Cholangiocarcinoma, risk factors,types,clinical features,managment,ESMO guidelines 2022,NCCN Guidelines Version 5.2021 Hepatobiliary Cancers

Cholangiocarcinoma, risk factors,types,clinical features,managment,ESMO guidelines 2022,NCCN Guidelines Version 5.2021 Hepatobiliary Cancers

1. CHOLANGIOCARCINOMA Vijay K.C. DM Gasteroenterology resident COMS, bharatpur Date: Friday,September 6, 2024

2. Bile duct anatomy Bile canaliculi - formed by the hepatocytes facing the perisinusoidal space Intralobular bile ducts ( cholangioles or Canals of Hering ): simple cuboidal epithelium, then by hepatocytes Interlobular bile ducts between the interlobar ducts and the lobules - simple columnar epithelium. Interlobar ducts (between the main hepatic ducts and the interlobular ducts): pseudostratified columnar epithelium. Lobar ducts (rt and left hepatic ducts): stratified columnar epithelium.

3. Intrahepatic bile ducts Bile canaliculi unite to form segmental bile ducts which drain each liver segment. The segmental ducts then combine to form sectional ducts with the following Pattern. segments VI and VIl : right posterior duct (RPD), coursing more horizontally segments V and VI: right anterior duct (RAD), coursing more vertically right posterior and anterior ducts unite to from the right hepatic duct (RHD) segmental bile ducts from Il-to-IV unite to form the left hepatic duct (LHD) The left and right hepatic ducts unite to form the common hepatic duct (CHD). Bile duct(s) from segment I drain into the angle of their union.

4. Extrahepatic bile ducts CHD is joined by the cystic duct to form CBD CBD travels @ free edge of the lesser omentum ➡︎ posteriorly the duodenum & pancreas ➡︎unite with MPD to form the ampulla of Vater➡︎ major duodenal papillae( medial wall of D2).

5. Lymphnode drainage Superior pancreaticoduodenal Retroportal Proper hepatic nodes first Peripancreatic Celiac I nteraortocaval lymph nodes.

6. Biliary malignancies C holangiocarcinomas: intra- and extrahepatic (2) Carcinoma of the gallbladder (3) Carcinoma of the ampulla of vater

7. cholangiocarcinoma Most CBD tumor Second most common primary hepatic malignancy Since the 1970s, the incidence of cholangiocarcinoma has increased worldwide

8. C holangiocarcinoma -subtypes Intrahepatic : arise within the liver parenchyma and above the 2 nd order bile ducts Perihilar ( Klatskin tumors ) : between 2 nd order bile ducts and insertion of the cystic duct D istal : below the insertion of the cystic duct Each anatomic subtype has a distinct epidemiology, pathogenesis, risk factors, management, and prognosis

9. Epidemiology It accounts < 2% of all malignancies Ninth most common GI malignancy. 3% of all GI malignancy Incidence varies from 5% in japan and 20% in korea to 90% thailand of the GI malignancy. Highest incidence in southeast asia : 113 per 100,000 population.( Chronic parasitic infestation) Hepatobiliary malignancies account for 13% and 3% of overall cancer-related mortality in the world and in the USA, respectively. Perihilar CCA (50% to 60%) distal CCA (20% to 30%) Intrahepatic CCA ≅20%

10. Epidemiology 10% to 20% of these deaths are caused by CCA. Average age at diagnosis: 50 yrs The male-to-female ratio- 1:1.5 in <40 yrs of age ,1:2.5 in 60s & 70s Common before 40 years in PSC cases.

