Jennifer Knox, MD
Jennifer Knox, MD, is a professor of medicine at the University of Toronto, and a staff medical oncologist at the Princess Margaret Cancer Center. Considered Canada’s top expert in cholangiocarcinoma, she spoke at the 25th World Congress on Gastrointestinal Cancer 2023 in Barcelona, Spain. (Photo by Larry Luxner)

BARCELONA, Spain—A noted authority on cholangiocarcinoma (CCA), which accounts for 3% of all gastrointestinal tumors, says the usually fatal disease has, in recent years, “become a poster child for precision medicine.”

Jennifer Knox, MD, considered Canada’s leading expert on CCA, is a medical oncologist at the Princess Margaret Cancer Center in Toronto, Ontario. She said that in the last 2 decades, she’s seen a “remarkable change” in the availability of potential therapies for the disease.

“Cholangiocarcinoma is part of a group of tumors called biliary tract cancers—either intrahepatic or extrahepatic cholangiocarcinoma—that used to be just lumped together as one sort of bad group, kind of like pancreas cancer, without a lot of options,” she said. “There’s been very little progress until the last few years when we started to recognize that these subgroups are actually very different.”

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Dr. Knox, who has treated hundreds of CCA patients from across Canada during her career, spoke to Rare Disease Advisor on the sidelines of the 25th Annual World Congress on Gastrointestinal Cancer, held here June 28-July 1, 2023.

“You can individualize the treatment for a patient if you have studied their tumor genetics or their mutations and vulnerabilities,” Dr. Knox said. “More and more drugs are now available that target those vulnerabilities or genetic aberrations, and that leads to improved survival.”

She added: “We’ve really gone from a cancer that had almost no options and a bad prognosis to one where we’re actually starting to tease out subgroups that are living longer and longer.”

Despite Progress, 5-Year Survival Rates Still Low

Michel Ducreux, MD, PhD, a French gastroenterologist at the Gustave Roussy Cancer Campus in Paris, cochaired the Barcelona meeting, which attracted 2700 participants from 92 countries.

French oncologist Michel Ducreux, MD, PhD, heads the gastrointestinal oncology unit at Gustave Roussy Cancer Campus in Paris. He cochaired the 25th World Congress on Gastrointestinal Cancer 2023 in Barcelona, Spain. (Photo by Larry Luxner)

He said the overall survival rate for CCA patients remains under 10%, even with all the progress in recent years—specifically with regard to drugs that inhibit the fibroblast growth factor receptor 2, or FGFR2.

“What we know is that adjuvant treatment does improve survival, but not dramatically,” Dr. Ducreux said. “About 20% of cholangiocarcinoma patients have a specific FGFR pathway. If we give them an anti-FGFR drug, we can control the disease for a year or a year and a half. But we don’t cure them.” 

Despite the obvious dangers of diseases like diabetes and pancreatic cancer, he said, at least risk factors for those conditions—smoking, obesity, lack of exercise, and the like—can be controlled. Other than exposure to liver fluke in Southeast Asia, however, doctors don’t know of any controllable risk factors related to cholangiocarcinoma. It is known, though, that people with inflammatory bowel disease have a greater chance of developing primary sclerosing cholangitis, an autoimmune disease of the liver which can later turn into cholangiocarcinoma.

Entrance to the 25th World Congress on Gastrointestinal Cancer 2023 in Barcelona, Spain. (Photo by Larry Luxner)

Angela Lamarca, MD, PhD, a medical oncologist with Spain’s Fundación Jiménez Díaz University Hospital in Madrid, said 70%-80% of patients with CCA are diagnosed at advanced stages, by which time surgery is no longer possible.

“Unfortunately, we have a lot of these patients being diagnosed late when only palliative treatment options are available,” said Dr. Lamarca, noting that her clinic is starting to see younger patients, in their 40s and 50s.

“Patients who have one specific molecular alteration may have a better prognosis because we have better treatment options for them. But outside that field, for patients who do not have one specific molecular alteration, our chemotherapy has limited benefit,” she said. “Even with the combination of immunotherapy, the benefit remains limited and something that we must improve.”

Durvalumab Approval Improves Outlook for Some

Angela Lamarca, MD, PhD, is an oncologist specializing in gastrointestinal tumors at the Madrid’s Fundación Jiménez Díaz University Hospital. She spoke during the 25th World Congress on Gastrointestinal Cancer 2023 in Barcelona, Spain. (Photo by Larry Luxner)

Part of the increase in CCA cases, Dr. Lamarca said, is the simple fact that doctors are doing a better job diagnosing patients. In addition, she said, “we have better-quality registries, and we are coding our cancer patients better, which means that now we know exactly which patients have epithelial carcinoma, and which have intrahepatic cholangiocarcinoma.”

Dr. Knox, who has a master’s degree in molecular biology from the University of Toronto, has made CCA the primary focus of her career over the last 20 years. She said she was encouraged by the September 5, 2022, approval by the US Food and Drug Administration (FDA) of durvalumab (Imfinzi®). The medication, developed by AstraZeneca, is designed to be taken in combination with standard-of-care chemotherapy (gemcitabine plus cisplatin) by patients with locally advanced or metastatic CCA.

In the TOPAZ-1 phase 3 clinical trial, a quarter of patients treated with durvalumab plus chemotherapy were alive 2 years later, compared with just 10% of those who received chemotherapy alone.

“That is the first general advancement in some time, and it was a very welcome one,” she said. “That data was very quickly embraced and has moved into standard-of-care. People were really ready for that change.”

One reason for that, she said, is that patients simply cannot handle the toxicity associated with taking numerous chemotherapies at the same time.

“A lot of cholangiocarcinoma studies that tried to intensify the chemotherapy have failed,” she said. “We need chemotherapy, but 3 to 4 super-intensive drugs is probably not the way to go. The strategy is to back off from that and move more towards optimizing the treatments we have.”