary drainage intervention.
• MRCP has higher sensitivity and specificity than ERCP in diagnosis and in pre treatment staging.
E U S
• Diagnostic biopsy may not needed if patient is under going resection. • Biopsy should always be taken through Intraluminal route and through peritoneal route. • Peritoneal route biopsy is contraindicated if patient is under going transplant. • In non resectable candidates, direct visualisation of the bile duct and direct biopsies is mode of management.
Cholangiocarcinoma
Gores GJ, Darwish Murad S, Heimbach JK, Rosen CB. Liver transplantation for perihilar cholangiocarcinoma. Dig Dis 2013;31:126129
Staging • Perihilar cholangiocarcinoma – TNM Staging Bismuth Corlette Staging Blamgart Staging helps in preoperative resectability, probability of metastasis and survival.
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Cholangiocarcinoma
Distal CCA STAGING
Treatment • SURGERY - • pCCA - Complete resection with negative margins is the only curative treatment. • Complete lobectomy along with biliary radicles, caudate lobe and porta hepatis LN • 5 year survival rate is 20-42 % • dCCA – Whipple’s procedure (+/- Hepatecetomy) • 5 year survival rate is 16-52 %
Cholangiocarcinoma
Extra Hepatic CCA Ro resection No/ Carcinoma In situ Observation alone Fluoropyridine based CRth Fluoropyridine alone Gemcitabine Cth
Adjuvant Cth and CRth 1. PHASE III BILCAP STUDY - Ro resection of CCA or GB Ca. • Adj Capecitabine Therapy group And Observation group • RFS with intent to treat was 24.4 months v/s 17.5 months, p=0.033 • Median OS was 51.1 v/s 36.4 months
2. PHASE III PRODIGE 12-ACCORD 18 TRAIL – • Gemcitabine / Oxaliplatin group and Surveillance group • No significant RFS/OS found in either group. • No more used since 2019 3. PHASE III JAPAN Study for evaluating Gemcitabine efficacy was negative, hence Gemcitabine monotherapy is not recommended.
4. HORGAN et al – • Systemic review and meta analysis of 6712 patients with biliary tract cancer showed some OS with adjuvant therapy. • Highest with CRth rather than Rth alone.
5. PHASE II SWOG S0809 TRAIL – • Both Extra CCA and GB ca. • Adj Cth and CRth with Cepacitabine/Gemcitabine followed by cocurrent Capecitabine Rth. • 2 yr survival was 65% and Median OS of 35 months. • 86% generally tolerated the complete therapy • Confirmatory PHASE III trail is needed. • Concurrent Gemicitabine CRth is not recommended due to toxicity.
Non resectablity in pCCA 1. Atrophy of one liver lobe with encasement of the contralateral portal vein branch 2. Atrophy of one liver lobe with contralateral secondary biliary radicle involvement 3. Bilateral portal vein branch encasement 4. Bilateral hepatic artery encasement 5. Distant lymph node metastases 6. Hilar cholangiocarcinoma, Bismuth-Corlette type IV 7. PSC and 8. Significant comorbid conditions
• Non resectable, cam be considered for biliary drainage – - surgical drainage - PTBD - ERCP
Advanced Biliary Tract Cancer • The unrandomized phase 2 data, the UK NCRN (Advanced Biliary Cancer) ABC-01 study compared Cisplatin and Gemcitabine (Cisplatin 25 mg/m2 followed by Gemcitabine 1000 mg/m2, each on days 1 and 8 of a 21-day cycle, CisGem) with Gemcitabine (Gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) with 6-month progressive free survival (PFS) as the primary endpoint. • It demonstrated improved 6-month PFS in favor of CisGem compared to Gemcitabine alone (57.1 vs. 45.5%). Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al.Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study – The UK ABC-01 Study. Br J Cancer 2009;101:621–627.
• A phase 3 study with the primary endpoint which became overall survival and the addition of quality of life analysis, in the UK ABC-02 study. • Median overall survival was 11.7 months for patients receiving CisGem compared to 8.1 months in patients receiving Gem alone. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine vs. gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273–1281.
MODIFIED GEMOX PHASE III TRAIL – • Gemcitabine and Oxaliplatin OR Cisplatin • Median OS of 9.5, 4.6 and 4.5 months with GEMOX, Fluorouracil and supportive treatment respectively.
