Cancers of the biliary tract are rare tumors. Although surgery for early-stage disease may offer patients a chance for a cure, most cases are inoperable at the time of diagnosis. They often only produce non-specific symptoms (e.g.: nausea, emesis, anorexia, weight loss, abdominal pain, jaundice). Gallbladder carcinomas and cholangiocarcinomas are tumors with different biology. However, due to the relative rarity of each, they are frequently combined in clinical trials. This guideline was developed to outline the management recommendations for patients with cholangiocarcinoma and adenocarcinoma of the gallbladder. For specific recommendations for the management of malignant biliary obstruction, please refer to the Malignant Biliary Obstruction clinical practice guideline

# Guideline Questions
- What are the management recommendations for adult patients with localized and potentially resectable cancers of the biliary tree or gallbladder? - What are the management recommendations for adult patients with unresectable or metastatic cancers of the biliary tree or gallbladder?

# Search Strategy
This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data. The 2023 update did not necessitate a full literature review and focused on adjuvant therapy. Recommendations were modified based on a consensus discussion at the 2023 Annual Gastrointestinal Tumour Team Meeting.

# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with cancers of the biliary tree and gallbladder. Different principles may apply to pediatric patients.

# Recommendations and Discussion

# Suggested Diagnostic Work-Up
A complete diagnostic work-up provides the multidisciplinary team with the necessary information required to define and offer the optimal care to patients with biliary cancers. The multidisciplinary team should be composed of radiologists, general and hepatobiliary surgeons, gastroenterologists and hepatologists, and oncologists. The diagnostic work-up should evaluate the liver for local and vascular extension/invasion.
Unresectable or metastatic disease represents an incurable situation for which palliative options should be considered.
An abdominal ultrasound confirms biliary duct dilation, localizes the site of obstruction, and excludes gallstones. A three-phase CT scan detects the disease, locates the level of biliary obstruction, and identifies any regional lymphadenopathy or metastatic disease.

# Proximal Cholangiocarcinoma and Gallbladder Carcinoma:
To establish resectability, the diagnostic work-up should define the proximal extent of the tumor in both lobes of the liver. This can be achieved with MR cholangiopancreatography (MRCP), but percutaneous transhepatic cholangiography (PTC) may be required. Patients should not undergo percutaneous biopsy prior to surgical assessment.
MR cholangiopancreatography is preferred over an endoscopic retrograde cholangiopancreatogram (ERCP) for proximal tumors because of the lower risk of septic complications. If MRCP is not possible, then PTC is preferred over ERCP. Non-interventional imaging studies (e.g.: MRCP) should precede interventional procedures (e.g.: PTC, ERCP, stent placement).
Endoechosonography obtains a biopsy to distinguish between a benign stricture and a cholangiocarcinoma.

# Distal Cholangiocarcinoma:
ERCP is a useful procedure in patients with distal cholangiocarcinomas. MRCP should be reserved for those patients in whom biliary drainage is not imminently required. The other staging procedures are the same as for proximal cholangiocarcinomas.

# Goals of Therapy
To render the patient free of disease, to delay or prevent recurrence, and to improve or prolong survival.
All patients without overt metastatic disease should be referred to a hepatobiliary surgeon or surgical oncologist for assessment of resectability. Adenocarcinoma of the Gallbladder:  - If a gallbladder cancer is suspected pre-operatively, an attempt at laparoscopic resection is contraindicated. Refer patients to a hepatobiliary surgeon or surgical oncologist. - For patients with Tis-1aN0M0 disease identified incidentally at pathologic review of the cholecystectomy specimen, no further therapy is necessary provided an "R0" margin (microscopically negative) is achieved . - When an "R0" (microscopically negative) margin is anticipated for T2-3N0M0 disease, a hepatobiliary surgeon or surgical oncologist may consider a partial hepatectomy with peri-portal lymph node dissection. Consider a laparoscopy to exclude previously unrecognized peritoneal metastases before proceeding to laparotomy 12. The role of radical surgery is controversial for T1b tumors. Cholangiocarcinoma:  - Assessment for resectability should precede instrumentation (e.g.: ERCP, PTC) and biopsy. - Resectability depends upon the extent of tumor within the biliary tree and hepatic parenchyma as well as the absence of invasion into the vasculature, unilateral hepatic lobar atrophy with contralateral extension of disease into the segmental bile ducts, regional lymphadenopathy, and metastatic disease.
- For tumors that involve the confluence of the bile ducts, an "R0" resection involves excision of the tumor, regional lymphadenectomy, cholecystectomy, and (often) partial hepatectomy (possibly to include the caudate lobe). - When an "R0" (microscopically negative) margin is anticipated, lesions distal to the cystic duct require a pancreaticoduodenectomy. Multidisciplinary assessment by hepatology, radiology, and hepatobiliary surgery is crucial. Patients who are poor candidates for surgical resection may be offered locoregional therapy or other approaches.
- The BILCAP trial demonstrated an improvement in overall survival (OS) in the per protocol analysis for patients randomized to 8 cycles of capecitabine versus observation after complete resection of cholangiocarcinoma or gallbladder, median OS was 53 months for Capecitabine and 36 months for Observation, HR 0.75 (95%CI 0.58-0.97; p = 0.028). In this trial, patients with ECOG PS 2, were randomized 1:1 to Capecitabine (1250 mg/m2 D1-14 every 21 days, for 8 cycles) or observation [n=447, resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. In the intent to treat population, there was a clinically relevant improvement in OS (median OS 51 months with capecitabine versus 36 months for observation, HR 0.80, CI95% 0.63-1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55 -0.92 p < 0.01) 16,17. The dose of capecitabine may be determined by institutional and regional practices.

# Unresectable or Metastatic Disease
- Offer palliative maneuvers to maintain and/or improve quality of life. Once resection has been deemed impossible, relieve biliary obstruction (if possible) by stent placement via either ERCP or PTC. In certain circumstances, radiotherapy or palliative surgery may be considered. Consider early referral to palliative care symptom management and palliative care guidelines can be found here. - Tissue diagnosis is important to confirm the histology and for potential involvement in clinical trials. Patients with adenocarcinoma of the gallbladder, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma are treated similarly, although the prognosis may vary according to the subtype. - Patients should have adequate biliary drainage, acceptable liver and kidney function, and a reasonable performance status. - Preferred: Durvalumab with Gemcitabine and Cisplatin for up to eight cycles followed by durvalumab. The double-blind phase III TOPAZ-1 trial randomized advanced biliary tract cancer patients 1:1 to Gemcitabine and Cisplatin + durvalumab or placebo. Patients had an ECOG status of 0-1 and recurred more than 6 months after curative surgery or the last dose of adjuvant therapy. The hazard ratio for death in the durvalumab arm was 0.80 (95%CI: 0.66-0.97, p=0.021). The hazard ratio for PFS was 0.75 (95%CI:0.63-0.89, p=0.001). The incidences of grade 3 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. 19 The treatment option is Health Canada approved, pCODR recommended, but at the time of publication of this guideline not funded in Alberta.

# Appendix A Staging

# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GI Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GI Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in March 2010.

# Levels of Evidence