Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

resectable disease

1st line – partial liver resection

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ACUTE
|
resectable disease
|
intrahepatic tumor
1st line – 

partial liver resection

Patients who have resectable tumors have: no evidence of metastases, regional lymph node involvement, portal vein extension, or bilateral ductal extension, and sufficient functional liver volume; imaging indicating the possibility that the surgeon will be able to resect with clear margins and be able to clear at least one side of the biliary tree of tumor; no comorbidities that prevent them from undergoing surgery.[7]

The goal of surgery is to achieve negative margins (there is a 20% to 43% 5-year survival rate if this occurs).[50][51][52][53]​​ Positive predictors of survival are negative margins, absence of lymph node involvement, solitary lesions, and lack of vascular invasion. Hilar involvement lowers medial survival to 12 to 24 months, from 18 to 30 months for more distal tumors. Staging laparoscopy may be considered in conjunction with surgery if no distant metastases are found.[34][48] In patients with high-risk disease with recurrent or primary small single tumors <3 cm, thermal ablation can be used as an alternative to surgical resection.[34][48]​​​

Consider – preoperative portal vein embolization or biliary drainage

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ACUTE
|
resectable disease
|
intrahepatic tumor
Consider – 

preoperative portal vein embolization or biliary drainage

Treatment recommended for SOME patients in selected patient group

Preoperative portal vein embolization may contribute to reduction of complications and surgery-related mortality, and may be considered for patients undergoing right hepatectomy or larger resection, such as trisegmentectomy.[66][67] It may also be considered for patients undergoing hepatectomy with a planned resection rate exceeding 50% to 60%, especially those with a jaundiced liver.

Preoperative biliary drainage has been used to reduce morbidity and mortality in patients with obstructive jaundice. However, systematic reviews and meta-analyses have found no evidence of clinical benefit, and it remains a controversial procedure.[68][69][70][71]​​​ Generally, preoperative biliary drainage is not required for patients with a resectable lesion when surgery can be performed within a few days of diagnosis. European Society of Gastrointestinal Endoscopy (ESGE) and the American College of Gastroenterology (ACG) guidelines recommend against routine preoperative biliary drainage specifically for patients with malignant extrahepatic biliary obstruction.[72][73]​ ESGE and ACG guidelines also recommend that preoperative biliary drainage should be reserved for patients with cholangitis, severe symptomatic jaundice (e.g., intense pruritus), delayed surgery, or for before neoadjuvant chemotherapy in patients with jaundice.[72][73]​​ However, American Association for the Study of Liver Diseases (AASLD) guidance notes that in patients undergoing resection for perihilar or distal cholangiocarcinoma, preoperative biliary drainage of the remnant liver is recommended if biliary obstruction is present.[7]

Consider – chemotherapy ± immunotherapy ± radiation

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ACUTE
|
resectable disease
|
intrahepatic tumor
Consider – 

chemotherapy ± immunotherapy ± radiation

Treatment recommended for SOME patients in selected patient group

If resection is successful and there is no local residual disease, patients can be followed up by observation, enrolled in a clinical trial, or offered chemotherapy.[34][48]​​​​ Based on evidence from one phase 3 randomized controlled trial, the American Society of Clinical Oncology, the US National Comprehensive Cancer Network (NCCN), and the American Association for the Study of Liver Diseases (AASLD), recommend adjuvant capecitabine chemotherapy for a duration of 6 months for all patients following resection.[7][34]​​​[48][55][56]​​​​​

Furthermore, NCCN recommends treatment with durvalumab, in combination with gemcitabine and cisplatin, in patients who develop recurrent disease more than 6 months after surgery with curative intent and more than 6 months after completion of adjuvant therapy.[34][48][57]​​​​​ Patients with high-risk features after resection, such as positive lymph nodes, may benefit from adjuvant radiation therapy with concurrent chemotherapy.[61]

See local specialist protocol for dosing guidelines of chemotherapeutic agents.

1st line – surgical excision

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ACUTE
|
resectable disease
|
extrahepatic tumor
1st line – 

surgical excision

Patients who have resectable tumors have: no evidence of metastases, regional lymph node involvement, portal vein extension, or bilateral ductal extension, and sufficient functional liver volume; ​imaging indicating the possibility that the surgeon will be able to resect with clear margins and be able to clear at least one side of the biliary tree of tumor; no comorbidities that prevent them from undergoing surgery.[7]

For patients with an extrahepatic cholangiocarcinoma, the type of surgery depends on the location of the tumor:

Tumors that are within the proximal third of the extrahepatic biliary tree should be removed by hilar resection, partial hepatectomy combined with caudate lobe resection, and lymphadenectomy.[62]

Tumors within the mid-third should undergo major bile duct excision with lymphadenectomy. Either partial hepatectomy or pancreaticoduodenectomy may be required to achieve complete tumor clearance.