Cholangiocarcinoma
Cholangiocarcinoma
Targeted therapy PEMBROLIZUMAB – • dMMR CCA are sensitive to PD1 blockage. • Approved in dMMR or MSI-H CCA positive tumours, • when tumour is non resectable or has distant metastasis. TRASTUZUMAB – • HER2/NEU receptor antagonist • Retrospective showed response in GB Ca and none in CCA
IDH1/2 INHIBITORS • Inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221) and pan- IDH1– IDH2 (AG881) are currently being tested in patients with iCCA. • AG120 (ivosidenib) phase III trial in which 185 patients with IDH-1 mutant CCA were randomly assigned to ivosidenib or placebo, ivosidenib showed a benefit in terms of progression free- survival (HR 0.37). • Median OS was 10.8 months in patients receiving ivosidenib and 9.7 months in patients receiving placebo (HR 0.69
Addition of EGFR-mAbs ( cetuximab and panitumumab) to gemcitabine-based first-line CHT in advanced BTC does not result in a statistically significant benefit in OS, PFS and ORR with increased grade 3-4 toxicity.

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Cholangiocarcinoma

  • 2. Introduction • Cholangiocarcinoma is an epithelial carcinoma with differentiated features of biliary epithelium that arises from the intra- and extrahepatic biliary tract. • It is the most common bile duct tumor and second most common primary hepatic malignancy (after HCC). • Ninth most common GI malignancy.
  • 3. Epidemology • Global incidence rates for cholangiocarcinoma are heterogeneous. • Highest incidence in Southeast Asia, with age-adjusted incidence rates up to 113 per 100,000 population, and the lowest incidence is observed in Australia, with rates as low as 0.1 per 100,000 population. • Rates are higher for males than females ( 1.2-1.5:1 ). • Average age at diagnosis is around 50 years.
  • 5. Classification Biliary malignancies are divided into 3 categories: 1. carcinomas of the intra- and extrahepatic bile ducts (cholangiocarcinomas) 2. carcinoma of the gallbladder, and 3. carcinoma of the ampulla of Vater
  • 6. Cholangiocarcinoma Anatomic classification Intrahepatic cholangiocarcinoma 20% Perihilar or Hilar cholangiocarcinoma 50-60% KLATSKIN TUMORS Bismuth Corlette classification Type I Type II Type IIIa Type IIIb Type IV Distal cholangiocarcinoma 20-30%
  • 7. Anatomic classification • iCCA – Above 2nd segment of bile duct • pCCA – Between 2nd segment of bile duct and insertion of cystic duct • dCCA – between cystic duct insertion and ampulla of Vater (not including).
  • 10. iCCA mass forming MC 80% periductal intradctal pCCA Periductal MC nodular intraductal
  • 11. • Mass forming invades the liver parenchyma via lymphatics. • Periductal invades the GLISSON’S CAPSULE via lymphatics. • Intraductal spreads along the superficial mucosa without infiltrating the fibromuscular wall. • Intraductal spread is commonly associated with Hilar and Peri pancreatic LN metastasis.
  • 12. Etiology • In the majority of cases, the etiology of cholangiocarcinoma is unknown • Most cases are sporadic and occur in the absence of several known risk factors • The risk factors are characterized by their association with inflammation and cholestasis
  • 13. DEFINITE • Caroli disease • Choledochal cyst • Hepatolithiasis • Opisthorchis viverrini infection • PSC • Thorotrast • Hepatitis C • NAFLD PROBABLE • Biliary-enteric drainage procedures • Cirrhosis • Clonorchis sinensis infection • Heavy alcohol consumption • Toxins (dioxins, polyvinyl chloride)
  • 14. • Odds ratios of 22.92 [95% confidence interval (CI): 18.24–28.79] for cirrhosis, • hepatitis C with OR of 4.84 (95% CI: 2.41– 9.71) and • hepatitis B with OR of 5.10 (95% CI: 2.91–8.95). Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012; 57: 69–76.
