Cholangiocarcinoma News

Controversies in Resectable Intrahepatic Cholangiocarcinoma

December 2021, Vol 2, No 4

Neoadjuvant approaches to cholangiocarcinoma (CCA) involve controversies and a lack of data. New clinical trials investigating protocols for hepatic artery infusion (HAI) pumps and liver transplant, were discussed during Session VIII, “New Frontiers in Surgery for CCA,” at the 3rd Annual CCA Summit.

Skye C. Mayo, MD, MPH, Oregon Health and Science University Knight Cancer Institute, Portland, OR, discussed the use of adjunct therapies and pushing the limits of resection. Hepatic resection for biliary tract cancer is rarely curative alone, he said.

Biologic resectability is determined by underlying tumor biology and the ability to achieve long-term survival and potential cure. Technical resectability is determined by a surgeon, based on appropriate inflow, biliary outflow, and adequate future liver remnants.

“Appreciating the nuances in these definitions helps us navigate the fine line between can and should, especially in patients with advanced disease, where the quality of life needs to be considered, since quantity is, unfortunately, often limited,” said Dr Mayo.

The multicenter OPT-IC clinical trial in patients with resectable intrahepatic CCA is designed to investigate the feasibility of using GAP in 1 cycle, an FGFR2 inhibitor (for patients with an FGFR2 fusion) in 2 cycles, followed by liver resection and adjuvant therapy. Secondary outcomes include response and recurrence-free survival.

The HELIX ICC clinical trial is designed to place an HAI pump in patients and evaluate the efficacy and safety of the FOLFIRINOX regimen. Prescreening revealed 2 patients with metastatic disease at laparoscopy who were not able to enroll in the study.

Ryan C. Fields, MD, Washington University School of Medicine, St. Louis, MO, and Alice C. Wei, MD, MSc, Memorial Sloan Kettering Cancer Center, Weill-Cornell School of Medicine, New York, NY, debated controversies related to resection in multifocal and metastatic disease.

Dr Fields presented the case for upfront resection in patients with CCA that is technically resectable. Currently, there is a lack of data for neoadjuvant approaches for technically resectable intrahepatic CCA. According to the National Comprehensive Cancer Network guidelines, hepatic resection with negative margins is the goal of surgical therapy, and the guidelines do not mention HAI pump for CCA. The only supportive data on HAI pump chemotherapy available for this patient population are from the BILCAP clinical trial in the adjuvant setting.

The morbidity associated with resection is low, providing patients with appropriate, pathology-driven treatment in the adjuvant setting. The use of HAI pumps can lead to unpredictable and significant complications that may result in the inability to attempt resection with a curative intent. Half of patients using HAI pumps do not receive intended treatment, and some patients with curable tumors can become incurable if complications occur.

“If it’s resectable, we should remove it,” said Dr Fields.

Dr Wei presented the argument supporting the role of HAI pump chemotherapy in patients with intrahepatic CCA. For patients in whom surgery would be feasible and easy, HAI should be performed first, she said. It achieves survival similar to resection in node-positive intrahepatic CCA, and it allows for easier recovery. There is currently no role for induction chemotherapy in resectable disease. Controversies exist in cases with ipsilateral metastases, multifocal disease, and regional lymphadenopathy.

For patients with unresectable intrahepatic CCA, locoregional therapy can be beneficial. This approach also presents the opportunity for converting patients from initially unresectable to resectable intrahepatic CCA with HAI pump therapy.

Subcutaneous pump implantation is required for HAI therapy, and the robotic approach is ideal in unresectable intrahepatic CCA, which promotes rapid recovery, less disruption in treatment, and earlier return to oncologic therapy. This does require a multidisciplinary surgical team and the side effects include biliary sclerosis and toxicity.

Dr Wei said that HAI-floxuridine plus systemic therapy led to improved survival in patients with intrahepatic CCA, including 176 patients who received HAI chemotherapy plus systemic therapy, 288 patients receiving systemic therapy, 250 patients undergoing resection, and 140 patients receiving chemotherapy alone. Survival with HAI-floxuridine was similar to survival in patients who had resection alone among those with node-positive disease.

Dr Wei highlighted the advantages of HAI pump chemotherapy for patients with intrahepatic CCA, including control of dominant liver disease, reduction of symptoms of mass effects, improved tolerance of systemic therapy, and the potential of downsizing to resectability status. “I hope I’ve convinced you,” said Dr Wei.

Finally, Shimul A. Shah, MD, MHCM, University of Cincinnati College of Medicine, OH, provided an update on recent transplantation clinical trial results. The first study in 1988 demonstrated dismal survival after liver transplantation in CCA. In 2014, the 5-year survival in patients with tumors <2 cm who had undergone a transplant was 80%; the addition of neoadjuvant therapy contributed to this improved survival rate.

Dr Shah proposed a new protocol for liver transplant in patients with intrahepatic CCA stage I or II—patients demonstrating stability with at least 6 months of neoadjuvant chemotherapy can be considered candidates for liver transplant if they have good performance status and meet standard liver transplant criteria.

Currently, the combination of gemcitabine plus cisplatin is the standard for induction therapy. With the evidence for biologic variability in CCA, there will likely be a variety of therapeutic options for transplantation-related neoadjuvant treatment. Dr Shah noted that they have had bad experiences with immunotherapy after transplant, so there is more to learn in this area.

“If we’ve done our job right and selected the patients well enough, then the expectation is that with transplantation you’ve taken out all of the disease, including anything that might have been micrometastatic,” Dr Fields concluded. “And so I think the argument for adjuvant therapy should be relatively low in this situation.”

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