Key points
- Bile duct cancer (cholangiocarcinoma) starts in the tubes that carry bile from the liver to the bowel; gallbladder cancer starts in the small pouch under the liver that stores bile [1, 6]. Both are rare, but they are more common in some parts of the world [1, 7].
- The most important sign is painless jaundice: yellowing of the skin and the whites of the eyes, with itching, dark urine and pale stools [3, 5]. Gallbladder cancer and the type inside the liver often cause no symptoms until late [2, 6].
- Most gallbladder cancers occur together with gallstones, but fewer than 1 in 100 people with gallstones develop this cancer [4, 14]. If the cancer is found very early, after a routine gallstone operation, it is almost always cured [14].
- The only cure is complete surgery in a specialist centre, followed by 6 months of capecitabine tablets [1, 15, 22]. About 2 in 10 patients can have surgery when they are diagnosed [23].
- In advanced disease, chemotherapy together with immunotherapy is the first treatment, and it has helped people live longer [20, 28, 30].
- Ask for genetic testing of the tumour from the start: in some patients it finds a change that a targeted drug can act on [20, 21].
What is bile duct and gallbladder cancer (cholangiocarcinoma)?
Every day the liver makes a fluid called bile, which helps digest fat. Bile leaves the liver through a network of tubes called the bile ducts and drains into the small bowel [5]. The gallbladder is a pear-shaped organ under the liver that stores bile [6].
Cancer that starts in the lining of the bile ducts is called cholangiocarcinoma, and cancer that starts in the wall of the gallbladder is gallbladder cancer; together they are called biliary tract cancers [1]. Gallbladder cancer is the most common of them [4].
These cancers are different from liver cancer, which starts in the liver cells themselves, and they are treated differently [2]. They are rare in most high-income countries, but they are a major problem in some regions, and the type inside the liver is becoming more common worldwide [1]. In 2024 about 126,000 people worldwide were diagnosed with gallbladder cancer and about 92,000 died of it; nearly three quarters of these patients were in Asia [7].
Types: inside the liver, at the liver hilum, in the lower bile duct and in the gallbladder
| Type | Where it starts | How common it is | Main sign |
|---|---|---|---|
| Intrahepatic (inside the liver) | Bile ducts inside the liver [5] | 1 to 2 in every 10 cholangiocarcinomas [2] | Often no symptoms or abdominal pain; in about 1 in 4 or 5 patients it is found by chance on a scan [2, 3] |
| Perihilar (at the liver hilum) | Where the right and left ducts leave the liver and join [5] | The most common type; 5 to 6 in every 10 cholangiocarcinomas [2] | Painless jaundice [3] |
| Distal (lower bile duct) | Where the duct from the liver and the duct from the gallbladder join to form the common bile duct, down to the bowel [5] | 2 to 3 in every 10 cholangiocarcinomas [2] | Painless jaundice [3] |
| Gallbladder | The wall of the gallbladder [6] | The most common cancer of the biliary tract [4] | Usually no symptoms in the early stages; sometimes found after gallstone surgery [4, 6] |
Where the tumour starts matters, because the type of surgery and the genetic tests needed depend on it [1, 20].
Symptoms of bile duct and gallbladder cancer
These cancers usually cause no symptoms in the early stages [2]. When a tumour narrows or blocks a bile duct, bile cannot reach the bowel and builds up in the blood. The main signs are [5, 3]:
- jaundice (yellow skin and whites of the eyes), which in cancer at the liver hilum or in the lower bile duct is often painless [3]
- itchy skin
- dark urine
- pale or clay-coloured stools
- abdominal pain
- fever
- nausea and vomiting
- unexplained weight loss
Gallbladder cancer may show itself with pain in the upper abdomen, bloating, fever or a lump in the abdomen [6]. Because the gallbladder is hidden behind the liver and its symptoms are like those of more common illnesses, it is often found late [6]. Cancer inside the liver is also mostly found because of abdominal pain or by chance on an ultrasound or CT scan, and jaundice is less common and comes later [2, 3].
Jaundice has other causes too, such as gallstones or liver disease, but it should always be checked promptly [6]. Jaundice is also a sign of pancreatic cancer; read more: Symptoms of pancreatic cancer and jaundice
When should I see a doctor?
If you have any of these, see a doctor within the next few days:
- yellowing of the skin or the whites of the eyes, even without pain [3, 5]
- dark urine or pale stools lasting several days, or new, unexplained itching all over the body [5]
- unexplained weight loss or pain in the upper abdomen that does not go away [5, 6]
- a gallbladder polyp on an ultrasound; talk to your doctor about follow-up or surgery [11]
Go to an emergency department the same day or call your local emergency number if you have jaundice with fever and shivering, or if you have a biliary stent (tube) and develop fever, shivering or jaundice again; the bile duct may be blocked or infected, and antibiotics and reopening of the duct may be needed [32, 47].
Risk factors and prevention
In most patients no clear cause is found; known risk factors are present in only about 1 in 5 patients with bile duct cancer [2]. What most of them have in common is long-lasting inflammation of the bile ducts or gallbladder and bile that does not drain properly [2, 4].
Gallbladder cancer
- Gallstones: the most important risk factor; 7 to 9 in every 10 gallbladder cancers occur with gallstones [4]. But fewer than 1 in 100 people with gallstones develop this cancer [4, 14].
- Porcelain gallbladder (calcification of the gallbladder wall), which usually occurs with gallstones and is linked to gallbladder cancer [12]
- Gallbladder polyps, especially 1 cm or larger [4, 11]
- an abnormal junction of the pancreatic and bile ducts present from birth [4]
- older age, female sex, obesity, diabetes, and being a carrier of the typhoid bacterium (Salmonella Typhi) [4]
Bile duct cancer (cholangiocarcinoma)
- Bile duct cysts present from birth (choledochal cysts): the largest increase in risk [8]
- Primary sclerosing cholangitis: a disease in which inflammation and scarring narrow and block the bile ducts [10]. Over 20 years, about 1 in 5 patients develop a cancer of the liver, bile ducts or pancreas, most often cholangiocarcinoma [3]. Long-standing ulcerative colitis (a type of inflammatory bowel disease) also increases the risk [10].
