Approach
General approach
It is recommended that management of a patient with cholangiocarcinoma be carried out by a multi-disciplinary team consisting of specialist surgeons, radiologists, oncologists, and palliative care consultants. Referral to a centre with expertise in hepatobiliary malignancies is desirable.[7]
Surgical resection is the only potential cure, but only a small percentage of patients are successfully treated this way. Other options include liver transplant (although only a few select patients qualify for this), chemotherapy, immunotherapy, and/or radiotherapy and palliation.
Although management for intrahepatic and extrahepatic cholangiocarcinoma does differ, patients can generally be divided into those who have resectable tumours and those who do not.
Resectable tumours
Patients who have resectable tumours have:
No evidence of metastases, regional lymph node involvement, portal vein extension, or bilateral ductal extension
Sufficient functional liver volume[7]
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 tumour
No comorbidities that prevent the patient from undergoing surgery.
The goal of surgery is to achieve negative margins (there is a 20% to 43% 5-year survival rate if this occurs).[48][49][50][51] 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 tumours.
Adjuvant therapies after radical resection have been shown in one meta-analysis to increase overall survival and disease-free survival compared to observation alone, and should be considered for eligible patients.[52] However, the authors noted a lack of head-to-head studies between adjuvant chemotherapy, radiotherapy, or chemoradiotherapy.
Intrahepatic tumours
Patients with a resectable intrahepatic cholangiocarcinoma should undergo a partial liver resection.[34][53]
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][53]
Based on evidence from one phase 3 randomised 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][53][54][55]
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][53][56]
Durvalumab is a human IgG1 monoclonal antibody that binds with high affinity and specificity to the programmed cell death ligand 1 (PD-L1).[57] It is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80.[57]
Its efficacy was evaluated in one phase 3, randomised, double-blind, placebo-controlled trial in patients with histologically confirmed unresectable, locally advanced, or metastatic biliary tract cancer, who had not previously received systemic therapy for advanced disease.[56] The trial showed that durvalumab plus chemotherapy significantly improved overall survival, compared with placebo plus chemotherapy.[56][58] Addition of durvalumab to chemotherapy did not have detrimental effects on patient-related outcomes, and the combination can be considered a tolerable treatment regimen in patients with advanced biliary tract cancer.[59]
Patients with high-risk features after resection, such as positive lymph nodes, may benefit from adjuvant radiotherapy with concurrent chemotherapy.[60]
Staging laparoscopy may be considered in conjunction with surgery if no distant metastases are found.[34][53]
Thermal ablation can be used as an alternative to surgical resection in patients with high-risk disease with recurrent or primary small single tumours <3 cm.[34][53]
Extrahepatic tumours
For patients with an extrahepatic cholangiocarcinoma, the type of surgery depends on the location of the tumour:
Tumours 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.[61]
Tumours within the mid-third should undergo major bile duct excision with lymphadenectomy. Either partial hepatectomy or pancreaticoduodenectomy may be required to achieve complete tumour clearance.
Distal extrahepatic tumours should be removed with pancreaticoduodenectomy with lymphadenectomy.
Tumours can be resected by portal vein resection when the portal vein is involved. This approach confers a marginal benefit over not undergoing resection.[62]
If the tumour 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 radiotherapy.[34][53] Treatment with adjuvant capecitabine chemotherapy for a duration of 6 months is recommended for all patients following resection.[7][32][34][53][55]
If resection margins are positive or lymph nodes are involved, the patient may be offered chemotherapy, either alone or in conjunction with radiotherapy.[34][53][55][63][64]
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][53][56]
Pre-operative portal vein embolisation 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.[65][66] It may also be considered for patients undergoing hepatectomy with a planned resection rate exceeding 50% to 60%, especially those with a jaundiced liver.
Pre-operative 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.[67][68][69][70] Generally, pre-operative 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 pre-operative biliary drainage specifically for patients with malignant extrahepatic biliary obstruction.[71][72] ESGE and ACG guidelines also recommend that pre-operative 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.[71][72] 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]
Unresectable tumours
Criteria that make a tumour unresectable are:[73]
Patient factors
Comorbidity
Coexistent hepatic cirrhosis.
Tumour-related factors
Tumour 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 tumour extension to secondary biliary radicles
Unilateral tumour 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.
Liver transplant
Results are mixed for liver transplant, but it can be supported in highly selected groups of patients with unresectable disease:
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.[7][74][75][76]
Regional lymph node involvement and the presence of distant metastasis exclude the patient from liver transplant.
Most high-volume centres performing this procedure use neoadjuvant chemotherapy or chemoradiotherapy, with the thought that it will limit recurrence from metastasis and lymphatic spread.[77]
Chemotherapy ± immunotherapy ± radiotherapy
Each patient is considered on an individual basis, but patients who are not transplant candidates are typically offered chemotherapy with gemcitabine plus a platinum compound, either alone or in combination with radiotherapy.[7][63][64] Upon progression on gemcitabine and platinum chemotherapy, the combination of FOLFOX (folinic acid, fluorouracil, and oxaliplatin) may be an appropriate second line therapy.[7][34][53][78] However, due to the limited response rate in this tumour, treatment may be discontinued if progression of disease is confirmed by imaging. A number of tumours that are downstaged may be considered resectable post chemoradiotherapy.[79]
In patients with unresectable cholangiocarcinoma, transarterial chemotherapy-based treatment may confer a survival benefit of 2-7 months compared with systemic therapy.[80]
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][53][56][81]
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.[82]
Chemotherapy may be combined with chemoradiation.[34][53]
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][53]
Palliative therapy
The alternative option for unresectable tumours is palliative care. The goal of palliation is symptom resolution and enhanced quality of life. Biliary obstruction is the most common complication when a tumour 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 morbidity and mortality.
Locoregional therapy or liver-directed therapeutic options (broadly categorised into ablation, arterially directed therapies, and radiotherapy) may be considered for liver-limited, locally-advanced unresectable intrahepatic cholangiocarcinoma.[7][34][53]
Ablation options include cryoablation, photodynamic therapy, radiofrequency ablation, microwave ablation, and irreversible electroporation.[34][53]
Arterially directed therapies include transarterial embolisation, transarterial chemoembolisation, transarterial chemoembolisation with drug-eluting beads, and yttrium 90.[34][53] 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][53]
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