11. Risk Factors for Cholangiocarcinoma DEFINITE Caroli disease Choledochal cyst Hepatolithiasis Opisthorchis viverrini infection PSC Thorotrast PROBABLE Biliary-enteric drainage procedures Cirrhosis Clonorchis sinensis infection Heavy alcohol consumption Hepatitis C HIV Toxins (dioxins, polyvinyl chloride) Diabetes Obesity Lynch syndrome & biliary papillomatosis

12. E merging risk factors Newly discovered likely risk factors Obesity diabetes fatty liver disease. emerging risk factors Asbestos metabolic syndrome

13. Primary sclerosing cholangitis (PSC) 30% cholangiocarcinoma diagnosed in PSC + UC Develops at younger age (30-50yrs) in PSC Lifetime risk of cholangiocarcinoma in PSC - 10-15% Alcohol consumption to be a risk factor for development of cholangiocarcinoma in PSC Burak Ket al. Am JGastroenterol 2004; 99:523 Claessen MM et al. J Hepatol 2009; 50:158 Bergquist Aet al. Hepatology 1998; 27:311

14. Fibro-cystic liver disease Caroli's syndrome, congenital hepatic fibrosis, choledochal cysts - 15% risk of malignant change Related to biliary stasis, reflux of pancreatic juice or deconjugation of carcinogens Average age at diagnosis – 34 yrs Incidence in pts with untreated cysts - 28% Lipsett PA et al. Ann Surg 1994; 220:644

15. Parasitic infection Liver flukes: Clonorchis and Opisthorchis Intra-hepatic cholangiocarcinoma Chronic inflammation in proximal biliary tree Common in Thailand

16. Cholelithiasis & hepatolithiasis Strong risk factor for gall bladder cancer Association with cholangiocarcinoma, less well established Strong association between hepatolithiasis and cholangiocarcinoma

17. Viral hepatitis HCV, HBV, cirrhosis - risk factors for iCCA . Prospective study from Japan reported risk of CCA in cirrhosis related to HCV - 3.5% at 10 yrs. Data are less compelling for association between HBV and CCA. Kobayashi Met al. Cancer 2000; 88:2471

18. Metformin and CCA Metformin significantly reduces the overall risk of BTC by 50%–60%. A dose-response effect is observed and users of approximately 2 years show significantly reduced risk. However, metformin does not affect the overall survival in patients with BTC. use of Metformin is associated with significantly improved post-operative survival Metformin also showed significant improvement in patients taking chemotherapy. Studies

19. Patholog y H ighly desmoplastic tumor Macroscopic types: Intrahepatic CCA can have 3 subtypes: mass-forming (>90 %) periductal-infiltrating intraductal growth type. P erihilar CCA : periductal-infiltrating Nodular intraductal growth pattern Histological types 90% are adenocarcinomas intestinal-type adenocarcinoma clear cell adenocarcinoma signet-ring cell carcinoma adenosquamous carcinoma squamous cell carcinoma small cell carcinoma.

20. Pathology Adenocarcinoma - >90% Sclerosing: Most common type Characteristic feature - desmoplastic reaction Extensive fibrosis - pre-operative diagnosis difficult Early invasion of bile duct wall low resectibility and cure rate. Nakeeb Aet al. Ann Surg 1996; 224:463 Two main histologic subtypes Bile ductular type (mixed), arising from small intrahepatic bile ducts, and Bile duct type (mucinous) arising from large intrahepatic and extrahepatic bile ducts.

21. Pathogenesis C omplex and likely related to inflammation in the microenvironment, environmental factors, and genetic aberrations of the tumor cells L iver fluke–related CCA : TP53 mutations IDH1 , IDH2 , and BAP1 mutations : non- liver fluke–related CCA.. ( FGFR ) 1-3, IDH 1 and 2 , and BAP1 are higher in iCCA . ARID1B , PBRM1 , and protein kinase cyclic AMP-activated catalytic subunit alpha ( PRKACA ) and beta ( PRKACB ) are : distal and perihilar CCA . Inactivating mutations in E74-like ETS transcription factor 3 ( ELF3 ) : distal CCA Oncogenes: K- ras , c-erbB-2, BRAF, PIK3CA, CTNNB1, EGFR Tumor suppressor genes : p53, SMAD4, CDKN2A

22. Molecular aberration

23. An overview of common affected pathways in CCA S. Kongpetch et al. / Best Practice & Research Clinical Gastroenterology 29 (2015) 233 e 244

24. CCA-Clinical Features iCCA Abdominal pain Systemic symptoms such as cachexia, malaise, fever, wt. loss and fatigue pCCA and d CCA Painless jaundice secondary to malignant biliary obstruction. Atrophy-hypertrophy” complex Signs: 1.Pts with extrahepatic CCA include jaundice, hepatomegaly, and palpable mass in the right upper quadrant area. 2. Pts. with intrahepatic CCA usually have no symptoms other than right upper quadrant tenderness. 