  • 15. • Hepatolithiasis has been defined as a well-known risk factor for iCCA (upto 20%) in Asian countries but not in Western countries*. • Opisthorchis viverrini infection and Clonorchis sinensis infection accounts for iCCA with a OR of 27%** *Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011;54:173–84. **Shin HR, Lee CU, Park HJ, Seol SY, Chung JM, Choi HC, et al. Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea. Int J Epidemiol 1996;25:933–940.
  • 16. • Choledochal cystic diseases, such as Caroli’s disease, are uncommon inherited abnormalities of the pancreatobiliary ducts which result in reflux of pancreatic enzymes, cholestasis, and biliary inflammation. • Strongly associated with CCA, with an overall lifetime risk ranging from 5% to 30%. • Caroli’s disease Types I (solitary, extrahepatic) and IV (intra- plus extrahepatic) bile-duct cysts have the greatest predisposition to CCA. • CCA incidence increases with age, the average age at CCA diagnosis is 32 years. • More common in Asian than Western countries. Soreide K, Korner H, Havnen J, Soreide JA. Bile duct cysts in adults. Br J Surg 2004;91:1538–1548.
  • 17. • A recent Korean case-control study confirmed a strong association between bile duct cysts and iCCA, with an OR of 10.7 * • A US SEER-based study reported strong associations between bile duct cysts and increased risk of iCCA (OR 36.9) and extrahepatic CCA (OR 47.1)** *Lee TY, Lee SS, Jung SW, Jeon SH, Yun SC, Oh HC, et al. Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case-control study. Am J Gastroenterol 2008;103:1716–1720. **Welzel TM, Mellemkjaer L, Gloria G, Sakoda LC, Hsing AW, El Ghormli L, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007;120: 638–641.
  • 22. Cholangiocarcinoma and PSC • Accounts for 10% CCA • Annual incidence is 0.6-1.5% • 27-37% patient’s develop CCA within a year of PSC diagnosis.
  • 23. Intrahepatic Cholangiocarcinoma (iCCA) • Least common subtype. • Multiple cells of origin – • Biliary epithelial cells • Intrahepatic biliary tract • Hepatic bipotent progenitor cells • Mature hepatocytes • Differentiated hepatocyte and cholangiocytes in adults maintain the cell turn over.
  • 25. INJURY Canal of hering carrying bipotent cells Increase in hepatocytes and cholangiocytes carcinoma Adult hepatocytes dedifferentiate into bipotent cells Increase in hepatocytes and cholangiocytes carcinoma
  • 26. Molecular pathogenesis Mutations – • KRAS, one of the most frequent genetic mutations found in iCCA (5–54%). • KRAS is a bonafide oncogene inducing iCCA in genetically engineered mouse models. • Loss-of-function mutations of TP53 occur in 20% of cases. • BRAF, NRAS, PI3K, EGFR, and MET mutations are rare events involving <5% of cases. • Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) have been identified in 10–23%. • These mutations cooccurred with TP53 mutations and were associated with DNA hypermethylation.
  • 27. Copy number variations - Chromosomal gains on 8q, 17q, and 20q and deletions on 3p (60%), 4q, 9p,and 17p. High level amplifications (e.g., 1p31, 11q13) and focal deletions (e.g.,9p21, 14q22) in 4–12% of cases. Protein fusions - Fusions including the kinase domain of FGFR2. Seen in 8-14%. Epigenome changes - Hypermethylation of p16INK4A in 18–83% of cases [82], SOCS-3 in 88% [83], RASSF1A in 49% [75], and p14ARF in 25%.
  • 28. Signaling pathways activated in iCCA – IL6-STAT3 pathway – JAK/STAT signaling activation occurs in 50% of iCCA, and may affect more than 70% of the iCCA inflammation subclass. IL-6 promotes growth of malignant cholangiocytes, and its over- expression is due to silencing of SOCS-3 (the inhibitor of IL-6 cytokine signaling).
  • 29. EGFR signaling - Over-expression of EGFR (10–32%) and HER-2/neu have been reported in iCCA patients. Aberrant EGFR phosphorylation activates MAPK/ERK and p38, which in turn increases COX-2. Hepatocyte growth factor/Met signaling - C-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF) is over-expressed in iCCA (12–58%).
