Bile Duct Tumors Treatment & Management

Indications for bile duct tumor surgery include the following:

• The tumor is resectable - Criteria for resectability include absence of liver metastases, absence of carcinomatosis, and absence of vascular invasion
• The patient is fit for surgery

If the tumor is limited to the bifurcation of the hepatic ducts or a single lobe of the liver or if it involves the portal vein or hepatic artery on the same side, the lesion may be resectable. Preoperative imaging is aimed at establishing whether a viable unit of liver that is large enough to maintain adequate liver function will remain after surgical removal of the tumor. The remaining liver tissue must contain a normal branch of the portal vein and hepatic artery and must also contain a bile duct large enough to anastomose to the bowel (see the image below).

Operative photograph of choledochojejunostomy, showing ample size of common duct.

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Contraindications for surgery include the following:

• Unresectable tumors - If tumors are extensive or fixed to adjoining structures, including the main portal vein or hepatic artery, they are unresectable; cholangiographic evidence of invasion of the secondary hepatic duct in both lobes of the liver or angiographic evidence of encasement of the main portal vein or hepatic artery indicates unresectability.
• Metastases including diffuse peritoneal involvement
• Vascular invasion
• Patients who are at high risk from general anesthesia and surgery because of general medical conditions
• Advanced age

The role of adjuvant radiotherapy and chemotherapy has been controversial. ^{[25, 26, 27]}  A meta-analysis by Ma et al found that adjuvant chemotherapy was associated with improved overall survival and should be considered in patients with intrahepatic cholangiocarcinoma following curative resection. ^[28]

The use of hormones in treatment, including somatostatin analogues, cholecystokinin, and cholecystokinin antagonists, is being investigated.

It has been suggested that preoperative endoscopic retrograde cholangiopancreatography (ERCP) with biliary drainage in patients with tumors of the bile duct increases the risk of implantation metastases after resection of the tumor. ^[29] Therefore, preoperative radiotherapy is advocated in such patients, but the benefit has not been definitely proved. ^[30]

Transarterial chemoembolization (TACE), infusion of 5-fluorouracil (5-FU) into the hepatic artery or bile ducts, and percutaneous injection of ethanol (PEI) into the lesions are other modalities that are investigational.

Photodynamic therapy may be useful in relieving obstruction, especially when obstruction occurs as a result of tumor outgrowth into an endoprosthesis. ^{[31, 32]}  Radiofrequency ablation (RFA) and intraluminal brachytherapy are being studied as well. ^{[33, 34]}

Liver transplantation, when performed for cholangiocarcinoma, is associated with poor survival. ^[35]

For more information on treatment of malignant bile duct tumors (cholangiocarcinomas), see Cholangiocarcinoma.

Medical therapy is indicated for patients who are unfit for surgery or who have an unresectable tumor. Jaundice and itching can be reduced with the placement of an endoprosthesis, either endoscopically or percutaneously, across strictures.

Endoscopic techniques for the relief of obstruction include sphincterotomy, balloon dilatation of the stricture, and the placement of stents. ^{[36, 20]} Larger, expandable metal stents, which have better patency rates than do plastic stents, include Metal-Palmaz, Strecker, Gianturco Z stent, and Wall stents. ^[37] One meta-analysis suggested that covered self-expandable metal stents have a trend toward later obstruction as compared with uncovered self-expandable metal stents. ^[38]

Percutaneous transhepatic endoprosthetic insertion also is successful, but an increased risk of complications, such as blood and bile leakage, exists. Ninety percent of stents can be placed by a combination of endoscopic and percutaneous techniques after a failed endoscopic attempt.