25. A trophy hypertrophy complex Refers to the controlled restoration of liver parenchyma following hepatocyte loss. Different types of injury (e.g., toxins, ischemia/reperfusion, biliary obstruction, and resection) elicit the same hypertrophic response in the remnant liver. The AHC involves complex anatomical, histological, cellular, and molecular processes. The signals responsible for these processes are both intrinsic and extrinsic to the liver and involve both physical and molecular events Causes: Biliary obstruction Portal vein obstruction Hepatic vein thrombosis

26. D ifferential diagnosis Hepatocellular carcinoma Liver metastases Pancreatic cancer Fasciola hepatica infection mimicking as CCA Cholangitis Cholecystitis or choledocholithiasis Biliary strictures IgG4-associated cholangiopathy

27. Challenges of Patients Diagnosed With CCA

28. Diagnosis A multidisciplinary approach:

29. Laboratory analysis CBC LFT CA 19-9 CEA B i lliary insulin like growth factor Ig G4 level AFP- r/o HCC from iCCA

30. CA 19-9 level W ith PSC, the sensitivity and specificity of CA 19-9 are 79% and 98%, respectively (cutoff value is 129 U/ mL. without PSC, the sensitivity is 53% with a cutoff value of 100 U/ mL. High levels of CA 19-9 levels (>1000 U/mL) a/w metastatic cholangiocarcinoma. CA 19-9 : false high in bacterial cholangitis and choledocholithiasis 1/3 of elevated Ca 19-9 pt don’t have CCA. Elevated CA 19-9 pancreatic exocrine and neuro-endocrine tumors biliary cancer HCC gastric cancer colo -rectal cancer acute cholangitis cirhhosis

31. CEA Neither sufficiently sensitive nor specific to diagnose cholangiocarcinoma S. CEA >5.2ng/ml - sensitivity 68%, specificity 82% Biliary CEA elevated five-fold compared to those with benign strictures Elevated CEA Gastritis, PUD Diverticulitis COPD DM liver disease Siqueira Eet al. Gastrointest Endosc 2002; 56:40 Nakeeb A et al. Am J Surg 1996; 171:147

32. CEA +CA19-9 Combined index = CA 19-9 + (CEA X 40) Correctly identified 10/15 pts with cholangiocarcinoma even in radiographically occult disease In 333 pts with PSC, 45 had both tests Sensitivity -100%, specificity - 78% for CEA (>5.2ng/ml) +CA 19-9 (>180 U/ml) Ramage JK et al. Gastroenterology 1995; 108:865 Siqueira E et al. Gastrointest Endosc 2002; 56:40

33. Biliary insulin like growth factor Insulin like growth factor secreted by cholangiocarcinoma cells Biliary levels highly accurate in differentiating cholangiocarcinoma from pancreatic cancers. Alvaro D et al. Ann Intern Med 2007; 147:451

34. Fluorescence in situ hybridization Established method to assess cellular aneuploidy and chromosomal duplication in CCA. FISH utilizes fluorescently labeled DNA probes to detect cholangiocytes with chromosomal alterations. A positive test is defined when ≥5cells display gains of ≥2. chromosomes,or ≥10 cells demonstrate a gain of a single chromosome.