Distal extrahepatic tumors should be removed with pancreaticoduodenectomy with lymphadenectomy.

Tumors can be resected by portal vein resection when the portal vein is involved. This approach confers a marginal benefit over not undergoing resection.[63]

Consider – preoperative portal vein embolization or biliary drainage

Back
ACUTE
|
resectable disease
|
extrahepatic tumor
Consider – 

preoperative portal vein embolization or biliary drainage

Treatment recommended for SOME patients in selected patient group

Preoperative portal vein embolization may contribute to reduction of complications and surgery-related mortality, and may be considered for patients undergoing right hepatectomy or larger resection, such as trisegmentectomy.[66][67] It may also be considered for patients undergoing hepatectomy with a planned resection rate exceeding 50% to 60%, especially those with a jaundiced liver.

Preoperative biliary drainage has been used to reduce morbidity and mortality in patients with obstructive jaundice. However, systematic reviews and meta-analyses have found no evidence of clinical benefit, and it remains a controversial procedure.[68][69][70][71]​​ Generally, preoperative biliary drainage is not required for patients with a resectable lesion when surgery can be performed within a few days of diagnosis. European Society of Gastrointestinal Endoscopy (ESGE) and the American College of Gastroenterology (ACG) guidelines recommend against routine preoperative biliary drainage specifically for patients with malignant extrahepatic biliary obstruction.[72][73]​ ESGE and ACG guidelines also recommend that preoperative biliary drainage should be reserved for patients with cholangitis, severe symptomatic jaundice (e.g., intense pruritus), delayed surgery, or for before neoadjuvant chemotherapy in patients with jaundice.[72][73]​​ However, AASLD guidance notes that in patients undergoing resection for perihilar or distal cholangiocarcinoma, preoperative biliary drainage of the remnant liver is recommended if biliary obstruction is present.[7]

Consider – chemotherapy ± immunotherapy ± radiation

Back
ACUTE
|
resectable disease
|
extrahepatic tumor
Consider – 

chemotherapy ± immunotherapy ± radiation

Treatment recommended for SOME patients in selected patient group

If the tumor is resected successfully and there are no positive lymph nodes, the patient can be followed up by observation, enrolled in a clinical trial, or undergo chemotherapy with/without radiation.[34][48]​​​​ Treatment with adjuvant capecitabine chemotherapy for a duration of 6 months is recommended for all patients following resection.[7][34][48][55]​​​​

If resection margins are positive or lymph nodes are involved, the patient may be offered chemotherapy, either alone or in combination with radiation therapy.[34][48][55][64][65]​​​​

Patients who develop recurrent disease more than 6 months after surgery with curative intent and more than 6 months after completion of adjuvant therapy may be offered immunotherapy in conjunction with chemotherapy (durvalumab, in combination with gemcitabine and cisplatin).[34][48][57]​​​​

See local specialist protocol for dosing guidelines of chemotherapeutic agents.

unresectable disease

1st line – liver transplant

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ACUTE
|
unresectable disease
|
liver transplant candidate
1st line – 

liver transplant

Most cholangiocarcinomas present as unresectable. Criteria that make a tumor unresectable are:[74]

Patient factors: comorbidity; coexistent hepatic cirrhosis.

Tumor-related factors: tumor extension to secondary biliary radicles; encasement or occlusion of main portal vein proximal to the bifurcation; atrophy of one hepatic lobe with contralateral portal vein branch encasement or occlusion; atrophy of one hepatic lobe with contralateral tumor extension to secondary biliary radicles; unilateral tumor extension to secondary biliary radicles with contralateral portal vein branch encasement or occlusion; histologically proven metastasis to regional lymph nodes; lung, liver, or peritoneal metastasis.

Results are mixed concerning liver transplant, but it can be supported in highly selected groups of patients with unresectable disease. They include patients with locally advanced disease (typically hilar) involving the surrounding large vessels (portal vein, hepatic artery) and extension to secondary biliary radicles. Patients with underlying biliary inflammation (e.g., primary sclerosing cholangitis) or hepatic dysfunction precluding surgery may also qualify for liver transplant.[7][75][76][77] Regional lymph node involvement and the presence of distant metastasis exclude the patient from transplant.