- stones in the bile ducts and gallbladder [8]
- Liver flukes (Clonorchis and Opisthorchis), parasites caught by eating raw or undercooked freshwater fish in East and Southeast Asia (for example Thailand, Laos, Korea and China); these parasites are known to cause cancer [3, 9]
- Hepatitis B and C and liver cirrhosis [8]
- inflammatory bowel disease, chronic pancreatitis, type 2 diabetes, fatty liver, alcohol and smoking, with a smaller increase in risk [2]
For prevention: hepatitis B vaccination, treatment of hepatitis B and C and of fatty liver, avoiding alcohol and smoking, and a healthy weight help [2]. Where liver flukes are common, do not eat raw or undercooked freshwater fish; the infection is treated with the drug praziquantel [3]. Read more: Can cancer be prevented?
For people at average risk, no. Having gallstones on its own is not a reason for great worry, because only very few of these people get cancer; surgery also has its own risks, so decide about an operation for gallstones without symptoms together with a surgeon [4].
- Gallbladder polyps: a polyp of 1 cm or larger is a reason to remove the gallbladder; so is a 6–9 mm polyp if the person is over 60, has primary sclerosing cholangitis, is of Asian ethnicity, or the polyp is flat without a stalk (sessile) [11]. A 6–9 mm polyp without these factors, or a polyp of 5 mm or smaller with one of them, is followed with ultrasound at 6 months, 1 year and 2 years; a polyp of 5 mm or smaller without risk factors needs no follow-up [11].
- Primary sclerosing cholangitis: some centres do a yearly MRI scan of the bile ducts (MRCP) and a CA 19-9 blood test, but not all guidelines recommend this yet; agree a follow-up plan with your liver specialist [3].
Diagnosis and staging
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How bile duct and gallbladder cancer is diagnosed
- 1
Blood tests
Liver tests (bilirubin and enzymes) show whether bile is flowing [6]. The marker CA 19-9 is also measured, but it cannot make the diagnosis on its own: about 3 in 10 patients have a normal level, and it can also rise when a bile duct is simply blocked [17, 3]. Read more: What is a tumour marker?
- 2
- 3
CT and MRI with MRCP
- 4
ERCP and brush sampling
A tube with a camera (endoscope) is passed through the mouth into the small bowel, and the doctor injects dye to see the bile ducts; a small brush can take cells from the narrowed area, and a stent can be placed at the same time to relieve jaundice [3, 6]. The brush sample misses the cancer in more than half of patients, so it sometimes has to be repeated or another method used [3].
- 5
Endoscopic ultrasound (EUS)
Ultrasound from inside the stomach and bowel gives a detailed picture of the bile duct and lymph nodes, and a needle sample can be taken with it [3]. When a tumour at the liver hilum or in the lower bile duct can be removed by surgery, a needle biopsy through the skin is avoided [20]. Worried about a biopsy? Read: Does a biopsy spread cancer?
- 6
Needle biopsy
If surgery is not possible, an adequate needle sample must be taken before drug treatment starts, both for the diagnosis and for genetic testing [19].
- 7
Genetic testing of the tumour
| Situation | What it means | Main treatment |
|---|---|---|
| Operable | The tumour can be removed completely by surgery [16] | Surgery, then capecitabine tablets [22] |
| Locally advanced (inoperable) | The tumour has reached the main blood vessels of the liver or nearby tissues and cannot be removed completely [16] | Chemotherapy with immunotherapy; if the tumour shrinks well, sometimes surgery or local treatment [20] |
| Spread (metastatic) | It has reached distant places such as the lungs, bones or distant lymph nodes [16] | Chemotherapy with immunotherapy, then targeted drugs based on the tumour's genes [20, 21] |
| Recurrent | It has come back after treatment [16] | As for spread disease [20] |
The exact stage (0 to 4) is set separately for each type; but for choosing treatment, the most important question is whether the tumour can be removed completely [16, 15].
For physicians
Imaging: according to ESMO 2023, MRI is the reference test for assessing the local extent of perihilar and distal cholangiocarcinoma and for detecting liver metastases, and CT of the chest, abdomen and pelvis for assessing lymph nodes and metastases [III, A] [19]. The sensitivity and specificity of MRCP in distinguishing benign from malignant hilar obstruction are 87% and 85% [3]. CT or MRCP should be done before biliary drainage [2].
Tissue sampling: the sensitivity of brush cytology for pCCA was 43% in one meta-analysis; FISH is more sensitive than cytology (65% vs 19% in one series) with similar specificity; EUS–FNA is more sensitive for dCCA than for pCCA (81% vs 59%), and EUS sampling of pCCA is controversial because of the risk of tumour seeding [3]. In resectable perihilar or distal CCA, percutaneous biopsy should be avoided [20]. Before any non-surgical treatment, a core biopsy is needed for pathological diagnosis and molecular profiling [III, A] [19].
CA 19-9: in a meta-analysis (31 studies, 1264 patients), pooled sensitivity was 0.72 and specificity 0.84 (area under the curve 0.83), with lower sensitivity in European patients [17]. Its specificity is low and it also rises with biliary obstruction, but levels above 1000 U/mL are concerning for metastatic disease [3].
Molecular profiling: ESMO recommends molecular profiling when first-line systemic therapy starts in locally advanced or metastatic disease [I, A]; the panel should include at least IDH1, FGFR2, BRAF, HER2, NTRK, RET, BRCA1/2 and PALB2 [20]. ASCO 2026 recommends broad tissue DNA and RNA sequencing at diagnosis at any stage, and plasma liquid biopsy only when tissue is unavailable [21]. HER2 alterations (overexpression or amplification) are found in about 5–10% of cases, more often in extrahepatic CCA and gallbladder cancer, and IHC is best scored with the gastric cancer criteria [20]; FGFR2 rearrangements are found in about 6–12% [41] and IDH1 mutations in about 13% [42] of intrahepatic cholangiocarcinomas, BRAF mutations in about 5% of biliary tract tumours [37], and NTRK fusions in less than 0.1% [20].
Gallbladder cancer found after gallstone surgery
Sometimes the gallbladder is removed because of stones or inflammation and the pathologist finds cancer in it. This happens in about 1 in every 300 keyhole (laparoscopic) gallbladder operations, and about half of all gallbladder cancers are found this way [13].
This news is frightening, but these cancers are usually found at earlier stages and may be curable [4]. If the cancer is only in the inner layer (mucosa) of the gallbladder, the operation itself is usually enough and almost all these patients are cured [14]. If the cancer has grown deeper, a second operation is usually needed: removal of a small part of the liver next to where the gallbladder was, and of the nearby lymph nodes [4, 20]; in more than half of these patients some cancer cells are still left [14].
If you are told after an operation that cancer was found, take the pathology report to a specialist liver and bile duct surgery centre; a CT or MRI scan is needed before deciding on a second operation [4].
