Radiation Oncology/Bile duct/Overview

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Pathology Literature

Epidemiology

• Uncommon in U.S., incidence ~3,000/year
  • Incidence increases with age, peak in 8th decade
  • Overall incidence has been increasing, particularly intrahepatic cholangiocarcinoma
• Risk factors
  • Sporadic in most patients
  • primary sclerosing cholangitis risk ~160x
  • choledochal cysts 10-20%
  • liver fluke infestation in China and Southeast Asia
  • Cholelithiasis minimal impact, unlike for gallbladder cancer

• Texas A&M; 2002 PMID 11991810 -- "Worldwide trends in mortality from biliary tract malignancies." (Patel T, BMC Cancer. 2002 May 3;2:10.)
  • Conclusion: Marked global increase in mortality from intrahepatic, but not extrahepatic, biliary tract malignancies

Anatomy

• Cholangiocarcinoma - malignancy of the biliary duct epithelium. The term is somewhat ambiguous, as it may refer only to cancers of the intrahepatic bile duct (originally), or include entire bile duct (commonly today), or even include the gall bladder
• Intrahepatic bile ducts form part of the portal triad within liver, together with hepatic artery and portal vein
• Left and right hepatic ducts join together at the hilum to form the common hepatic duct
• Common hepatic duct and cystic duct from gallbladder join to form common bile duct, which travels in the porta hepatis along portal vein and hepatic artery. This can lead to early vessel involvement
• Common bile duct travels within head of pancreas, joins pancreatic duct, and empties together with it into duodenum in Ampulla of Vater
• Tumor location (from UK 2002 Consensus Document), based on classification of Nakeeb (PMID 8857851):

Location	Frequency
Intrahepatic	20-25%
Perihilar	50-60%
Distal bile duct	20-25%
Multifocal	~5%

• Perihilar tumors can be further described according to Bismuth classification (Bismuth H, Castaing D. Hepatobiliary malignancy. London: Edward Arnold, 1994.)

	Bismuth Classification
Type I	occluding common hepatic duct, below bifurcation of left and right hepatic ducts
Type II	occluding common hepatic duct, reaching bifurcation but not involving either left or right hepatic duct
Type III	occluding common hepatic duct, and either left or right hepatic duct
Type IV	occluding both left and right hepatic side, OR multifocal

• Klatskin tumors are perihilar cholangiocarcinomas that involve the confluence of the left and right hepatic ducts (Bismuth Type II), named after Dr. Klatskin who described them in 1965 (PMID 14256720)

Pathology

• 90% adenocarcinoma (papillary, nodular, sclerosing)
  • CA19-9 and CA-50 are positive in 80-90% of chalnciocarcinomas and rarely in hepatomas
  • AFP is rarely positive in cholangiocarcinoma but in 35-75% of hepatomas
  • Presence of MIB-1 and AgNOR, and lack of CD44 (esp. CD44v6) appears correlated with LN mets and tumor progression
• 10% all other histologies (squamous cell, mucoepidermoid, etc.)

They are locally invasive, and rarely metastatic PMID 4354116

Please see Bile Duct Pathology for literature review

Diagnosis

• Clinical: S/S of biliary obstruction (jaundice, pale stool, dark urine, pruritus)
• Blood tests: none diagnostic, LFTs consistent with obstruction (elevated bilirubins, AP, GGT)
• Tumor markers: CA19-9 (85% patients, but also other GI tumors), CA125 (40-50% patients)
• Imaging:
  • U/S first line investigation
  • Contrast-enhanced spiral CT or MRI
  • Cholangiography (MRCP, ERCP, PTC). PTC may be better than ERCP due to 1) better define the proximal extent of tumor and 2) place percutaneous transhepatic catheters for decompression
  • Endoscopic U/S and PET are under evaluation
• Confirmatory histology
• Met from a primary located elsewhere work-up:
  • Pancreas
  • Stomach
  • Breast
  • Lung
  • Colon

Carcinoid tumor of bile duct

• UT Southwestern PMID 11075851 -- Carcinoid tumors of the extrahepatic bile ducts: a study of seven cases. (2000 Maitra A, Am J Surg Pathol. 2000 Nov;24(11):1501-10.)
  • "Because carcinoid tumors of the EHBD are of low malignant potential, they should be separated from the more common adenocarcinomas in this location."

Imaging

• Princess Margaret ASTRO Abstract A Prospective Comparison Study of Liver Tumour Target Definition Based on Triphasic CT and Gadolinium MR (2005 Voroney JJ, ASTRO 2005 #2088)
  • 23 patients (CCA 4, HCC 10, liver mets 9) on protocol; liver immobilized using ABC/voluntary breath hold. Best CT (arterial phase for HCA, venous phase for CCA and mets), best MRI T1 gado
  • Average GTV difference 11cc (1-263); CT GTV larger in 3/7 mets, 4/4 CCA, 6/11 HCA
  • Conclusion: "MR defined GTVs can be significantly different than CT defined GTVs and this should be considered for high precision liver cancer radiotherapy."

