Cholangiocarcinomas May Shrink When Internal Radiation Is Added to Chemotherapy

With the addition of radiotherapy to chemotherapy, nearly one-quarter of patients with inoperable intrahepatic cholangiocarcinoma experienced enough tumor shrinkage to undergo surgery.

Eligibility for surgery was meaningful for patients in the study because removal of their tumors was associated with a longer period of time without disease progression or relapse. The finding came out of a small, single-arm phase 2 study conducted in France by Dr. Julien Edeline and colleagues and published in JAMA Oncology.

Cholangiocarcinomas are tumors that arise in the bile ducts — tubes connecting the liver to the small intestine that carry bile, a fluid that helps digest fats and excrete wastes. Diagnosed in over 8,000 Americans per year, the disease has long been treated with surgery, chemotherapy and/or radiation. Cholangiocarcinomas that occur in the small bile ducts within the liver are termed “intrahepatic.” Those that arise in the bile ducts but outside the liver are “extrahepatic.”

Only 35% of patients with cholangiocarcinoma have operable disease at diagnosis, Drs. Aaron J. Scott and Rochna T. Shroff noted in a JAMA editorial response to the study.

Selective internal radiation therapy (SIRT) was used in the trial. A doctor administers it by putting tiny radioactive beads into an artery that moves blood to the liver. The beads get stuck in the tumor and the small blood vessels around it, and the radiation they emit kills the cancer cells.

The SIRT was given along with cisplatin and gemcitabine to 41 patients with inoperable intrahepatic cholangiocarcinoma who had never previously received chemotherapy or intra-arterial therapy. More than half of patients were male, and their mean age was 64. The treatment represented their first for inoperable cholangiocarcinoma, although they were eligible to participate if their cancer was a recurrence of a previously removed cholangiocarcinoma. They were treated at seven centers between November 2013 and June 2016.

Researchers conducted the study — known as the Yttrium-90 Microspheres in Cholangiocarcinoma [MISPHE] trial — because the strategy seemed promising but had not previously been evaluated. “Patients with unresectable intrahepatic cholangiocarcinoma have a poor prognosis,” they wrote. “Selective internal radiotherapy is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge.”

Patients received chemotherapy twice during each three-week cycle, undergoing a median of six cycles, and were implanted with radioactive seeds either in cycle 1 only, or in cycles 1 and 3.

The main outcome the study measured was response rate, meaning the percentage of patients whose cancer shrinks or disappears after treatment. Three months after treatment, the response rate was 39%. Among the patients, 98% achieved disease control, meaning their cancer was gone, smaller or remained stable.

Progression-free survival (PFS) — the time from the start of treatment until disease progression — was also measured in the trial. Measured at 36 months, the median PFS was 14 months. At 12 months, the PFS rate was 55%, and at 24 months it was 30%. The study also measured overall survival (OS), the length of time from the start of treatment that patients lived. Median overall survival was 22 months. At 12 months, OS was 75%; at 24 months, it was 45%.

A total of nine patients (22%) experienced enough cancer shrinkage to allow them to undergo surgery. Afterwards, eight of them (20%) had no remaining cancer cells that were visible via microscope. At a median of 46 months after surgery, there had been two disease recurrences and three deaths among those patients, but it was too soon to measure the median time from the start of treatment until disease relapse for the group.

A side effect of particular note was that 75% of patients with cirrhosis experienced some amount of liver failure, compared with 17% of patients without cirrhosis. In many of these patients, the liver failure was irreversible.

The most common mild and moderate side effects with the combination regimen included gastrointestinal tract disturbances such as nausea, numbness or tingling in the extremities, rash, anemia, decreased appetite and weakness. Serious or severe side effects included weakness and also affected the gastrointestinal tract and lowered blood counts.

The authors concluded that, while some treatment guidelines already recommend the use of SIRT in this population of patients, their findings will help support the practice.

“Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention,” the authors concluded. “This finding suggests that downstaging with SIRT combined with secondary surgical intervention has a potential for curative treatment in patients otherwise considered for palliative treatment.”

They noted that a phase 3 trial of this treatment strategy is in progress.

The authors of the editorial cautioned against choosing patients with cirrhosis for this treatment strategy, and stressed the importance of choosing patients healthy enough to withstand the potentially severe side effects of the regimen. They emphasized the need for a phase 3 trial to confirm the study’s results before the strategy is widely used.