Newly Diagnosed With Bile Duct Cancer: First Steps

Bile duct cancer is also called cholangiocarcinoma. NCI calls it extremely rare. The true incidence is unknown, because the diagnosis is hard to pin down.

The bile ducts carry bile from the liver to the small bowel. Where a tumor sits along that route decides most of what follows.

• Perihilar, about 50 percent. The hilum is where the right and left hepatic ducts leave the liver and join. Also called Klatskin tumors.
• Distal, about 40 percent. The common bile duct, down to where it meets the small intestine.
• Intrahepatic, about 10 percent. These start inside the liver.

Get your subtype named on paper. NCI also notes that many of these cancers are multifocal, meaning more than one site is involved.

Distal and perihilar tumors block the bile duct. That blockage causes the classic picture:

• Jaundice, meaning yellowing of the skin and eyes.
• Pruritus, meaning intense itching.
• Abdominal pain.
• Weight loss.
• Fever.

Intrahepatic tumors act differently. NCI calls them relatively indolent, and hard to tell apart from cancer that spread to the liver from elsewhere. That distinction matters. The treatment for each is completely different.

NCI lists four conditions seen more often in people who develop this cancer:

• Primary sclerosing cholangitis, a chronic scarring disease of the bile ducts.
• Chronic ulcerative colitis.
• Choledochal cysts, which are congenital swellings of the bile duct.
• Infection with the liver fluke Clonorchis sinensis, a parasite from raw or undercooked freshwater fish.

Most people with bile duct cancer have none of these.

NCI lists liver function tests and other blood work, abdominal ultrasound, CT, MRI, and MRCP. MRCP is magnetic resonance cholangiopancreatography, an MRI method that maps the ducts without a scope.

These tests answer two questions. How far does the tumor extend, and has it spread?

If you are fit for surgery and the tumor looks removable, surgical exploration follows. NCI notes that examining the removed specimen sets the final pathological stage.

This is the hardest sentence in the summary. Better to read it now than be surprised later. NCI states that in most patients the tumor cannot be fully removed, and is incurable.

Location drives that. Total resection is possible in 25 to 30 percent of distal bile duct tumors. The rate falls for tumors closer to the liver. Major blood vessels sit nearby, and the disease spreads within the liver.

Complete resection with negative margins is the only chance of cure. Two findings on the pathology report worsen the outlook: involved lymph nodes, and perineural invasion, which means cancer tracking along nerves.

For intrahepatic tumors specifically, NCI lists four factors linked to worse outcomes: a history of primary sclerosing cholangitis, an elevated CA 19-9 level, a periductal infiltrating growth pattern, and invasion into hepatic veins.

When cure is not possible, other measures still matter a great deal. NCI lists resection, radiation such as brachytherapy or external-beam therapy, and stenting to keep bile draining.

Two procedures relieve a blocked duct. A stent is a thin, flexible tube placed to drain built-up bile. A biliary bypass cuts the duct or gallbladder above the blockage and sews it to the duct below, or to the small intestine, making a new path around it. Either one can end the itching and jaundice, and let other treatment proceed.

The reference standard is capecitabine, a pill form of chemotherapy.

That comes from BILCAP, a UK trial of 447 patients who had a complete resection. Half got eight cycles of capecitabine tablets twice daily, at a strength calculated from body size. Each cycle ran 21 days, with the drug on days 1 through 14. The other half were observed.

Follow-up ran a median of 106 months. Median overall survival was 49.6 months with capecitabine and 36.1 months with observation. That gap was not statistically significant. The adjusted hazard ratio was 0.84, with a 95 percent confidence interval of 0.67 to 1.06. Median recurrence-free survival was 24.3 months versus 17.4 months.

A later trial, STAMP, put capecitabine against cisplatin plus gemcitabine. It enrolled 101 patients with node-positive perihilar or distal disease. Median disease-free survival was 14.3 months with cisplatin and gemcitabine, and 11.1 months with capecitabine. Median overall survival was 35.7 months in both arms.

The toxicity gap decided it. Grade 3 to 4 adverse events hit 84 percent on cisplatin and gemcitabine, most often low white counts. On capecitabine it was 16 percent, most often hand-foot syndrome. Capecitabine remains the reference standard.