  • 30. • The NOTCH signaling pathway is known to play an important role during embryonic development and is essential for a proper maturation of the liver architecture. • NOTCH pathway deregulation has been implicated in induction of inflammation and the development and progression of iCCA. • In human CCAs, upregulation of NOTCH1 and NOTCH4 has been reported in 82.9% and 56.1%, respectively. • The inhibition of NOTCH2 reduced tumor burden, NOTCH1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CCA-like tumors.
  • 31. • The WNT signaling pathway is highly activated in the tumor epithelium of human CCAs and is often characterized by overexpression of the ligands WNT7B and WNT10A along with several target gene. • The WNT pathway was progressively activated during the course of iCCA development, and treatment invitro and in vivo with WNT inhibitors (ICG001 and C59) successfully inhibited tumor growth.
  • 32. Clinical features and Diagnosis • Diagnosis of cholangiocarcinoma is challenging due to insidious presentation , and results of diagnostic studies are frequently nonspecific. • Biliary tract obstruction occurs infrequently with iCCA • Patients with early stage disease are usually asymptomatic.
  • 33. • At more advanced stages, patients may present with weight loss, malaise, abdominal discomfort, jaundice, hepatomegaly, or a palpable abdominal mass, fever with night sweats. • A multidisciplinary approach including clinical evaluation and laboratory, endoscopic, and imaging studies is required.
  • 34. • CCA should be considered in patients with underlying hepatolithiasis or PSC with worsening performance status, unexplained loss of weight, or failure to thrive.
  • 35. Diagnostic tools TUMOUR MARKERS – • CA 19-9, has a sensitivity of 62 % and specificity of 63%. - > 100 U/ml ; worse recurrence free survival. - increased in bile duct obstruction and cholangitis. - HALF LIFE of 1-3 days, to be repeated after 3 days post biliary drainage and/or intervention. NOTE - absence of Lewis antigen expression on red blood cells or in body fluids (approximately 5% to 10% of the general population) have undetectable serum CA 19-9 level.
  • 36. • CK 7 and CK 20, specific for biliary origin, helpful in mixed HCC-iCCA. • Newer markers Cytokeratin-19 fragment (CYFRA 21-1) and CA-242, have higher specificity, still under trail.
  • 37. Imaging modalities • USG, shows hypoechoic mass, with peripheral ductal dilatation (non sp). • CONTRAST USG, Hyperenhancement (non sp).
  • 38. • CT ABDOMEN, - Unenhanced phase → hypodense mass with irregular margins - Arterial phase → Peripheral rim enhancement - Venous phase and → Progressive hyperattenuation delayed phase
  • 41. • ADVANTAGES – • CT can also detect the level of biliary obstruction, capsular retraction or hepatic atrophy. • Dynamic CT scanning can help distinguish between iCCA and HCC. • LIMITATION – • Cannot detect small mass • Cannot differentiate HCC and iCCA if fibrosis or cirrhosis co exist. • Cannot differentiate Distant Adeno Mets in liver with iCCA
  • 42. “POOLING OF CONTRAST ON A DELAYED PHASE IMAGES IS INDICATIVE OF FIBROSIS / iCCA”
  • 43. • MRI ABDOMEN – T1-weighted - iCCA appear hypointense T2-weighted – hyperintense, may also show central hypointensity corresponding to areas of fibrosis. Dynamic images show peripheral enhancement in the arterial phase followed by progressive and concentric filling-in of the tumor with contrast material.
  • 47. • MRCP – MRI with cholangiopancreatography (MRI/MRCP) can be helpful to visualize the ductal system and vascular structures and thereby to determine the anatomic extent of tumor.
  • 49. • PET CT – • There is limited clinical utility of CT/PET for diagnosis of iCCA in the liver when CT or MRI imaging has been performed as it doesn’t differentiate between types (HCC, iCCA or distant Mets). • Doesn’t provide extent of biliary duct infiltration. • Mass forming iCCA as small as 1 cm can be detected with a reported sensitivity of 85–95%. • However FDG-PET is less useful for infiltrating tumors.
  • 51. To assess extent of disease/tumour • Radiological studies are necessary for assessment of the extent of local-regional, or distant spread, staging, and resectability. • Invasion into the portal vein or hepatic artery, and volumetric assessment of uninvolved liver are important determinants of resectability.