Chance of cure and survival in gallbladder and bile duct cancer
The chance of cure depends above all on whether the tumour can be removed completely by surgery [15, 6]. Most patients are diagnosed when the disease is already advanced [1]. The figures below are averages for large groups of patients treated in past years and cannot predict what will happen to any one person; newer treatments have improved results [29].
| Situation | Outcome |
|---|---|
| Stage 1 gallbladder cancer found and removed during gallstone surgery | Almost all are alive after 5 years [14] |
| After complete surgery for cancer at the liver hilum or in the lower bile duct | 2 to 5 in 10 are alive after 5 years [15] |
| All patients with gallbladder cancer, all stages | About 3 in 10 are alive after 5 years [44] |
| All patients with cancer of the bile ducts outside the liver, all stages | About 2 in 10 are alive after 5 years [44] |
| All patients with cancer of the bile ducts inside the liver, all stages | About 1 in 10 is alive after 5 years [44] |
| Advanced disease treated with chemotherapy plus immunotherapy | About 1 in 7 was alive after 3 years; roughly twice as many as with chemotherapy alone [29] |
The "all stages" figures come from the South Korean cancer registry (2006 to 2017), where survival is compared with people of the same age without cancer [44].
For physicians
In the Korean national cancer registry (97,676 patients, 2006 to 2017), 5-year relative survival was 48.5% for ampulla of Vater cancer, 28.5% for gallbladder cancer, 19.9% for extrahepatic bile duct cancer and 10.8% for intrahepatic bile duct cancer, and it improved over time except for intrahepatic disease; 52.8% of intrahepatic and 39.6% of gallbladder patients received no active anticancer treatment [44]. After aggressive resection of perihilar and distal tumours, 5-year survival of 20–50% has been reported, and complete resection is possible in 25–30% of distal lesions and less often in proximal ones [15]. Stage I gallbladder cancer found incidentally and resected has 5-year survival of nearly 100%; estimated 5-year survival of pathological T2 to T4 tumours has been reported as 42.5% if N0 and 31% if N+ [14]. In advanced disease, 36-month survival with durvalumab plus gemcitabine–cisplatin was 14.6% vs 6.9% [29].
Cholangiocarcinoma and gallbladder cancer treatment by stage
Pillars of treatment
Surgery
Opening a blocked duct (stent)
Capecitabine tablets after surgery
Chemotherapy with immunotherapy
The first treatment for advanced or spread disease: gemcitabine and cisplatin together with pembrolizumab or durvalumab [20, 21].
Targeted therapy
Radiotherapy and local treatments
Palliative care
Control of pain, itching, nausea and nutrition, and emotional support, from the start and alongside cancer treatment [45].
Treatment at each stage in plain words
- 1
Operable tumour
Surgery in a specialist centre [1], then 6 months of capecitabine tablets [22, 23]. If the surgical margin is involved in cancer of the bile ducts outside the liver or in gallbladder cancer, chemoradiotherapy may also be offered [22].
- 2
- 3
Locally advanced (inoperable)
Chemotherapy with immunotherapy; if the tumour shrinks well, surgery or a local treatment is reconsidered [20].
- 4
- 5
- 6
At every stage
Palliative care to control symptoms and support patients and families, from the start [45].
Surgery: the only cure
The type of surgery depends on where the tumour is [2, 58]:
- Inside the liver: removal of part of the liver with the nearby lymph nodes [2]
- At the liver hilum: usually removal of half of the liver or more, with the bile duct and lymph nodes [2]
- Lower bile duct: the Whipple operation, which removes the head of the pancreas, the gallbladder, part of the stomach and small bowel, and the bile duct [58]
- Gallbladder: removal of the gallbladder with a small part of the liver and the nearby lymph nodes [4]
Before surgery for a tumour at the liver hilum, the bile duct of the part of the liver that will remain is sometimes drained first so the liver works better after the operation, and the volume of the remaining liver is measured [2, 20]. Only about 2 in 10 patients can have surgery when they are diagnosed [23]; if you are told surgery is not possible, it is worth asking a specialist liver and bile duct team as well [1].
A liver transplant has been done only in a very particular group of patients with cancer at the liver hilum who cannot have ordinary surgery, in a few specialist centres and with chemoradiotherapy before the transplant [2]; the European guideline does not consider it standard treatment and recommends it within clinical studies [19].
Opening a blocked duct: stents and bile drainage
When a tumour blocks the bile duct, opening it relieves jaundice and itching, and it is often needed before surgery or chemotherapy as well [18, 32]. The methods are [18, 58]:
- Stent by endoscopy (ERCP): the first choice for most patients; a plastic or metal tube is placed in the narrowing [18].
- Drainage guided by endoscopic ultrasound: if ERCP is not possible or does not work [18].
- Drainage through the skin: a tube placed into the liver through the side of the body under imaging guidance, when endoscopic methods do not work [18, 58].
- Surgical bypass of the bile duct: in particular cases [58].
For a tumour at the liver hilum, usually more than half of the liver needs to be drained for the jaundice to clear well [18]. A stent may block after a while and need replacing [18]; if fever, shivering, jaundice or itching comes back, contact your care team the same day [32].
After surgery: capecitabine tablets
Even after complete surgery, this cancer comes back in many patients [25]. To lower that risk, 6 months of capecitabine tablets are recommended [22, 19]. In a large study, patients who took capecitabine lived longer and their cancer came back later; this difference did not reach a definite result in the main analysis, but it was also seen in further analyses and after about 9 years of follow-up, and guidelines regard capecitabine as standard treatment [23, 24, 22].
The tablets are taken twice a day for 2 weeks, followed by 1 week off, and this cycle is repeated 8 times [23]. The most common severe side effect was redness and pain of the palms and soles, which happened in about 1 in 5 patients; diarrhoea and tiredness were also seen [23]. Before starting, a genetic test for lack of the enzyme DPD is recommended, because complete lack of it causes dangerous side effects [48].
In a recent study, the combination of two drip drugs, gemcitabine and cisplatin, after surgery was not better than capecitabine and had slightly more serious side effects; so capecitabine remains the standard treatment [25].
Advanced disease: chemotherapy with immunotherapy
When surgery is not possible or the disease has spread, the first treatment is two chemotherapy drugs, gemcitabine and cisplatin, together with an immunotherapy drug: pembrolizumab or durvalumab [20, 21]. The drugs are given by drip on days 1 and 8 of each 3-week cycle; cisplatin is given for up to 8 cycles, and immunotherapy continues after that [28, 30].