• Essen Germany PMID 14764888 -- Intraoperative radiation therapy in liver tissue in a pig model: monitoring with dual-modality PET/CT. (2004 Antoch G, Radiology. 2004 Mar;230(3):753-60. Epub 2004 Feb 5.)
  • Conclusion: "The morphologic and functional changes due to IORT in liver tissue can be accurately monitored with dual-modality PET/CT. By enabling the integration of functional and morphologic data, PET/CT may have an important role in monitoring radiation treatment."

• Jichi Japan PMID 10744810 -- Intraductal US in assessing the effects of radiation therapy and prediction of patency of metallic stents in extrahepatic bile duct carcinoma. (2000 Tamada K, Gastrointest Endosc. 2000 Apr;51(4 Pt 1):405-11.)
  • Conclusion: "Assessment of local radiation effects by intraductal US is useful for predicting patency of metallic stents in bile duct cancer."

Treatment Overview

Adapted partially from the 2002 UK Consensus document

• Surgery
  • The only curative treatment, but only <50% are resectable, and <30% have negative margins. Residual tumor amount is a significant predictor of post-op prognosis
  • LN are positive in ~50% of patients at presentation, and signify worse prognosis. It appears patients with 5+ LNs have significantly worse survival than patients with 1-4 LNs
  • 5-year OS for proximal lesions is 9-18%, for distal lesions 20-30%
  • For unresectable patients, palliative stenting procedures for relief of obstructive symptoms improve OS

• Chemotherapy
  • No evidence to support adjuvant therapy outside of clinical trials
  • 5-FU: ~10-20% response rate
  • Newer agents (e.g. Gemcitabine): 20-30% response rate
  • Combination therapy: 20-40% response rate
  • Gemcitabine + cisplatin: 30-50% response rate
  • Hepatic artery / portal vein infusion: good concentration, but no distal coverage

• External Beam RT
  • No evidence to support adjuvant therapy outside of clinical trials
    • No prospective adjuvant randomized trials
    • One prospective nonrandomized trial negative in perihilar tumors
    • Retrospective studies are suggestive of some value, particularly with higher doses and in patients with positive surgical margins
  • Based on retrospective reports, RT has value in palliation
  • The role of EBRT vs. ILRT vs. EBRT+ILRT has not been determined

A study from Wisconsin suggests significantly improved outcomes since 1998 in resected patients (~30%), owing to improvements in patient selection and chemoradiation.

Review Papers

• 2005 PMID 16214602 -- "Cholangiocarcinoma." (Khan, Lancet. 2005 Oct 8;366(9493):1303-14.)

• 2005 PMID 15757418 -- "Biliary tract cancers: current concepts and controversies." (Leonard GD, Expert Opin Pharmacother. 2005 Feb;6(2):211-23.)

• 2004 PMID 15011829 -- "Diagnosis and management of cholangiocarcinomas: a comprehensive review." (Yalcin, Hepatogastroenterology. 2004 Jan-Feb;51(55):43-50.)

• 2004 PMID 14755014 -- "Diagnosis and treatment of cholangiocarcinoma." (Anderson, Oncologist. 2004;9(1):43-57)

• 2004 PMID 15218306 -- "A review and update on cholangiocarcinoma." (Olnes, Oncology. 2004;66(3):167-79.)

• 2003 PMID 14603159 -- "Intrahepatic cholangiocarcinoma. Current management." (Martin R, Minerva Chir. 2003 Aug;58(4):469-78.)

• 2002 PMID 12607581 -- "Palliative and postoperative radiotherapy in biliary tract cancer." (Macdonald, Surg Oncol Clin N Am. 2002 Oct;11(4):941-54.)

• 2002 PMID 11879588 -- "Cholangiocarcinoma of the Hepatic Hilum (Klatskin Tumor)." (Byrnes, Curr Treat Options Gastroenterol. 2002 Apr;5(2):87-94.)

• 2002 PMID 12164560 -- "Cancers of the gallbladder and biliary ducts." (Yee, Oncology (Williston Park). 2002 Jul;16(7):939-46, 949; discussion 949-50, 952-3, 956-7.)

• 2001 PMID 11455468 -- "Radiotherapy as a component of multidisciplinary treatment of bile duct cancer: a surgeon's perspective." (Todoroki, J Hepatobiliary Pancreat Surg. 2001;8(2):130-6.)

• 1999 PMID 10536130 -- "Biliary tract cancers." (de Groen, N Engl J Med. 1999 Oct 28;341(18):1368-78.)

• 1999 PMID 10436829 -- "Chemoradiation for pancreatic and biliary cancer: current status of RTOG studies." (Rich, Ann Oncol. 1999;10 Suppl 4:231-3.)

• 1998 PMID 9849443 -- "The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature." (Hejna, Eur J Cancer. 1998 Jun;34(7):977-86)