  • 52. • Color Doppler duplex US - can identify vascular invasion, encasement, or occlusion of the portal vein and the hepatic artery. • Preoperative US detected 13 of 16 cases of liver tumors involving the hepatic vein with 81% sensitivity and 97% specificity, and an 87% positive predictive value. • In another study, preoperative US detected 38 of 41 patients with CCA and portal vein involvement at surgery, with 93% sensitivity, 99% specificity, and 97% and 98% positive and negative predictive values, respectively. • Angiography with computed tomographic arterial portography 90% sensitivity, 99% specificity, 95% positive predictive value, and 97% negative predictive value.
  • 53. Staging Three staging systems are used – 1. AJCC/UICC TNM Staging 2. Liver Cancer Study Group of Japan Staging System 3. National Cancer Centre of Japan Staging System
  • 55. • Out of three staging system only the TNM staging has shown correlation between staging and survival. • Limitation – requires tissue diagnosis for Tis and T4 stage.
  • 56. Liver Cancer Study Group of Japan Staging System
  • 57. Liver Cancer Study Group of Japan Staging System • TNM Classification – 1. Tumour 2 cms or less 2. Single nodule 3. No serosal or vascular membrane invasion T 1 1+2+3 T 2 any 2/3 T 3 any 1/3 T 4 None N 0 No LN N 1 any group lymph nodes M 0 No metastasis M 1 distant metastasis Stage 1 T1N0M0 Stage 2 T2N0M0 Stage 3 T3N0M0 Stage IVa T4N0M0 or Any T N1M0 Stage IVb any T, any N with M1
  • 58. NATIONAL CANCER CENTRE OF JAPAN STAGING SYSTEM T1 Solitary tumour without vascular invasion T2 Solitary tumour with vascular invasion T3 Multiple tumours with or without vascular invasion N0 No regional lymph node N1 Regional lymph node metastasis M0 No distant metastasis M1 Distant metastasis
  • 59. Treatment • Surgery • Locoregional therapy • Systemic therapy • Liver transplantation
  • 60. Surgery • Surgical resection (segmental) is the mainstay for treatment of iCCA. • Goal is to remove all the disease with negative microscopic (R0) margins while preserving an adequate remnant liver volume. • Removal of clinically suspicious nodal disease is mandatory, the role of routine lymphadenectomy is less defined but • portal lymphadenectomy helps in accurate staging and hence is recommended.
  • 62. Recurrence has been reported to occur in up to 50–60% of patients with a median-disease free survival of 26 months. Liver is the most common site of recurrence (e.g., 50–60%), and recurrence in regional lymph nodes or the peritoneum is (20–25%). Five-year survival and overall survival after surgical resection of iCCA ranges from 15% to 40% in most series. Metastatic nodal disease is one of the most powerful, independent determinants of survival.
  • 63. The presence of either intrahepatic metastasis or major vascular invasion similarly have a 5-year survival in the range of 20% or less with the vast majority of patients experiencing a recurrence. Relatively strong contraindications to surgical resection. For those patients undergoing resection – especially those with N1 disease – adjuvant therapy should be strongly considered.
  • 64. • RIBERO et al, - Ro resection showed 5 year survival 39.8% v/s 4.7% - Recurrence rates 53.9% v/s 73.6% - Resected margin width was not a consideration • FARGES et al, Ro resection is matter only when No, if N+, Ro doesn’t make difference.
  • 65. Loco regional therapy • Loco-regional therapies for patients with unresectable iCCA include 1. radiation therapy (RT), 2. transarterial chemoembolization (TACE), 3. transarterial chemoinfusion (TACI)/ Hepatic Arterial Infusion (HAI), 4. radioembolization and 5. radiofrequency ablation (RFA). • Provides symptomatic relief, and might have a positive effect on survival.
  • 66. RADIATION THERAPY (RT) – (i) external-beam RT (EBRT), including three dimensional-conformal RT (3D-CRT), intensity-modulated RT (IMRT) and stereotactic body radiotherapy (SBRT), (ii) brachytherapy, and (iii) proton therapy. To date, no prospective randomized studies have shown that EBRT benefits.