These two chemotherapy drugs have been the basic treatment for years, and in a large study they helped people live longer than gemcitabine alone [27]. Adding immunotherapy helped people live longer still in two large studies [28, 30]: in one of them, the number of patients alive after 2 years more than doubled [28], and the benefit was still there after 3 years [29, 31]. No test yet shows which immunotherapy drug is better for whom, and the two drugs give similar results [20].
Common side effects: tiredness, nausea, constipation, loss of appetite, abdominal pain, skin rash, fever and low blood counts [47]. Immunotherapy sometimes harms the bowel, liver, lungs or hormone glands [46]. Read more: Immunotherapy side effects and Low blood counts and preventing infection
If the disease grows after this treatment and there is no targetable genetic change, FOLFOX chemotherapy (oxaliplatin, fluorouracil and leucovorin) every 2 weeks is offered [20, 21, 32]. In one study, a year later more than twice as many patients were alive with FOLFOX as in the group that had symptom treatment only [32]. If the body is weak, lighter chemotherapy or symptom treatment only is also a sound choice [20, 21].
Targeted drugs based on the tumour's genes
In advanced disease, genetic testing of the tumour finds, in some patients, a change that has its own drug; these changes are more common in cancer inside the liver [20]. These drugs are usually used after the first treatment [20, 21]:
- DNA repair defect (MSI-H or dMMR): pembrolizumab immunotherapy on its own, if you have not had immunotherapy before [20, 21, 33].
- HER2-positive (more common in gallbladder cancer and cancer of the bile ducts outside the liver): trastuzumab deruxtecan or zanidatamab, both given by drip [20]. In studies, the tumour shrank in about half of patients whose HER2 was very strong (3+) [20, 36].
- BRAF V600E mutation: two tablets, dabrafenib and trametinib, taken together; the tumour shrank in about half of patients [37].
- FGFR2 gene change (mostly in cancer inside the liver): pemigatinib or futibatinib tablets; the tumour shrank in about 4 in 10 patients [39, 40]. A rise in blood phosphate, dry eyes and hair loss are common, and regular eye checks are needed [39, 53, 54].
- IDH1 mutation (mostly in cancer inside the liver): ivosidenib tablets, which slowed the growth of the disease and were well tolerated [42, 43].
- Rare NTRK or RET changes: tablets made for that change [20].
If genetic testing has not been done, ask your doctor whether it is possible on your sample. Read more: What is targeted cancer therapy?
Palliative care and symptom control
Palliative care means controlling symptoms and supporting patients and families, and it is not only for the last days; guidelines recommend starting it early in advanced disease, alongside cancer treatment [45]. In these cancers the most important parts are:
- keeping the bile duct open for jaundice and itching, and treating duct infection early [18, 32]
- pain control with regular painkillers: Cancer pain
- nutrition and preventing weight loss: Nutrition during treatment
- control of nausea and tiredness, and emotional support: Nausea and vomiting and Fatigue
What should I do after the diagnosis?
Frequently asked questions
What is cholangiocarcinoma?
What is the difference between bile duct cancer and liver cancer?
Do gallstones cause cancer?
Can gallbladder cancer be cured?
If it is found early, yes. When stage 1 cancer is found and removed during gallstone surgery, almost all patients are cured [14]. At later stages, complete surgery in a specialist centre still offers a chance of cure [14, 4]. If the disease has spread, a cure is usually not possible, but chemotherapy with immunotherapy and targeted drugs help people live longer and reduce symptoms [20, 28].
Does jaundice mean I have cancer?
Not necessarily; jaundice has other causes, and the symptoms of these cancers are like those of more common illnesses [6]. But painless jaundice, especially with weight loss, dark urine or pale stools, should be checked promptly, because it is the main sign of cancer at the liver hilum and in the lower bile duct [3].
Does a high CA 19-9 mean cancer?
What is a biliary stent?
Is a liver transplant a treatment for this cancer?
Evidence and recent advances (for doctors)
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Surgery and adjuvant therapy
Complete resection with negative margins is the only chance of cure [15]. In pCCA, preoperative drainage of the future liver remnant is done to prevent post-hepatectomy liver failure; staging laparoscopy before laparotomy detects occult metastases (in about 15%), and 90-day mortality of up to 10% has been reported in experienced European centres [2]. In iCCA, most patients need an (extended) hemihepatectomy with lymphadenectomy of at least 6 regional nodes [2]. In incidental gallbladder cancer of stage T1b or higher, completion surgery is recommended [20]; at re-resection of T2 disease, residual disease was found in 57% (nodal involvement 31% and liver 10%), and the need for re-resection in T1b is debated [14].
BILCAP (447 patients with cholangiocarcinoma or muscle-invasive gallbladder cancer after macroscopically complete resection): capecitabine 1250 mg/m² twice daily on days 1–14 every 21 days for 8 cycles vs observation. In the ITT analysis, median overall survival was 51.1 vs 36.4 months (adjusted HR 0.81; 95% CI 0.63–1.04; P=0.097); in the prespecified sensitivity analysis HR 0.71 (0.55–0.92; P=0.010) and in the per-protocol analysis HR 0.75 (0.58–0.97; P=0.028); median recurrence-free survival 24.4 vs 17.5 months. Grade 3 toxicity occurred in 44%, most commonly hand-foot syndrome (20%) [23]. With a median follow-up of 106 months, median overall survival was 49.6 vs 36.1 months (adjusted HR 0.84; 0.67–1.06; sensitivity analysis 0.74; 0.59–0.94) [24].
ACTICCA-1 (591 patients; 24 weeks of gemcitabine–cisplatin vs capecitabine; median follow-up 4.8 years): median disease-free survival 25.7 vs 17.9 months (log-rank P=0.097). Because the proportional hazards assumption was violated, RMST was analysed: on average 2.6 months more disease-free survival over the first 3 years (95% CI 0.6–4.68; P=0.011), without a significant improvement in overall survival (RMST P=0.076; median 58.1 vs 48.2 months); serious adverse events 130 vs 113. The authors concluded that the combination should not be the adjuvant standard of care [25].
Guidelines: ASCO recommends 6 months of adjuvant capecitabine for resected patients (the dose may follow institutional or regional practice) and considers that chemoradiotherapy may be offered, with shared decision-making, in extrahepatic CCA or gallbladder cancer with an R1 margin [22]; ESMO also recommends adjuvant capecitabine [II, A] [19]. In SWOG S0809 (phase 2; 79 patients with extrahepatic CCA or gallbladder cancer and pT2–4, N+ or positive margins), gemcitabine–capecitabine followed by chemoradiotherapy with capecitabine gave a 2-year survival of 65% (R0 67% and R1 60%) and a median overall survival of 35 months; grade 3 and 4 adverse events in 52% and 11% [26].