Cisplatin plus gemcitabine is the reference first-line chemotherapy backbone. After the TOPAZ-1 and KEYNOTE-966 trials, adding an immune checkpoint inhibitor, either durvalumab or pembrolizumab, became standard of care.

Alternatives NCI lists include fluorouracil with liposomal irinotecan, gemcitabine with capecitabine, GEMOX, and XELOX.

For second line, the evidence is thinner. The ABC-06 trial took 162 patients who had progressed on cisplatin and gemcitabine. They got either FOLFOX plus active symptom control, or symptom control alone. Median overall survival was 6.2 months versus 5.3 months. The adjusted hazard ratio was 0.69, with P equal to .031. Survival at 12 months was 25.9 percent versus 11.4 percent.

This is the part that can change your options completely, and it requires asking.

IDH1. The ClarIDHy trial enrolled 187 patients with IDH1 variants whose disease had progressed. Ivosidenib gave a median progression-free survival of 2.7 months versus 1.4 months for placebo, with a hazard ratio of 0.37. No placebo patient was progression-free at 6 months, versus 32 percent on ivosidenib.

FGFR2. Fusions turn up in roughly 15 percent of intrahepatic cholangiocarcinomas. In the FIGHT-202 trial, 108 patients with FGFR2 fusions took pemigatinib by mouth daily for 14 days, then 7 days off, at the trial's standard strength; if you are offered it, your own prescription sets the amount. The response rate was 37 percent. Median progression-free survival was 7.0 months, and median overall survival 17.5 months. Patients without an FGFR rearrangement had a median progression-free survival of only 1.5 months. In 2020 the FDA gave accelerated approval for previously treated, unresectable or metastatic disease with an FGFR2 fusion or other rearrangement. Futibatinib is another FGFR inhibitor here.

High blood phosphate, called hyperphosphatemia, was the most common side effect at 58.5 percent. None was grade 3 or higher.

Capecitabine is broken down by the enzyme the DPYD gene makes. NCI estimates 1 to 2 percent of people carry variants that weaken it. Those with the DPYD*2A variant may have severe, life-threatening, sometimes fatal toxicity.

Based on genotype, the drug may be avoided or the dose cut by 50 percent. Testing costs under $200, but coverage varies. It can delay therapy by about 2 weeks.

• Call 911 or go to an emergency department if fever and chills come together with pain under your right ribs and you become confused, drowsy, or lightheaded. That combination points to an infected, blocked bile duct, and it can turn septic fast.
• Call your care team at once, at any hour, if your temperature reaches 100.4°F (38°C) or more at any point while you are receiving chemotherapy, gemcitabine and cisplatin included. Those drugs flatten the white cell count, which makes any fever during a cycle a medical emergency. If you cannot get through quickly, go to an emergency department rather than leaving a message for the clinic.
• Call your care team the same day if you are not on chemotherapy and your temperature reaches 100.4°F (38°C) or more with chills and upper abdominal pain, even without confusion. A blocked duct behind an infection usually has to be drained, not just treated with tablets.
• Call your care team the same day if a biliary drain or stent stops draining, leaks around the site, or slips out of place.
• Call your care team the same day if the yellow in your skin or eyes deepens, your stools turn pale, or your urine turns dark. These say the duct is obstructing again.
• Call your care team within a day or two if itching becomes unbearable or is keeping you awake, since it can be eased rather than endured.
• Call your care team within a day or two if you are on capecitabine and develop mouth ulcers, diarrhoea, or painful red peeling on your palms and soles. Severe toxicity here can reflect a weak DPYD enzyme, and doses are often held or cut.

• Is my tumor intrahepatic, perihilar, or distal?
• Am I resectable, and who decided? Has a hepatobiliary surgeon reviewed my scans?
• Has my tumor been tested for IDH1 and FGFR2, and when will results be back?
• What is my CA 19-9, and was it drawn before or after my duct was drained?
• If I need a stent, will it be plastic or metal, and how often is it changed?
• Which clinical trials fit my subtype and mutation status?

https://www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq

https://www.cancer.gov/types/liver/patient/bile-duct-treatment-pdq