  • 67. • EBRT in form of either 3D-CRT or IMRT. • DOSAGE – 45 Gy at 1.8 Gy/fraction OR 50 to 60 Gy at 1.8 to 2.0 Gy/fraction to tumour bed.
  • 68. • A single institute prospective study including 79 patients, CRT at high doses with photons or protons showed 3 year benefit of OS (73% vs 38% respectively, p=0.017), and local control (78% vs 48% respectively, p=0.04) compared to lower doses. Tao R, Krishnan S, Bhosale PR, et al. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis [published correction appears in J Clin Oncol. 2019 Apr 10;37(11):942]. J Clin Oncol. 2016;34(3):219-226. doi:10.1200/JCO.2015.61.3778
  • 69. Transarterial chemoembolization (TACE), transarterial chemoinfusion (TACI), and transarterial radioembolization (TARE) A single-center, retrospective cohort study of 155 patients with iCCA reported a median overall survival that was significantly longer in the patients treated with cTACE group (12.2 months) than in the non-TACE treated cohort (3.3 months), and that the tumor control rate in the former group was 89%, including partial responses in 23% and stable disease in 66%. Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP. Transarterial chemoembolization vs. supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin Radiol 2011;66: 322–328.
  • 70. • HAI, has shown better OS and tumour response, with Median tumour response of 57% compared to TACE, DEB-TACE and TARE. • HAI plus chemotherapy with (gemcitabine, irinitectan or 5-FU) had OS greater than chemotherapy alone, 30.8 months to 18.4 months respectively, p < o.oo1. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer. 2016;122(5):758-765. doi:10.1002/cncr.29824
  • 71. • A recent meta-analysis of 14 trials of transarterial therapies in patients with unresectable cholangiocarcinoma found that the calculated weighted cumulative median overall survival from date of diagnosis was 15.6 ± 1.1 months; 49.8% of all patients had stable disease by Response Criteria in Solid Tumors (RECIST) criteria. Edwards A, Ray JC. Transarterial therapies for unresectable cholangiocarcinoma: a meta-analysis. J Vasc Interv Radiol 2012;23:S101.
  • 72. Radiofrequency Ablation • Rates of primary technical effectiveness and early necrosis of small (roughly 3.0 cm) tumors were reported to be 90–100%. • Median overall survival ranged from 33 to 38.5 months, one-year survival rates from 84.6% to 100%, and three-year survival rates from 43.3% to 83.3%. • In patients with local recurrence or residual tumor after surgery with curative intent, RFA resulted in a median overall survival of 27.4 to 51 months.
  • 73. • Primary treatment care for unresectable patients include – 1. Clinical trail 2. systemic therapy 3. best supportive care
  • 74. systemic therapy Intra CCA Ro resection Observation alone Fluropyridimine therapy Gemcitabine alone R1 Resection Fluropyrmidine chemotherapy Fluropyrimmidine based CRth Gemcitabine based chemothrapy
  • 76. Liver transplantation for iCCA and mixed HCC- iCCA – • Liver transplantation (LT) for iCCA is highly controversial. • LT is not recommended for iCCA (3 yr survival 50-60 % not definite) or mixed HCC-iCCA (5 yr recurrence 65%) as results are well below those published for standard indications (cirrhosis 5 yr survival 75%). • LT should only be offered in centers with designed clinical research protocols employing adjuvant or neoadjuvant therapy.
  • 77. • Seven predictive features were identified – multifocality, perineural invasion, infiltrative pattern of tumor growth, lack of adjuvant or neoadjuvant anti-cancer therapy, lymphovascular invasion, and history of PSC. • The UCLA group, patients without adverse prognostic factors received adjuvant and neoadjuvant therapy and they had excellent long-term survival. • The iCCA and pCCA were grouped together, hence it is difficult to dissect the prognostic index to iCCA.
  • 78. PROGNOSIS • Five year survival rate was higher for patients who lacked multiple lesions, vascular lesions and N1 lesion and was 38.3%, 27.3% and 18.1% respectively. • EGD and Colonoscopy should be part of diagnostic procedures to rule out primary adenocarcinoma, and the mass in liver to be metastatic. • IDH1 mutation is associated with poor outcome. • FGFR mutation has favourable outcome.
