The Lynx Group
Cholangiocarcinoma News

The Future of Chemotherapy in Cholangiocarcinoma

December 2021, Vol 2, No 4

Personalization of therapy and novel regimens are needed to improve options for patients with cholangiocarcinoma (CCA). This was the focus of Session III, “The Future of Chemotherapy in CCA: How Do We Build on the Chemo Backbone?”

Angela Lamarca, MD, PhD, MSc, Christie NHS Foundation Trust, University of Manchester, UK, reviewed novel chemotherapy options for CCA, at the 3rd Annual CCA Summit.

Precision medicine is not for all patients with CCA, Dr Lamarca said, because quality tissue samples are not always available, and targetable alterations occur in approximately 40% of patients with CCA. Therefore, new approaches are needed for chemotherapy.

Triple-drug chemotherapy in the first-line setting, for example, is beneficial, with longer survival seen after treatment with cisplatin, gemcitabine, and nab-paclitaxel. However, as the AMEBICA study demonstrated, the modified FOLFIRINOX regimen did not lead to a benefit of 6-month progression-free survival compared with only cisplatin plus gemcitabine.

The benefit from second-line chemotherapy remains modest, and improved treatment options are urgently needed. Results from the NIFTY study demonstrated improved progression-free survival with liposomal irinotecan plus 5-fluorouracil (5-FU) compared with 5-FU alone. However, this regimen’s superiority to the FOLFOX regimen cannot be confirmed, and these regimens should be seen as complementary rather than as competitors.

“We definitely need better treatments and new agents for our patients,” said Dr Lamarca.

Juan W. Valle, MBChB, MSc, also of the Christie NHS Foundation Trust at the University of Manchester, discussed novel methods of chemotherapy delivery. “Dual blood flow of the liver allows the delivery of chemotherapy directly into the liver, thereby enlarging the therapeutic window,” he noted.

Systemic therapies for localized, inoperable disease include hepatic arterial embolization, chemosaturation, stereotactic body radiotherapy, hepatic arterial infusion, radioembolization, and proton beam therapy.

“There has been an increasing interest in locoregional therapy,” Dr Valle said, but it has not been thoroughly evaluated. “As a community, this is the direction we want to explore, and maybe we can move toward delivering practice-changing clinical studies going forward.”

He discussed a systematic review and meta-analysis of locoregional therapies for patients with intrahepatic CCA. The recommendations, however, are weak, with a low level of evidence.

Novel delivery of chemotherapy can be completed with antibody–drug conjugates. A phase 2 clinical trial was designed to investigate trastuzumab deruxtecan in HER2-expressing tumors, including a cohort of patients with biliary tract cancer.

Ardaman Shergill, MD, of the University of Chicago Medicine, IL, discussed novel sequencing of therapies, with chemotherapy as the backbone.

As of now, first-line therapy includes gemcitabine and cisplatin, based on the ABC-02 study. Second-line options include FOLFOX, based on the ABC-06 study, and liposomal irinotecan plus 5-FU plus leucovorin based on the NIFTY study. “Is it possible to improve upon this backbone?” Dr Shergill asked.

MEK inhibitor has been combined with cisplatin and gemcitabine in the first-line setting. Careful patient selection is needed, because some patients derive benefit. A study of MEK inhibitor monotherapy was stopped early because of a lack of response.

“We are really in the era of discovery for cholangiocarcinoma treatment,” said Dr Shergill. “Sequencing and personalizing available [chemotherapy] options is key for our patients.”

Dr Shergill explained that targeted therapy is being moved up front, with chemotherapy as the backbone in addition to therapy intensification in the first-line setting.

“We are also trying to see if we can identify patients who benefit from second-line treatment and personalizing their therapy in the second-line setting, and how we can sequence even third-line treatments,” said Dr Shergill.

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