35. FISH I ncrease the sensitivity and specificity of cytology for diagnosing cholangiocarcinoma in patients with and without PSC A ssessment of chromosomal aneusomy (gains or losses of chromosomes An optimized FISH probe set (targeting the 1q21, 7p12, 8q24, 9p21 loci) has enhanced sensitivity and specificity (93% and 100%, respectively) for the detection of pancreaticobiliary malignancies

36. radiology USG CT scan MRCP ERCP Cholangiography Endoscopic ultrasound Intra-ductal USG PETscan

37. USG Pts with surgical obstructive jaundice over 10 year - sensitivity-94%, specificity- 96% Intra-hepatic lesions: mass lesion, dilatation of intra-hepatic ducts alone Peri-hilar and extra-hepatic lesions: intra-hepatic and extra-hepatic ductal dilatation. Obstructing lesion suggested by ductal dilatation (>6mm) in absence of stones. Klatskin tumors - segmental dilatation and non-union of RHD and LHD Tumor with PSC or cirrhosis - bile ducts may not visibly dilated Sharma MP et al. Trop Gastroenterol 1999; 20:167 Saini. NEngl JMed 1997; 336:1889

38. CT scan Useful for detection of intra-hepatic tumors, level of biliary obstruction, liver atrophy Klatskin tumor - ductal dilataion in both lobes, contracted gall bladder, non-union of RHD and LHD + thickened wall. CBD tumor - distended gall bladder, dilated intra- hepatic and extra-hepatic ducts PV branch invasion - biliary duct dilatation within atrophied lobe with hypertrophic c/l lobe Tri-phasic CT: Differentiate benign from malignant intra-hepatic ductal strictures (particularly in PV phase)

39. CT scan Peripheral intra-hepatic tumors - hypodense lesion with peripheral enhancement, biliary dilatation, contrast enhancement on delayed images Small sized intra-hepatic cholangiocarcinoma - enhancement in arterial phase and mimic HCC Peri-hilar tumors - limited sensitivity for extra- regional nodal disease Relationship of tumor to vessel and surrounding organ - more easily evaluated on CT

40. MRI/MRCP Non-invasive technique for evaluation of duct system Not require contrast material defining anatomic extent of tumor and cause of jaundice Cholangiocarcinoma - T1- image - Hypo-intense lesion -T2- image - Hyper-intense lesion - Central hypo-intensity (fibrosis) Magnetic resonance imaging of a 3 cm intrahepatic cholangiocarcinoma in segment III

41. MRCP of hilar CCA : Smooth luminal narrowing (arrow); B: Complete hilar obstruction (arrow); C: Irregular asymmetric complete obstruction (arrow); D: Intraluminal filling defect (arrow).

42. Cholangiography ERCP or PTC Preoperative cholangiography (diagnostic or therapeutic) in biliary obstruction MRCP + spiral CT replaced invasive cholangiography in obstructive jaundice due to proximal lesion Still cholangiography is indicated in; Distal obstruction Pre-operative biliary drainage is needed - Tissue diagnosis

43. PTC showing complete obstruction of common hepatic duct with patent primary biliary confluence (arrow, A), blocked primary biliary confluence with irregular outline (arrow, B) and intraluminal polypoidal filling defect (arrow, C)

44. ERCP

45. Endoscopic ultrasound To visualize local extent of primary tumor and status of regional nodes in distal bile duct lesion EUS-guided FNAB of tumors / enlarged nodes No contamination of biliary tree EUS + FNAB - greater sensitivity in distal tumors than ERCP +brushing cytology.

46. EUS of D istal CCA

47. Bursh cytology and biopsy Endoscopic brush cytology - sensitivity 35-70% Endoscopic cytology +biopsy - sensitivity 43-88% Brush cytology + tumor marker - better diagnostic accuracy. + ve brush cytology +CA 19-9 > 180 U/ml -sensitivity - 88%, specificity- 97% Sugiyama M et al. Am J Gastroenterol 1996; 91:465 Siqueira E et al. Gastrointest Endosc 2002; 56:40

48. Spyglass cholangioscopy Single-operator cholangioscopy : simplest technique, because it uses a disposable 10-French cholangioscope inserted through the working channel of a standard duodenoscope that can be easily handled by a single endoscopist. M other-baby scope system: requires two endoscopists to operate, while using an ultrathin gastroscope to perform ERCP is technically more difficult: as the diameter of the ultrathin gastroscope is larger, ranging from 4.9 mm to 5.8 mm, it cannot be used in non-dilated ducts