Liver transplantation: in a multicentre retrospective study at 12 US centres (216 patients with early-stage unresectable pCCA treated with neoadjuvant chemoradiotherapy followed by transplantation), 5-year disease-free survival was 65% and intention-to-treat 5-year survival 53% [2]; ESMO does not consider transplantation standard treatment for pCCA and encourages participation in trials [III, D] [19].
Advanced disease: first line
ABC-02 (410 patients): cisplatin 25 mg/m² followed by gemcitabine 1000 mg/m² on days 1 and 8 every 3 weeks for 8 cycles, vs gemcitabine alone, increased median overall survival from 8.1 to 11.7 months (HR 0.64; 0.52–0.80; P<0.001), with median progression-free survival 8.0 vs 5.0 months [27].
TOPAZ-1 (685 patients): adding durvalumab to gemcitabine–cisplatin (up to 8 cycles, then durvalumab monotherapy) improved overall survival (HR 0.80; 0.66–0.97; P=0.021); 24-month survival was 24.9% vs 10.4%, progression-free survival HR 0.75 and objective response 26.7% vs 18.7%, with similar grade 3 or 4 adverse events (75.7% vs 77.8%) [28]. In the 3-year update (median follow-up 41.3 months), median overall survival was 12.9 vs 11.3 months (HR 0.74; 0.63–0.87) and 36-month survival 14.6% vs 6.9% [29].
KEYNOTE-966 (1069 patients): pembrolizumab 200 mg every 3 weeks (up to 35 cycles) with gemcitabine (no maximum duration) and cisplatin (up to 8 cycles) gave a median overall survival of 12.7 vs 10.9 months (HR 0.83; 0.72–0.95; one-sided P=0.0034); grade 3–4 treatment-related adverse events in 70% vs 69% [30]. With a median follow-up of 36.6 months, the HR was 0.86 (0.75–0.98) and 36-month survival 13% vs 11% [31].
Guidelines: ESMO 2025 recommends both cisplatin–gemcitabine–durvalumab and cisplatin–gemcitabine–pembrolizumab in the first line [I, A] and finds no clinical, biochemical or molecular marker, nor any difference in efficacy or toxicity, favouring one over the other; with poor performance status, gemcitabine monotherapy can be considered [20]. Triplet regimens (mFOLFIRINOX in PRODIGE 38 AMEBICA and cisplatin–gemcitabine–nab-paclitaxel in SWOG 1815) were not superior to cisplatin–gemcitabine and were more toxic; adding S-1 in the Japanese MITSUBA trial improved response and survival [20]. ASCO 2026 recommends an immune checkpoint inhibitor with chemotherapy for pMMR/MSS disease and also lists pembrolizumab monotherapy as an option for dMMR/MSI-H disease [21]. Regimen page: Gemcitabine–cisplatin with durvalumab
| Trial | Comparison | Patients | Median overall survival | Overall survival HR | Longer follow-up |
|---|---|---|---|---|---|
| ABC-02 [27] | Gemcitabine–cisplatin vs gemcitabine | 410 | 11.7 vs 8.1 months | 0.64 | — |
| KEYNOTE-966 [30, 31] | Pembrolizumab or placebo + gemcitabine–cisplatin | 1069 | 12.7 vs 10.9 months | 0.83 (final); 0.86 (3 years) | 36-month survival 13% vs 11% |
| TOPAZ-1 [28, 29] | Durvalumab or placebo + gemcitabine–cisplatin | 685 | 12.9 vs 11.3 months (3-year update) | 0.80 (primary); 0.74 (3 years) | 36-month survival 14.6% vs 6.9% |
There is no direct comparison between TOPAZ-1 and KEYNOTE-966; in TOPAZ-1 chemotherapy was limited to 8 cycles, while in KEYNOTE-966 gemcitabine continued without a maximum duration [28, 30].
After first line: chemotherapy and targeted therapy
ABC-06 (162 patients progressing after cisplatin–gemcitabine, ECOG 0–1): active symptom control plus FOLFOX vs active symptom control alone gave a median overall survival of 6.2 vs 5.3 months (adjusted HR 0.69; 0.50–0.97; P=0.031); 6-month survival 50.6% vs 35.5% and 12-month 25.9% vs 11.4%; grade 3–5 adverse events in 69% vs 52%, including 3 chemotherapy-related deaths [32]. ESMO 2023 considers FOLFOX the second-line standard [I, A] [19], and ASCO 2026 recommends FOLFOX with symptom control, or symptom control alone, for patients without a targetable marker [21].
FGFR2: in FIGHT-202, pemigatinib 13.5 mg daily (2 weeks on, 1 week off) gave an objective response of 35.5% in 107 patients with FGFR2 fusions or rearrangements in the first report, and the most common adverse event was hyperphosphataemia (60%) [38]; in the final analysis (median follow-up 45.4 months) in 108 patients with FGFR2 fusions or rearrangements, objective response was 37.0%, median duration of response 9.1 months, median progression-free survival 7.0 months and median overall survival 17.5 months; the most common adverse events were hyperphosphataemia (58.5%), alopecia (49.7%) and diarrhoea (47.6%) [39]. In FOENIX-CCA2 (103 patients with iCCA), futibatinib 20 mg daily, continuously, gave an objective response of 42%, median duration of response 9.7 months, progression-free survival 9.0 months and overall survival 21.7 months; treatment-related grade 3 hyperphosphataemia in 30% [40]. In the phase 3 FIGHT-302 (first line; 167 patients; closed early because the standard of care changed), pemigatinib vs gemcitabine–cisplatin gave a median progression-free survival of 8.3 vs 6.8 months (HR 0.58; 0.39–0.87; nominal P=0.0078) with response 47% vs 15%, but median overall survival was similar (24.4 vs 25.0 months) [41]. ESMO 2025 recommends futibatinib and pemigatinib after one or more lines of therapy [III, A; ESCAT I-B] [20].
IDH1: in ClarIDHy (185 patients, randomised 2:1), ivosidenib 500 mg daily improved progression-free survival (median 2.7 vs 1.4 months; HR 0.37; 0.25–0.54) [42]; in the final analysis (187 patients; 43 crossed over from placebo to ivosidenib), median overall survival was 10.3 vs 7.5 months (HR 0.79; 0.56–1.12; one-sided P=0.09), and after adjustment for crossover 5.1 months with placebo (HR 0.49; 0.34–0.70); the most common grade 3 or worse adverse event was ascites (9% vs 7%) [43]. ESMO 2023 recommends it after at least one line of therapy [I, A] [19].