Chemotherapy has been tried in these patients but has not been proved to be of definite benefit. ^[25] A phase II clinical trial by Schinzari et al suggested that the FOLFOX-4 regimen (5-fluorouracil/leucovorin plus oxaliplatin) is a potentially promising first-line treatment. ^[39] A regimen of gemcitabine plus cisplatin has been used for advanced cholangiocarcinoma. ^[40]

In April 2020, the US Food and Drug Administration (FDA) approved pemigatinib (Pemazyre) for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor (FGF) receptor (FGFR) 2 gene (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. Pemigatinib is a small-molecule kinase inhibitor that targets FGFR1, 2, and 3 by inhibiting FGFR1-3 phosphorylation and signaling. FGFR inhibition disrupts tumor cell proliferation, survival, migration, and angiogenesis. 

Approval of pemigatinib was supported by the FIGHT-202 study (n = 146). ^[41] Of the 146 patients enrolled, 107 had FGFR2 fusions or rearrangements, 20 had other FGF/FGFR alterations, 18 had no alterations, and 1 had an undetermined alteration. Thirty-eight (35.5%) of the 107 patients with FGFR2 fusions or rearrangements achieved an objective response (3 complete responses; 35 partial responses).

Radiotherapy may be administered by external beam therapy; intraoperative radiotherapy using biliary stents with iridium (¹⁹²Ir), radium, or cobalt (⁶⁰Co); radioimmunotherapy using sodium iodide (¹³¹I) anti-carcinoembryonic antigen (CEA) as a component of therapy; or charged particle irradiation. Internal radiotherapy may be combined with biliary drainage, but the value of this approach remains to be proved. ^{[26, 27]}

Pain may be relieved with the injection of 50% alcohol for chemical splanchnicectomy.

Immunotherapy has shown limited efficacy in cholangiocarcinoma (~5%). ^[42]  Some evidence suggests that immunotherapy targeting programmed cell death protein-1 (PD-1) may prove safe and effective for advanced intrahepatic cholangiocarcinoma. ^[43]

Resection is the best treatment for bile duct tumors and provides the best palliation in terms of duration and freedom from infectious complications. ^{[44, 45]} Benefits of resection include the possibility of cure or long-term survival, especially for patients with distal tumors. The type of surgical procedure performed depends on the site and extent of the disease.

Choice of surgical approach

Proximal tumors (Klatskin tumors) may be managed by a variety of techniques, including the following:

• Patients with perihilar tumors (Bismuth classification I and II), without evidence of vascular invasion, are candidates for local excision; if  negative margins cannot be achieved with local excision, resection of the corresponding lobe is indicated
• Type III tumors are best managed by means of right or left hepatic lobectomy; resection of the adjacent caudate lobe (segment I) may ensure adequate tumor-free margins in cases of involvement of the hepatic duct bifurcation
• Sometimes, extended right or left hepatectomy and (rarely) central liver resection may need to be combined for adequate resection of the tumor

Following resection of the bile duct, which may be combined with hepatic resection, reconstruction can be performed by means of unilateral or bilateral hepaticojejunostomy, using transhepatic stents. ^[37]

Surgical exploration is indicated in patients who are fit for surgery when preoperative evidence of metastases is absent or when locally unresectable disease exists. If metastases are detected at the time of surgical exploration, bilateral stents that may have been placed preoperatively are left in situ, and cholecystectomy is performed to prevent the subsequent development of acute cholecystitis.

Locally advanced and unresectable perihilar tumors also can be managed by means of Roux-en-Y cholecysto(docho)jejunostomy with intraoperative placement of Silastic biliary catheters or a segment III or V cholangiojejunostomy.

Midduct tumors can be managed with bile duct resection and Roux-en-Y reconstruction. Distal tumors may be amenable to Whipple resection (radical pancreaticoduodenectomy; see the image below) or pylorus-preserving pancreaticoduodenectomy. Unresectable tumors may be managed by cholecystectomy, a Roux-en-Y hepaticojejunostomy, or choledochojejunostomy proximal to the tumor, and additional gastrojejunostomy and chemical sympathectomy are considered.