49. Spyglass cholangioscopy visualisation and initiation of stone fragmentation and removal, was 92% complete stone clearance during the study’s SpyGlass session was lower, at 71% Context of biliary stricture evaluation, showed that the accuracy of SpyGlass visualisation was 89%, T argeted biopsies achieved a higher accuracy rate of 82%. Comparing SpyGlass targeted biopsies with brush and blind biopsies, Draganov et al showed a significantly higher accuracy rate (84.6% vs. 38.5% vs. 53.8%) Benign lesions in spyglass: appearance of a smooth surface and outline with no visible abnormal vessels; Malignant lesions in spyglass: villous mucosal projections; irregular mucosal nodularity; mass-forming lesions; or prominent vascularisation /neo-angiogenesis 

50. Intra-ductal USG Detection of early lesion - Longitudinal tumor extent Better evaluation of proximal biliary system Tumor extension into adjacent organs & major blood vessels Specificity- 100% Tamada K et al. Endoscopy 1995; 27:573

51. Imagings of intraductal ultrasonography (IDUS) and cholangiogram of cholangiocarcinoma (infiltrating type). Cholagiogram showing stenosis in the hepatic hilum. IDUS showing irrgular hypoechoic mass. (B) IDUS showing invasion to right hepatic artery. (C) IDUS showing irregular hypoechoic mass at the bifurcation of hepatic ducts. (D) No mass at the biurcation of B4. (E) IDUS showing heterogenous thickened wall in the middle of common bile duct.

52. PET scan Visualization of cholangiocarcinoma is possible due to high glucose uptake of bile duct epithelium Detect nodular tumor up-to 1cm Less helpful in infiltrating tumors Most important role in identifying occult metastasis Kim YJ et al. Eur J Nucl Med Mol Imaging 2003; 30:1467

53. ESMo guidelines 2023

54. Staging laparoscopy Peritoneal or liver metastasis - 20 to 40% cases at surgical exploration To avoid morbidity of unnecessary laparotomy

55. Intrahepatic Cholangiocarcinoma M ass lesion in liver I n cirrhotic pt difficuly to diffentiate with HCC. Dynamic CT & MRI if lesions >2 cm D ynamic CT or gadolinium-enhanced MRI with progressive centripetal enhancement in delayed phases is characteristic of intrahepatic CCA. A ssessment of resectability PET/CT has a sensitivity and specificity of 95% & 83 %.

56. Perihilar and Distal Cholangiocarcinoma Cholangiography: main tool ERCP, percutaneous transhepatic cholangiography (THC), and MRCP MRI with MRCP : extent of biliary neoplastic invasion in perihilar CCA CT is superior in detecting vascular enhancement and assessing resectability . Sensitivity and specificity of PET are only 69% and 67% in perihilar CCA.

57. Perihilar and Distal Cholangiocarcinoma EUS has a higher tumor detection: distal cholangiocarcinoma B rush cytology during ERCP: tissue diagnosis ( specificity 100 % & sensitivity 43 % ) Fluorescence in situ hybridization (FISH) for ↑cytology yield ( chromosomal abnormality ) Newer techniques : Cholangioscopy I ntraductal US, C onfocal laser endomicroscopy.

58. Algorithm for the diagnosis of perihilar CCA

59. Staging i CCA AJCC/UICC TNM staging system Liver Cancer Study Group of Japan staging system, National Cancer Center of Japan staging system. Of these 3 staging systems, only the AJCC/UICC TNM staging system (has shown a correlation between stage and survival pCCA Bismuth-Corlette classification Memorial Sloan-Kettering Cancer Center (MSKCC) staging system AJCC/UICC TNM staging system Mayo Clinic staging system dCCA AJCC/UICC TNM staging system

60. Cholangiocarcinoma-treatment

61. O’Kane L, V. Guarrera J, E. Lunsford K. Contemporary Surgical Treatment for Management of Cholangiocarcinoma [Internet]. Liver Cancer - Multidisciplinary Approach [Working Title]. IntechOpen ; 2024.