  • 80. • Extra hepatic biliary cancer • diagnosis • staging • treatment • Advanced biliary tract cancer • Adjuvant chemotherapy and chemoradiotherapy • Targeted therapy
  • 81. • The Hippo–YAP signalling pathway regulates organ size and cell proliferation, among other functions. • YAP is a transcriptional co- activator that is usually inhibited by Hippo (MST1 or MST2), but can be activated by Hippo- independent signals, such as inflammation and changes in ECM composition and stiffness. • Several groups have reported increased nuclear expression of YAP in CCA specimens and correlation with a worse prognosis. • In vitro studies on CCA cell lines have shown that YAP can be activated by IL-6, PDGF and fibroblast growth factor
  • 82. Perihilar and Distal Cholangiocarcioma • Most cases manifest with painless jaundice secondary to malignant biliary obstruction • In 10% of patients, bacterial cholangitis is the initial presenting symptom • An “atrophy-hypertrophy” complex can be documented by physical examination as palpable hypertrophy of the contralateral, unaffected lobe of the liver, with atrophy of the affected lobe as a result of vascular encasement and bile ductal obstruction
  • 83. Diagnostic tools TUMOUR MARKER – • With PSC, the sensitivity and specificity of CA 19-9 for the diagnosis of cholangiocarcinoma are 79% and 98%, respectively, with the cutoff value of 129 U/mL. • In patients without PSC, the sensitivity is 53% with a cutoff value of 100 U/mL. • High levels of CA 19-9 levels (>1000 U/mL) have been associated with metastatic cholangiocarcinoma.
  • 84. • IgG4 levels should be done in patients with doubtful Extrahepatic CCA to rule out IgG4 Cholangiopathy, as this too causes biliary strictures and jaundice and to avoid resection.
  • 85. • FISH Fluorescence in situ hybridization (FISH) increases the sensitivity and specificity of cytology for diagnosing cholangiocarcinoma in patients with and without PSC. • Assesses chromosomal aneusomy (gains or losses of chromosomes targeting the 1q21, 7p12, 8q24, 9p21 loci) via the use of fluorescently labeled DNA probes. • Sensitivity of 93% and specificity 100%, for the detection of pancreaticobiliary malignancies
  • 86. Imaging Modalities CECT ABDOMEN vascular invasion, surrounding structure association, intra and extra hepatic mets MRI/MRCP biliary invasion and extent, guide for intervention. SUPERIOR TO CT in assessing intrabiliary extension ERCP OR THC biliary invasion and extent, guide/ simultaneous intervention and TISUUE SAMPLING PET sens 63% spec 67%, LN positivity in 3-38%. FALSE POSITIVE PET (d/t inflammation) EUS SUPERIOR OF ALL. SAMPLES ONLY FROM LN
  • 87. Imaging modalities • CT ABDOMEN – gives vascular invasion, relation to other surrounding structures. • cross sectional imaging is must before going for MRI/MRCP, helps in guiding biliary drainage intervention.
  • 88. • MRCP has higher sensitivity and specificity than ERCP in diagnosis and in pre treatment staging.
  • 89. E U S
  • 90. • Diagnostic biopsy may not needed if patient is under going resection. • Biopsy should always be taken through Intraluminal route and through peritoneal route. • Peritoneal route biopsy is contraindicated if patient is under going transplant. • In non resectable candidates, direct visualisation of the bile duct and direct biopsies is mode of management.
  • 92. Gores GJ, Darwish Murad S, Heimbach JK, Rosen CB. Liver transplantation for perihilar cholangiocarcinoma. Dig Dis 2013;31:126129
  • 93. Staging • Perihilar cholangiocarcinoma – TNM Staging Bismuth Corlette Staging Blamgart Staging helps in preoperative resectability, probability of metastasis and survival.
