1. Fuerst, Mark L.

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How big a role does liver-directed therapy play in cholangiocarcinoma? The answer may be only a small role in select patients, according to a debate between two liver experts at the 2022 Great Debates & Updates in Gastrointestinal Malignancies meeting.

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Yes, Liver-Directed Therapy

Liver-directed therapy definitely plays a role in cholangiocarcinoma, said Efrat Dotan, MD, Chief of the Division of Gastrointestinal Medical Oncology at Fox Chase Cancer Center. "The majority of these patients have liver-predominant disease and ultimately die from tumor-related liver failure.


"We can provide significant improvement in outcomes. We can decrease the risk for biliary obstruction and increase the chance to allow patients to receive more therapy, fewer procedures, and perhaps avoid the need for stents. We can decrease the development of vascular compromise; tumor thrombosis is a common problem that leads to worsening sclerosis. And we can afford them time off from systemic chemotherapy in advanced disease. Liver-directed therapy can provide a bridge to get patients off systemic therapy so they can still receive treatment targeting their tumor."


Treatment Options

Dotan outlined four treatment options, including radiation therapy, chemoembolization with TACE, radioembolization (Y90), and hepatic artery infusion (HAI) pumps. She emphasized there are no randomized clinical trials in liver-directed therapy.


Patients who undergo radiation therapy directed to the liver have a lower rate of liver failure and death from liver failure when compared to chemotherapy, according to MD Anderson Cancer Center data of all patients who received liver-directed therapy over a decade, she said. National Cancer Database records of chemotherapy versus chemotherapy plus liver-directed therapy show almost a doubling of overall survival (OS) with liver-directed therapy (16.7 months) compared to chemotherapy alone (8.3 months) (JAMA Netw Open 2019; doi:10.1001/jamanetworkopen.2019.11154).


With TACE, OS is about 13 months with liver-directed therapy, "which is much higher than we would see with chemotherapy alone," said Dotan. Those who respond to liver-directed therapy have even better outcomes, with OS of 25 months.


A systematic review and meta-analysis of Y-90 radioembolization that included 12 trials found a median OS of 15.5 months and a 28 percent partial response rate, showing "a real opportunity to change the course of these patients," she said (Eur J Surg Oncol 2015; doi: 10.1016/j.ejso.2014.09.007).


Studies of HAI pumps also show significant improvement in 1-year OS (86%) and 2-year OS (55%).


In summary, Dotan said: "Liver-directed therapy can provide palliative treatment for patients with liver-predominant cholangiocarcinoma. Prospective data is lacking, but evidence of efficacy is available from single-institution studies and meta-analyses."


Patient selection is key and will influence outcomes. "We can select treatment based on anatomic location, vascularity, patient clinical presentation, amount of disease in the liver, and extra-hepatic disease. All of these can factor in to help select patients who can benefit from liver-directed treatment," she said.


Dotan noted that disease treatment is evolving. "We are learning about subgroups and the biology of tumors that respond to liver-directed therapy."


No to Liver-Directed Therapy

Liver-directed therapy is an option, but only for a small subset of patients, said Milind Javle, MD, Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center.


"We don't know how to select these patients," Javle noted. "Using patterns of recurrence after surgery, the question is: Is cholangiocarcinoma a liver-limited or systemic disease? Most recurrences occur within 2 years in distant or regional lymph nodes. This really is a systemic disease."


A post-hoc analysis of three ABC clinical trials by a United Kingdom cancer group pooled data of 534 advanced intrahepatic cholangiocarcinoma patients, including those with biliary tract cancer. Cholangiocarcinoma comprised only 20 percent of the patients, and of those, only 30 percent had liver-limited disease (J Natl Cancer Inst 2020; "Patients with intact hepatic cholangiocarcinoma limited to the liver who are unresectable are only a small population, about 5 percent," Javle stated.


In this study, those with locally advanced intrahepatic cholangiocarcinoma had a better survival than other biliary tract cancer types. "The median OS for patients with liver-only disease was 16.7 months, considerably longer than with biliary tract cancer, about 11 months. For those who received 6 months of chemotherapy, OS was 18.9 months," said Javle. "A lot of studies Efrat highlighted included patients who had prior chemotherapy, stable disease, then got TARE (radioembolization) or radiation. Principally, this is a subset of patients with good natural history."


Subset Within a Subset

Javle noted that Dotan pointed out a subset of patients with liver-limited disease can withstand large doses of radiation. "This group with a median OS of 30 months had prior chemotherapy for at least 6 months, stable disease, then improvement with liver-directed therapy. Again, they are a subset within a subset," he said.


Toxicities, including a shrunken liver and ascites, occur with liver-directed therapy, he pointed out. "The toxicities of radiotherapy and TARE are not minor. Patients can suffer from the consequences."


Javle concluded: "Will we treat all patients with liver-directed therapy? No. We have to choose patients carefully, based on genomics, underlying history, and underlying hepatic function. Systemic therapy remains the mainstay of therapy for unresectable cholangiocarcinoma. A minority of patients qualify for liver-directed therapy. Clinical trials of consolidative radiation (IMRT/SBRT/Y90) post-chemotherapy versus standard of care will be required to conclusively answer the question, but these trials are hard to conduct."


Mark L. Fuerst is a contributing writer.