62. Surgery Surgical resection (segmental) is the mainstay for treatment of iCCA . Goal is to remove all the disease with negative microscopic (RO) margins while preserving an adequate remnant liver volume. Removal of clinically suspicious nodal disease is mandatory, the role of routine lymphadenectomy is less defined . portal lymphadenectomy helps in accurate staging and hence is recommended.

63. Volumetric analysis: Future Liver remnant calculation In patients with iCCA and pCCA who require liver resection, the calculation of liver volumes and the FLR is critical to operative planning. FLR > 30% in healthy patients and > 40% in those with cirrhosis is required. FLR is calculated using CT-guided imaging with software that calculates liver volumes. Patients who have inadequate FLR require interventions to increase liver volumes. PVE is the most common technique L iver partition and portal vein ligation for staged hepatectomy and liver venous deprivation PVE results in hypertrophy of the FLR of up to 40%

64. Surgical Resection Intrahepatic CCA: Centrally located tumors: hepatic resection + extrahepatic bile resection + portal lymphadenectomy Peripheral lesion: hepatic resection only 5-yr-survival of resectable disease: 40-60%

65. Surgical treatment-CCA Resectability rates • Distal 91% • Intrahepatic 60% • Perihilar 56% Tumor-free margins • In 20 - 40% of proximal tumors • In 50% of distal tumors Resectability rates have increased over time, due to more aggressive operative strategies and broadened criteria for resectability Nakeeb A et al. Ann Surg 1996; 224:463

66. Criteria for resectaibility Absence of retro-pancreatic and para-celiac nodal metastases or distant liver metastases Absence of invasion of the portal vein or main hepatic artery Absence of extra-hepatic adjacent organ invasion Absence of disseminated disease Rajagopalan Vet al. Oncology (Williston Park) 2004; 18:889

67. Unresectability Peripheral and distal CCA Medically unfit patient Distant metastatic disease Nonsatellite hepatic metastases Lymph node metastases beyond portal vein,hepatic artery, (celiac axis, and peripancreatic) distribution Distant metastases in other organ/sites Extensive Local involvement Bilateral (or contralateral) involvement of Portal vein (some rarely resectable ) Hepatic artery Secondary biliary radicals Inadequate future liver remnant < 30% FLR in patient with normal ( nonatrophied ) hepatic parenchyma < 2 contiguous segments with adequate portal venous and hepatic arterial inflow, adequate hepatic venous drainage, and adequate biliary drainage d istal CCA Medically unfit patient Distant metastatic disease Distant metastases (liver +other organs) Lymph node metastases beyond portal vein. hepatic artery, peripancreatic, (and celiac axis) distribution Major vascular involvement Significant portal/SMV vein Superior mesenteric artery Common or proper hepatic artery

68. Surgical Resection and : i CCA iCCA Can mimic HCC or metastatic carcinoma Solitary iCCA : hepatic segmentectomy or lobectomy Recurrence rates following resection upto 62%. Overall 5-year survival rates after resection, range from 22% to 42% Neoadjuvant and adjuvant therapy : no survival benefit iCCA has traditionally been considered a contraindication to LT due to poor outcomes. Survival is positively correlated with R0 resection negative lymph node metastasis status (N0) solitary tumor, younger age better performance status

69. Surgical resection: Perihilar CCA Surgical resection: treatment of choice in the absence of PSC Perihilar CCA are resected by lobar or extended lobar hepatic and biliary duct resection with regional lymphadenectomy and Roux-en-Y hepaticojejunostomy. P reoperative portal vein embolization then extended partial hepatectomy .