  • 97. Treatment • SURGERY - • pCCA - Complete resection with negative margins is the only curative treatment. • Complete lobectomy along with biliary radicles, caudate lobe and porta hepatis LN • 5 year survival rate is 20-42 % • dCCA – Whipple’s procedure (+/- Hepatecetomy) • 5 year survival rate is 16-52 %
  • 99. Extra Hepatic CCA Ro resection No/ Carcinoma In situ Observation alone Fluoropyridine based CRth Fluoropyridine alone Gemcitabine Cth
  • 100. Adjuvant Cth and CRth 1. PHASE III BILCAP STUDY - Ro resection of CCA or GB Ca. • Adj Capecitabine Therapy group And Observation group • RFS with intent to treat was 24.4 months v/s 17.5 months, p=0.033 • Median OS was 51.1 v/s 36.4 months
  • 101. 2. PHASE III PRODIGE 12-ACCORD 18 TRAIL – • Gemcitabine / Oxaliplatin group and Surveillance group • No significant RFS/OS found in either group. • No more used since 2019 3. PHASE III JAPAN Study for evaluating Gemcitabine efficacy was negative, hence Gemcitabine monotherapy is not recommended.
  • 102. 4. HORGAN et al – • Systemic review and meta analysis of 6712 patients with biliary tract cancer showed some OS with adjuvant therapy. • Highest with CRth rather than Rth alone.
  • 103. 5. PHASE II SWOG S0809 TRAIL – • Both Extra CCA and GB ca. • Adj Cth and CRth with Cepacitabine/Gemcitabine followed by cocurrent Capecitabine Rth. • 2 yr survival was 65% and Median OS of 35 months. • 86% generally tolerated the complete therapy • Confirmatory PHASE III trail is needed. • Concurrent Gemicitabine CRth is not recommended due to toxicity.
  • 104. Non resectablity in pCCA 1. Atrophy of one liver lobe with encasement of the contralateral portal vein branch 2. Atrophy of one liver lobe with contralateral secondary biliary radicle involvement 3. Bilateral portal vein branch encasement 4. Bilateral hepatic artery encasement 5. Distant lymph node metastases 6. Hilar cholangiocarcinoma, Bismuth-Corlette type IV 7. PSC and 8. Significant comorbid conditions
  • 105. • Non resectable, cam be considered for biliary drainage – - surgical drainage - PTBD - ERCP
  • 106. Advanced Biliary Tract Cancer • The unrandomized phase 2 data, the UK NCRN (Advanced Biliary Cancer) ABC-01 study compared Cisplatin and Gemcitabine (Cisplatin 25 mg/m2 followed by Gemcitabine 1000 mg/m2, each on days 1 and 8 of a 21-day cycle, CisGem) with Gemcitabine (Gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) with 6-month progressive free survival (PFS) as the primary endpoint. • It demonstrated improved 6-month PFS in favor of CisGem compared to Gemcitabine alone (57.1 vs. 45.5%). Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al.Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study – The UK ABC-01 Study. Br J Cancer 2009;101:621–627.
  • 107. • A phase 3 study with the primary endpoint which became overall survival and the addition of quality of life analysis, in the UK ABC-02 study. • Median overall survival was 11.7 months for patients receiving CisGem compared to 8.1 months in patients receiving Gem alone. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine vs. gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273–1281.
  • 108. MODIFIED GEMOX PHASE III TRAIL – • Gemcitabine and Oxaliplatin OR Cisplatin • Median OS of 9.5, 4.6 and 4.5 months with GEMOX, Fluorouracil and supportive treatment respectively.
  • 111. Targeted therapy PEMBROLIZUMAB – • dMMR CCA are sensitive to PD1 blockage. • Approved in dMMR or MSI-H CCA positive tumours, • when tumour is non resectable or has distant metastasis. TRASTUZUMAB – • HER2/NEU receptor antagonist • Retrospective showed response in GB Ca and none in CCA
  • 112. IDH1/2 INHIBITORS • Inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221) and pan- IDH1– IDH2 (AG881) are currently being tested in patients with iCCA. • AG120 (ivosidenib) phase III trial in which 185 patients with IDH-1 mutant CCA were randomly assigned to ivosidenib or placebo, ivosidenib showed a benefit in terms of progression free- survival (HR 0.37). • Median OS was 10.8 months in patients receiving ivosidenib and 9.7 months in patients receiving placebo (HR 0.69
  • 113. Addition of EGFR-mAbs ( cetuximab and panitumumab) to gemcitabine-based first-line CHT in advanced BTC does not result in a statistically significant benefit in OS, PFS and ORR with increased grade 3-4 toxicity.