HER2: in HERIZON-BTC-01 (phase 2b; 80 patients with HER2 amplification and IHC 2+ or 3+), zanidatamab 20 mg/kg every 2 weeks gave a confirmed objective response of 41.3% [35]; in the final analysis (follow-up 33.4 months), median duration of response was 14.9 months and median overall survival 15.5 months; with IHC 3+, response was 51.6% and overall survival 18.1 months, but with IHC 2+ there was only one response (5.6%) and overall survival was 5.2 months [36]. DESTINY-PanTumor02 tested trastuzumab deruxtecan 5.4 mg/kg every 3 weeks in HER2-expressing solid tumours (response in all patients with centrally confirmed IHC 3+ 61.3%) [34]; in biliary tract patients with centrally confirmed IHC 3+, a response of 56.3% (investigator-assessed) and a median progression-free survival of 4.6 months were reported [20]. ESMO 2025: trastuzumab deruxtecan "should be considered" and zanidatamab "is recommended" [III, A; ESCAT I-C] [20].
BRAF V600E, MSI-H and others: in ROAR (43 patients with BRAF V600E mutation), dabrafenib 150 mg twice daily and trametinib 2 mg daily gave a response of 51% (investigator) and 47% (independent reviewer); the most common grade 3 or worse adverse event was increased GGT (12%) and the most common treatment-related serious adverse event was pyrexia (19%) [37]. In KEYNOTE-158 (233 patients with non-colorectal MSI-H/dMMR tumours, cholangiocarcinoma being among the most common), pembrolizumab gave an objective response of 34.3% [33]; ESMO recommends anti-PD-1 therapy for MSI-H/dMMR in patients who did not receive immunotherapy in the first line [20]. NTRK fusions (larotrectinib, entrectinib, repotrectinib) and RET fusions (selpercatinib) have been studied only in basket trials [III, A; ESCAT I-C] [20]. ASCO 2026 lists second-line options for dMMR/MSI-H, IDH1, FGFR2, BRAF V600E, HER2 overexpression and RET, NTRK1/2/3 and NRG1 fusions [21].
| Genetic alteration | Frequency | Drug | Key evidence | Guideline and approval |
|---|---|---|---|---|
| MSI-H/dMMR | — | Pembrolizumab monotherapy (if no immunotherapy in the first line) | KEYNOTE-158: response 34.3% in non-colorectal tumours [33] | ESMO 2025 and ASCO 2026 [20, 21] |
| HER2 (overexpression or amplification) | About 5–10%; more often in extrahepatic CCA and gallbladder cancer [20] | Trastuzumab deruxtecan; zanidatamab | IHC 3+: response 56.3% with trastuzumab deruxtecan [20]; 51.6% with zanidatamab and overall survival 18.1 months [36] | ESMO 2025 [III, A; ESCAT I-C]; FDA accelerated approval in IHC 3+ [20, 49, 50] |
| BRAF V600E | About 5% [37] | Dabrafenib + trametinib | ROAR: response 51% (investigator) and 47% (independent reviewer) [37] | FDA for previously treated solid tumours, accelerated approval [51] |
| FGFR2 fusion or rearrangement | About 6–12% of iCCA [41] | Pemigatinib; futibatinib | Response 37.0% and 42%; median overall survival 17.5 and 21.7 months [39, 40] | ESMO 2025 [III, A; ESCAT I-B]; FDA accelerated approval [20, 53, 54] |
| IDH1 mutation | About 13% of iCCA [42] | Ivosidenib | Progression-free survival HR 0.37; overall survival HR 0.79 (0.49 adjusted for crossover) [42, 43] | ESMO 2023 [I, A]; FDA [19, 55] |
| NTRK or RET fusion | NTRK less than 0.1% [20] | Larotrectinib, entrectinib, repotrectinib; selpercatinib | Basket trials only [20] | ESMO 2025 [III, A; ESCAT I-C] [20] |
The evidence for most of these drugs, except ivosidenib, comes from single-arm or basket phase 2 trials [20].
- First-line pemigatinib (FIGHT-302) improved progression-free survival, but overall survival was similar and the trial closed early; the FDA label indication remains previously treated cholangiocarcinoma [41, 53].
- FDA approvals of pemigatinib, futibatinib, zanidatamab, trastuzumab deruxtecan (HER2 IHC 3+ solid tumours) and dabrafenib–trametinib (BRAF V600E solid tumours) are accelerated approvals based on objective response and duration of response, and continued approval depends on confirmatory trials [49, 50, 51, 53, 54].
- Zanidatamab with standard first-line treatment in HER2-positive disease is being studied in the phase 3 HERIZON-BTC-302 trial [36].
- Triplet chemotherapy in the first line and gemcitabine–cisplatin in the adjuvant setting have not replaced the current standards [20, 25].
Treatment regimens and doses (for doctors)
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Treatment regimens and doses: index14 regimens
Cisplatin: adequate hydration and monitoring of renal function and electrolytes; dose reduction or an alternative treatment in renal impairment; neuropathy and ototoxicity are cumulative; strong prevention of nausea and vomiting [56].
Gemcitabine–cisplatin with immunotherapy: in TOPAZ-1, serious adverse events occurred in 47%, most commonly cholangitis (7%) [47]; check fever and rising bilirubin for cholangitis or stent occlusion before attributing them to an immune-related event. No dose reductions are recommended for checkpoint inhibitors; withhold or discontinue permanently according to the severity of the event [46, 47].
Capecitabine: test for DPYD variants before starting (unless immediate treatment is needed) and avoid in complete DPD deficiency; reduce the dose by 25% with creatinine clearance 30–50 mL/min, and no dose is established below 30; risk of bleeding with vitamin K antagonists [48].
Oxaliplatin: consider a dose reduction for persistent grade 2 sensory neuropathy and discontinuation for grade 3; reduce the dose with creatinine clearance below 30 mL/min [57].
FGFR inhibitors (pemigatinib, futibatinib): a full eye examination with OCT before starting, every 2 months for the first 6 months, then every 3 months, and urgently for visual symptoms (retinal pigment epithelial detachment); monitor phosphate and use phosphate-lowering therapy as in the label [53, 54].
Ivosidenib: ECG and electrolytes for QTc prolongation; with a strong CYP3A4 inhibitor, 250 mg; discontinue permanently in Guillain–Barré syndrome [55].