Reconstruction after classic radical pancreaticoduodenectomy requires 3 anastomoses: pancreaticojejunostomy, choledochojejunostomy, and gastrojejunostomy. Illustration used with permission from Carol EH Scott-Conner, MD, PhD (ed), Chassin's Operative Strategy in General Surgery, Springer-Verlag, 2002.

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Reconstruction involves anastomosis of bile ducts to a loop of jejunum (see the image below).

Cholangiogram showing completed choledochojejunostomy with widely patent anastomosis.

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Laparoscopic and robotic approaches to cholangiocarcinoma have been described.

Palliation

Surgical bypass is indicated in patients in whom placing a stent by means of either endoscopic or percutaneous techniques is impossible and in patients who are found to have unresectable disease or metastases at exploration. ^[20]

Bypass may be accomplished by performing either a Roux-en-Y hepaticojejunostomy with intraoperative placement of a Silastic transhepatic stent or a segment III bypass to the left intrahepatic ducts. In patients with distal bile duct tumors, the operation of choice is biliary enteric bypass using the upper end of the extrahepatic bile duct or gallbladder. Prophylactic gastrojejunostomy should be considered in these patients, because some of them may develop gastroduodenal obstruction prior to death. Bypass is less commonly required, because stents have improved, and even duodenal obstruction can now be effectively palliated.

Operative details

Staging of the disease is determined by evaluating the findings from computed tomography (CT) and magnetic resonance imaging (MRI). ^{[12, 14]}  Delineation of the tumor and its extent may be assessed by means of cholangiography (endoscopic and transhepatic) and magnetic resonance cholangiography. ^[16]  Vascular involvement can be identified and assessed by means of CT, MRI, and angiography, as previously described (see Imaging Studies).

Patient risk for surgery and anesthesia is determined, and cardiac and pulmonary assessment is performed.

If the clinical condition of the patient does not rule out surgical intervention, the resectability and extent of tumor involvement are assessed, and metastases are sought. Tumors in the lower and middle portions of the bile duct usually are resectable if angiography and venography exclude vascular invasion. Cancer of the hilar region tends to be less amenable to resection.

At surgery, further assessment is performed with intraoperative ultrasonography (US) and a search for lymph node involvement. Laparoscopy in patients with bile duct tumors can be useful in the identification of metastases and peritoneal disease and, hence, may assist in assessing resectability. Intraoperative US may be combined with laparoscopy.

Exploratory laparotomy is performed in patients who are fit for surgery and who are without any definite evidence of metastases or unresectability on preoperative investigation. One half of these patients are found to have evidence of intraperitoneal dissemination of the tumor or extensive involvement of the porta hepatis; therefore, they are candidates for minimal intervention, including bypass.

These patients are at risk for the development of general complications, including pneumonia, deep vein thrombosis (DVT), and infection. Routine perioperative antibiotic prophylaxis and coagulopathy are administered. Active physiotherapy, breathing exercises, and early ambulation are encouraged.

Complications specific to the procedure performed include anastomotic leakage and bile leakage. Stents may be placed across anastomoses and removed after cholangiography confirms the absence or healing of the leak. ^[37]

Postoperative complications may be general or local. General complications include the following:

• Myocardial infarction
• Pneumonia
• Surgical-site infection (SSI)
• DVT
• Pulmonary embolism (PE)

Technical complications related to the procedure performed include the following:

• Bile leakage
• Stricture
• Postoperative hemorrhage
• Pancreatic fistula – May occur after radical pancreaticoduodenectomy

Complications arising from the placement of stents include the following:

• Early - Cholangitis (7%) and perforation
• Late - Blockage and migration of stent

Patients who have evidence of positive tumor margins after resection or who develop recurrence may be candidates for adjuvant radiotherapy. ^{[26, 27]} This usually takes the form of extracorporeal therapy for positive surgical margins and intraluminal radiotherapy for positive duct margins. Chemotherapy has not been shown to be of benefit. ^[25]