Plus – chemotherapy ± radiation

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ACUTE
|
unresectable disease
|
liver transplant candidate
Plus – 

chemotherapy ± radiation

Treatment recommended for ALL patients in selected patient group

Most high-volume centers performing liver transplant use neoadjuvant chemotherapy or chemoradiation, with the thought that it will limit recurrence from metastasis and lymphatic spread.[78]

1st line – chemotherapy ± immunotherapy ± radiation

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ACUTE
|
unresectable disease
|
liver transplant non-candidate
1st line – 

chemotherapy ± immunotherapy ± radiation

Most cholangiocarcinomas present as unresectable. Criteria that make a tumor unresectable are:[74]

Patient factors: comorbidity; coexistent hepatic cirrhosis.

Tumor-related factors: tumor extension to secondary biliary radicles; encasement or occlusion of main portal vein proximal to the bifurcation; atrophy of one hepatic lobe with contralateral portal vein branch encasement or occlusion; atrophy of one hepatic lobe with contralateral tumor extension to secondary biliary radicles; unilateral tumor extension to secondary biliary radicles with contralateral portal vein branch encasement or occlusion; histologically proven metastasis to regional lymph nodes; lung, liver, or peritoneal metastasis.

Within the group of patients who have unresectable disease, only a small number qualify for a liver transplant. They include patients with locally advanced disease involving the surrounding large vessels (portal vein, hepatic artery) and extension to secondary biliary radicles. Patients with underlying biliary inflammation (e.g., primary sclerosing cholangitis) or hepatic dysfunction precluding surgery may also qualify for liver transplant.[7][75][76][77]

Each patient is considered on an individual basis. Patients who do not meet the above criteria are typically offered chemotherapy with gemcitabine plus a platinum compound, either alone or in combination with radiation therapy.[7]​​[64][65]​​​ Upon progression on gemcitabine and platinum chemotherapy, the combination of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) may be an appropriate second line therapy.[7][34][48][79]​​​​​ However, due to the limited response rate in this tumor, treatment may be discontinued if progression of disease is confirmed by imaging. A number of tumors that are downstaged may be considered resectable post chemoradiation.[80]​ In patients with unresectable cholangiocarcinoma, transarterial chemotherapy-based treatment may confer a survival benefit of 2-7 months compared with systemic therapy.[81]

NCCN guidelines recommend that durvalumab or pembrolizumab, in combination with gemcitabine and cisplatin, should be considered for the primary treatment of patients with unresectable and metastatic biliary tract cancers.[34]​​​​[48][57][82]​​ The National Institute for Health and Care Excellence (NICE) in the UK recommends durvalumab in combination with gemcitabine and cisplatin as an option for the treatment of patients with unresectable, locally advanced, or metastatic biliary tract cancers.[83]​​​​​​

Chemotherapy may be combined with chemoradiation.[34][48]​​​​​

Next generation sequencing should be considered to try to identify relevant targetable genetic alterations in the patient to further guide second-line treatment options.[7]​ Patients should be considered for inclusion in clinical trials.[34][48]​​​​

See local specialist protocol for dosing guidelines of chemotherapeutic agents.

1st line – palliative therapy

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ACUTE
|
unresectable disease
|
liver transplant non-candidate
1st line – 

palliative therapy

The alternative option for unresectable tumors is palliative care. The goal of palliation is symptom resolution and enhanced quality of life. Biliary obstruction is the most common complication when a tumor is unresectable or a patient is not suitable for surgery. Options for relieving biliary obstruction include surgical bypass, endoscopic biliary stenting, and percutaneous biliary drainage. Surgical biliary bypass is associated with the most procedural-associated morbidity and mortality.

Locoregional therapy or liver-directed therapeutic options (broadly categorized into ablation, arterially directed therapies, and radiation therapy) may be considered for liver-limited, locally-advanced unresectable intrahepatic cholangiocarcinoma.[7][34][48] Ablation options include cryoablation, photodynamic therapy, radiofrequency ablation, microwave ablation, and irreversible electroporation.[34][48] Arterially directed therapies include transarterial embolization, transarterial chemoembolization, transarterial chemoembolization with drug-eluting beads, and yttrium 90.[34][48] Patients with limited extrahepatic disease (hilar lymph node ≤3 cm or ≤5 lung nodules each ≤1 cm) may be considered for arterially directed therapy in combination with systemic therapy.[34][48]​​​​​

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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