70. Surgical resection: Distal CCA Whipple resection. 5 yr survival rates in N0 patients after R0 resection are 20% to 67% for pCCA and 27% to 37% for dCCA. Neither adjuvant nor neoadjuvant chemotherapy or radiation therapy has been shown to be effective

71. Post resection status Surveillance for Ro and R1 resection • Consider imaging every 3 to 6 months for 2 years • Every 6-12 months for upto 5 years or as clinically indicated

72. Liver transplantation in CCA PSC and perihilar CCA are considered nonresectable and should be considered for LT instead of resection. N eoadjuvant EBRT with concurrent systemic 5-FU ChT, followed by brachytherapy and oral maintenance ChT with capecitabine until transplantation. Without PSC, radial diameter of the perihilar tumor <3 cm, absence of intra- or and extrahepatic metastases, and nonresectability . “very early” iCCA (< 2 cm) without metastasis..

73. unresectable i CCA - Locoregional Therapies Transarterial chemoembolization (TACE): median overall survival of 12 to 15 months T ransarterial radioembolization (TARE) using yttrium-90 microspheres. Radiofrequency ablation(RFA) T ransarterial chemoinfusion (TACI)/ Hepatic Arterial Infusion (HAI) Radioembolization Microwave ablation

74. R adiofrequency 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% in a year, 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.

75. Photodynamic therapy For palliation of unresectable hilar CCA Photosensitising agent porphyrin or d- aminolevulinic acid given IV, which accumulates in cancer cells PDT delivered intraluminally to tumor by cholangioscopy Generation of oxygen free radical, tumor cell death Improve biliary drainage and improvement in cholestasis involves a single minimally invasive treatment that has a low complication rate and is well tolerated. PDT in conjunction with biliary stenting , reduces the local obstruction of tumor tissue by generating singlet oxygen and may result in long-term patency. PDT improved cholestasis and quality of life by diminishing the need for further procedures, such as stent revision and percutaneous biliary drainage

76. C hemotherapy/targeted therapy/immunotherapy Gemcitabine, cisplatin and durvalumab (TOPAZ-1 study)) Gemcitabine and Cisplatin (Gem/Cis) (ABC-02 study) Capecitabine ( BilCap study) FOLFOX Gemcitabine and Oxaliplatin (modified GEMOX study) CAPOX (Capecitabine and oxaliplatin) Gemcitabine (given alone)( BCAT study) Ivosidenib (for those with an IDH-1 mutation) (CLARDHY STUDY) Pemigatinib (for those with an FGFR2 fusion) Pembrolizumab and gemcitabine(KEYNOTE-966 study)

77. Chemotherapy No curative medical therapies available FDA approved chemotherapy for CCA is gemcitabine. In 2010, the Advanced Biliary Cancer-02 (ABC-02) trial showed a statistically significant 3-month overall and progression-free survival benefit for gemcitabine-cisplatin combination therapy compared with gemcitabine alone. Combination ChT : hematologic toxicity

78. Advanced Biliary Cancer-02 (ABC-02) trial Cisplatin and gemcitabine significantly improves overall survival compared with gemcitabine monotherapy (11.7 vs. 8.3 months). • Benefit gained with no clinically significant added toxicity • CisGem is recommended as a worldwide standard of care and the backbone for further studies Caution required in patients with PS ≥ 2.

79. 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.

80. I mmunotherapy Conventional chemotherapy has limited efficacy in metastatic cholangiocarcinoma, prompting interest in immunotherapy approaches. The only FDA-approved immunotherapy in cholangiocarcinoma is pembrolizumab, an anti-PD-1 antibody, which received tissue-agnostic approval for solid tumours with microsatellite instability or mismatch repair deficiency, including cholangiocarcinoma.

81. TOPAZ-1 trial Oh DY, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022 Aug;1(8)

82. KEYNOTE-966: Pembrolizumab/ GemCis vs PBO/ GemCis

83. Vaccine therapy R apidly evolving armamentarium in the field of cancer treatment. Activation of the immune system of the patient, enhancing immunogenicity and inducing cellular and humoral immune responses to block neoplastic evolution S eems to be a promising therapeutic strategy Experimental studies on rats suggest the efficacy of a DNA vaccine targeting CTLA-4 and PD-1 S tudies focus on developing mRNA vaccines for CCA targeting tumor antigens (CD247, TRRAP, FCGR1A) 

84. targeted therapy In recent years, targeted therapy progressed alot . Ongoing clinical trials showing good efficacy and safety in advanced CCA current targeted therapy of CCA still has many challenges Yuhang Li et al.(2024) Advances in targeted therapy of cholangiocarcinoma, Annals of Medicine

85. IDH1/2 INHIBITORS Inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221) and pan- IDH1-IDH2 (AG881) are currently being tested in patients with iCCA . 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).