Zanidatamab and trastuzumab deruxtecan: LVEF before starting and periodically, and premedication before every zanidatamab dose [50]; with trastuzumab deruxtecan, permanent discontinuation for grade 2 or higher interstitial lung disease or pneumonitis [49].
After surgery (adjuvant treatment)
Adjuvant capecitabine (BILCAP)
Cholangiocarcinoma (intrahepatic, perihilar or distal) or muscle-invasive gallbladder cancer after macroscopically complete resection; ECOG below 2; start within 16 weeks of surgeryCycle length: Every 21 days
Cholangiocarcinoma (intrahepatic, perihilar or distal) or muscle-invasive gallbladder cancer after macroscopically complete resection; ECOG below 2; start within 16 weeks of surgery
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Capecitabine | 1250 mg/m² twice daily | Oral | Days 1–14 |
Dose source: BILCAP [23]. ASCO: 6 months; the dose may follow institutional or regional practice [22]. Grade 3 toxicity in 44% (hand-foot syndrome 20%, diarrhoea 8%, fatigue 8%) [23]. DPYD testing before starting; reduce the dose by 25% with creatinine clearance 30–50 and no dose established below 30; tablets swallowed whole with water within 30 minutes after a meal [48]. In ACTICCA-1, adjuvant gemcitabine–cisplatin was not significantly better than capecitabine [25].
Evidence: BILCAP (2019)
Gemcitabine + capecitabine, then chemoradiotherapy with capecitabine (SWOG S0809)
Extrahepatic cholangiocarcinoma or gallbladder cancer after radical resection with pT2–4, N+ or positive margins; M0; ECOG 0–1; ASCO: may be offered for R1 margins with shared decision-making
Extrahepatic cholangiocarcinoma or gallbladder cancer after radical resection with pT2–4, N+ or positive margins; M0; ECOG 0–1; ASCO: may be offered for R1 margins with shared decision-making
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Phase 1: 4 cycles | |||
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 every 21 days |
| Capecitabine | 1500 mg/m² per day | Oral | Days 1–14 every 21 days |
| Phase 2: chemoradiotherapy | |||
| Capecitabine | 1330 mg/m² per day | Oral | During radiotherapy |
| Radiotherapy | 45 Gy to regional lymphatics; 54–59.4 Gy to the tumour bed | External beam | |
Dose source: SWOG S0809 abstract [26]; the division of the daily capecitabine dose and the details of the radiotherapy plan are in the full text. 86% completed treatment; grade 3 and 4 adverse events in 52% and 11% (neutropenia 44%, hand-foot syndrome 11%, diarrhoea 8%); one death from gastrointestinal haemorrhage [26]. ASCO: chemoradiotherapy for R1 after weighing benefit and harm [22].
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Advanced disease: first line
Gemcitabine + cisplatin + pembrolizumab (KEYNOTE-966)
Locally advanced unresectable or metastatic biliary tract cancer without previous treatment for advanced disease; ECOG 0–1Cycle length: Every 21 days
Locally advanced unresectable or metastatic biliary tract cancer without previous treatment for advanced disease; ECOG 0–1
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg every 3 weeks (or 400 mg every 6 weeks); 30-minute infusion | IV | Day 1, before chemotherapy |
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 every 3 weeks |
| Cisplatin | 25 mg/m² | IV | Days 1 and 8 every 3 weeks |
Dose source: the paper and the FDA label [30, 46]. Grade 3–4 treatment-related adverse events in 70% vs 69%; treatment-related deaths 2% vs 1% [30].
Evidence: KEYNOTE-966 (2023)
Gemcitabine + cisplatin + durvalumab (TOPAZ-1)
Locally advanced or metastatic biliary tract cancer without previous treatment, or recurrence
Locally advanced or metastatic biliary tract cancer without previous treatment, or recurrence
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Combination phase: up to 8 cycles | |||
| Durvalumab | 1500 mg (body weight below 30 kg: 20 mg/kg) | IV | Day 1 every 3 weeks |
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 |
| Cisplatin | 25 mg/m² | IV | Days 1 and 8 |
| Maintenance | |||
| Durvalumab | 1500 mg (body weight below 30 kg: 20 mg/kg) | IV | Every 4 weeks |
Dose source: FDA label and the paper [47, 28]. Grade 3 or 4 adverse events 75.7% vs 77.8% [28]. Regimen page: Gemcitabine–cisplatin with durvalumab
Evidence: TOPAZ-1 (2022)
Gemcitabine + cisplatin (ABC-02)
First line in patients who are not candidates for an immune checkpoint inhibitor; ECOG 0–1Cycle length: Every 21 days
First line in patients who are not candidates for an immune checkpoint inhibitor; ECOG 0–1
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cisplatin | 25 mg/m² | IV | Days 1 and 8, before gemcitabine |
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 |
Dose source: ABC-02 [27]. More neutropenia than with gemcitabine alone, with a similar rate of neutropenia-related infection [27]. ESMO 2023 considers cisplatin–gemcitabine standard for performance status 0–1 [I, A] [19]; ASCO lists separate options for patients who are not candidates for immunotherapy [21].
Evidence: ABC-02 (2010)
Gemcitabine monotherapy
Poor performance status or significant debility with a risk of platinum toxicity (ESMO)Cycle length: Every 28 days
Poor performance status or significant debility with a risk of platinum toxicity (ESMO)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Gemcitabine | 1000 mg/m² | IV | Days 1, 8 and 15 |
Evidence: ABC-02 (2010)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
After progression on first line: chemotherapy and targeted therapy
FOLFOX after cisplatin–gemcitabine (ABC-06)
Radiological progression after cisplatin–gemcitabine; ECOG 0–1; adequate biliary drainage; start within 6 weeks of progressionCycle length: Every 14 days
Radiological progression after cisplatin–gemcitabine; ECOG 0–1; adequate biliary drainage; start within 6 weeks of progression
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Oxaliplatin | 85 mg/m² (2-hour infusion) | IV | Day 1 |
| Leucovorin | L-folinic acid 175 mg (or folinic acid 350 mg), 2-hour infusion concurrently with oxaliplatin | IV | Day 1 |
| Fluorouracil | 400 mg/m² (bolus over 5–10 minutes) | IV | Day 1 |
| Fluorouracil | 2400 mg/m² (46-hour continuous infusion) | IV | Days 1–2 |
Dose source: ABC-06 [32]. From cycle 2, neutrophils at least 1.5×10⁹/L and platelets at least 75×10⁹/L. With creatinine clearance 30–60, oxaliplatin 65 mg/m²; over 70 years, fluorouracil may start at 80% of the dose at the physician's discretion; body surface area capped at 2.2 m²; two dose-reduction levels (20% and 50%) [32]. Regimen page: FOLFOX
Evidence: ABC-06 (2021)
Pembrolizumab monotherapy (MSI-H/dMMR)
Unresectable or metastatic MSI-H or dMMR solid tumour, previously treated (FDA label); ESMO: in patients who did not receive immunotherapy in the first lineCycle length: Every 3 or 6 weeks
Unresectable or metastatic MSI-H or dMMR solid tumour, previously treated (FDA label); ESMO: in patients who did not receive immunotherapy in the first line
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg every 3 weeks or 400 mg every 6 weeks; 30-minute infusion | IV | Day 1 |
Trastuzumab deruxtecan (HER2 IHC 3+)
Unresectable or metastatic HER2-positive (IHC 3+) solid tumour after previous systemic treatment, with no satisfactory alternative (FDA, accelerated approval)Cycle length: Every 21 days
Unresectable or metastatic HER2-positive (IHC 3+) solid tumour after previous systemic treatment, with no satisfactory alternative (FDA, accelerated approval)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan | 5.4 mg/kg (first infusion over 90 minutes; then 30 minutes if tolerated) | IV | Day 1 |
Dose source: FDA label [49]. Do not substitute for trastuzumab or trastuzumab emtansine; antiemetic premedication; interstitial lung disease or pneumonitis of grade 2 or higher → permanent discontinuation [49]. DESTINY-PanTumor02 dose: 5.4 mg/kg every 3 weeks [34].
Evidence: DESTINY-PanTumor02 (2024)
Zanidatamab (HER2 IHC 3+)
Unresectable or metastatic, previously treated, HER2-positive (IHC 3+) biliary tract cancer (FDA, accelerated approval)Cycle length: Every 14 days
Unresectable or metastatic, previously treated, HER2-positive (IHC 3+) biliary tract cancer (FDA, accelerated approval)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Zanidatamab | 20 mg/kg (first infusion 120, second 90 and then 60 minutes if tolerated) | IV | Every 2 weeks |
Dose source: FDA label [50]. Premedication 30–60 minutes before each dose: paracetamol (acetaminophen), an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone). Dose reduction: 15 mg/kg every 2 weeks; intolerance → permanent discontinuation. LVEF before starting and periodically; an absolute decrease of 16 percentage points or more, or LVEF below 50% with a decrease of 10 points or more → withhold for at least 4 weeks [50]. In HERIZON-BTC-01, treatment-related grade 3 adverse events occurred in 18% (diarrhoea 5%, decreased ejection fraction 3%) [35].
Evidence: HERIZON-BTC-01 (2023)
Dabrafenib + trametinib (BRAF V600E)
Unresectable or metastatic solid tumour with a BRAF V600E mutation that has progressed after previous treatment, with no satisfactory alternative (FDA, accelerated approval)Cycle length: Continuous
Unresectable or metastatic solid tumour with a BRAF V600E mutation that has progressed after previous treatment, with no satisfactory alternative (FDA, accelerated approval)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Dabrafenib | 150 mg twice daily | Oral | Daily, at least 1 hour before or 2 hours after a meal |
| Trametinib | 2 mg once daily | Oral | Daily |
Pemigatinib (FGFR2)
Previously treated, locally advanced unresectable or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement (FDA, accelerated approval)
Previously treated, locally advanced unresectable or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement (FDA, accelerated approval)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pemigatinib | 13.5 mg once daily | Oral | Days 1–14 |
Dose source: FDA label [53]. Dose reductions: 9 mg, then 4.5 mg (days 1–14); intolerance of 4.5 mg → discontinue. Severe renal or hepatic impairment: 9 mg. Phosphate above 7 to 10 mg/dL: phosphate-lowering therapy and weekly monitoring, and withhold if not below 7 within 2 weeks. Avoid strong and moderate CYP3A inducers; with a strong or moderate inhibitor, 13.5 to 9 mg and 9 to 4.5 mg. Eye examination with OCT before starting, every 2 months for the first 6 months, then every 3 months [53]. In first-line FIGHT-302, continuous dosing at 13.5 mg was used; this use is not in the label [41, 53].
Futibatinib (FGFR2)
Previously treated, unresectable or metastatic intrahepatic cholangiocarcinoma with an FGFR2 fusion or rearrangement (FDA, accelerated approval)Cycle length: Continuous
Previously treated, unresectable or metastatic intrahepatic cholangiocarcinoma with an FGFR2 fusion or rearrangement (FDA, accelerated approval)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Futibatinib | 20 mg once daily | Oral | Daily, continuously |
Dose source: FDA label [54]. Dose reductions: 16 mg, then 12 mg; intolerance of 12 mg → discontinue. Eye examination with OCT before starting, every 2 months for the first 6 months, then every 3 months, and urgently for visual symptoms; monitor phosphate [54]. In FOENIX-CCA2, treatment-related grade 3 hyperphosphataemia occurred in 30% [40].
Evidence: FOENIX-CCA2 (2023)
Ivosidenib (IDH1)
Previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation
Previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Ivosidenib | 500 mg once daily | Oral | Daily; not with a high-fat meal |
Dose source: FDA label [55] and ClarIDHy [42]. With a strong CYP3A4 inhibitor: 250 mg. QTc above 480 to 500 ms: withhold and resume at 500 mg once 480 or less; above 500: withhold and resume at 250 mg. In cholangiocarcinoma, grade 3 toxicity: withhold until grade 1, then 500 mg; grade 4: 250 mg. Guillain–Barré syndrome: permanent discontinuation [55].
Evidence: ClarIDHy (2020)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Scientific evidence
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Key studies
10 itemsPembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial
Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer
Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study
Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial
Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial
Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study
Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma
Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer
Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study
Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study
Related drugs
Treatment regimens (physicians)
References
58 referencesShow all references, 12 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
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- 9A review of human carcinogens--Part B: biological agents
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- 13Incidence and Preoperative Predictor Factors of Gallbladder Cancer Before Laparoscopic Cholecystectomy: a Systematic Review
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- 34Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial
- 35Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study
- 36
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- 38Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study
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- 52MEKINIST (TRAMETINIB) — Prescribing Information
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- 56Cisplatin injection: Prescribing Information
- 57OXALIPLATIN injection, for intravenous use — Prescribing Information
- 58
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