86. ClarlDHy : Double-Blind Study With Ivosidenib vs PBO

87. Reversible and Irreversible FGFRi s in CCA

88. Radiation Therapy E xternal-beam RT (EBRT), including three dimensional-conformal RT (3D-CRT), intensity-modulated RT (IMRT) and stereotactic body radiotherapy (SBRT), B rachytherapy P roton 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.

89. R T- brachytherapy Placement, by an interventional diagnostic radiologist, of a percutaneous drainage catheter through the area of tumor. Then a catheter is thread inside the drainage system catheter. When a low-dose-rate system is employed, a wire with ir-192 is then placed at the desired location inside the catheter. If a remote high-dose-rate after loading system is employed, then the appropriate dwell time and position are selected and programmed. Acute complications of external beam and intraluminal radiotherapy include - nausea, Vomiting, and Transient elevation of transaminases. Late complications are - gastrointestinal bleeding biliary bleeding duodenal stenosis

90. Palliative Procedure P alliative treatments are essential in the management of cholestasis, abdominal pain, and cachexia, which limit the quality of life. Palliation of symptomatic jaundice Intraop findings of unresectability or when distal CBD margin + ve biliary-enteric bypass Preoperative : PTBD or ERCP Palliation of pain : Narcotics Palliation of duodenal obstruction : Duodenal stenting

91. Palliative Treatment- cont Unilateral restoration of bile flow is generally sufficient Bilateral restoration of biliary drainage has been associated with increased survival Early intervention in a patient with malignant biliary obstruction is recommended External beam radiation and intraoperative or intraductal brachytherapy S urvival benefit with TACE .

92. E ndoscopic therapy M ainly palliative and limited to biliary drainage in patients with obstructive jaundice N ewer treatment options: photodynamic therapy radiofrequency ablation brachytherapy

93. percutaneous methods PTBD can be performed in two clinical scenarios: Before surgery to relieve biliary obstruction and cholestasis with improved survival. As a palliative technique with goal to decrease the bilirubin then allow chemotherapy.

94. ERCP vs PTC

95. Prognostic factors Tumor location Stage of the primary tumor Extent of surgery Co-morbidities Histologic margin status Metastasis Lymph node status

96. Poor Outcomes in Patients With Advanced CCA

97. Villard C, et al. eGastroenterology 2024; 2 :e100045. doi:10.1136/egastro-2023-100045

98. summary Cholangiocarcinoma (CCA) is the second most common liver-related cancer. It accounts for 10%-20% of mortalities from hepatobiliary malignancies. Hilar CCA is the most frequent typ e. A larming mortality rate owing to its silent presentation. H ighly aggressive nature and resistance to treatment. Early diagnosis, molecular characterization, accurate staging and personalized MDT are cornerstone of management S urgical resection, tissue diagnosis, PBD, PVE and palliative drainage. Surgical resection remains the curative option. Role of adjuvant ChT , RT, CRT are minimal. Immunotherapy and targeted therapy is gaining prominence and presents a potential for enhanced survival.

99. R efrences: Sleisenger and fordtran’s gastrointestinal and liver disease, 11th Edition Banales Jm et.al Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 S. Kongpetch et al. / Best Practice & Research Clinical Gastroenterology 29 (2015) 233e244. ESMO guidelines 2022 British Society of Gastroenterology guidelines 2023. NCCN Guidelines Version 5.2021 Hepatobiliary Cancers Fischer's Mastery of Surgery 7th edition Sabiston Textbook of Surgery First South East Asian Edition NIH guidelines 2024.