Cholangiocarcinoma News

Key Topics in Cholangiocarcinoma Presented at the Americas Hepato-Pancreato-Biliary Association Annual Meeting

September/October 2021, Vol 2, No 3

Interest among oncology specialists in cholangiocarcinoma (CCA) is on the rise, according to Flavio G. Rocha, MD, FACP, Director of Research, Digestive Disease Institute, and Associate Medical Director, Cancer Institute, University of Washington, Virginia Mason Medical Center, Seattle. At the CCA Summit, Dr Rocha reviewed hot topics in CCA that were presented at the 2021 Americas Hepato-Pancreato-Biliary Association (AHPBA) meeting.

“The surgical oncologists, hepatobiliary surgeons, and transplant surgeons who treat this disease are very much interested in the application of multimodal therapy and predictors of response, recurrence, and survival,” said Dr Rocha. “We should be working together with our medical and radiation oncology colleagues to improve outcomes across all disease stages.”

In This Article

Neoadjuvant Chemotherapy and Survival in High-Risk Intrahepatic CCA

The outcomes related to neoadjuvant chemotherapy in high-risk patients with intrahepatic cholangiocarcinoma (CCA) have not been well-characterized, and the significance of pathologic response remains unclear, according to Natalia Paez-Arango, MD, of the M.D. Anderson Cancer Center in Houston, TX.

At the AHPBA meeting, Dr Paez-Arango presented the results of “Neoadjuvant Chemotherapy for High-Risk Intrahepatic Cholangiocarcinoma—Does Pathologic Response Mean Better Outcomes?” This single-institution study was conducted by a team of experts from M.D. Anderson Cancer Center.

The study included 45 patients with intrahepatic CCA who received neoadjuvant chemotherapy followed by definitive resection between 2006 and 2019. Specimens from the resected tumors were evaluated for response to therapy. Overall, 40 (89%) patients had stage III disease at the time of diagnosis, and the median follow-up was 30 months.

The indications for neoadjuvant chemotherapy consisted of nodal involvement or poor performance status in 38 (84%) of the patients with initially unresectable disease, which was then converted to resectable status in 7 patients.

The neoadjuvant chemotherapy regimens were “somewhat heterogeneous,” Dr Rocha said, and included gemcitabine and cisplatin (64%), gemcitabine, cisplatin, and nab-paclitaxel (27%), gemcitabine and carboplatin (4%), and the FOLFOX regimen (4%).

The median overall survival (OS) was 45 months, and the recurrence-free survival (RFS) was 9 months. Of the 45 patients in the study, 16 (39%) had a major pathologic response, defined as <50% viable tumor cells in the resection specimen. This rate included 2 patients with complete pathologic responses; 4 patients did not have a report on their pathologic response and were therefore not part of the analysis.

Based on the study results, major pathologic response does not necessarily mean better outcomes for patients with high-risk intrahepatic CCA who undergo definitive resection, Dr Paez-Arango noted.

She reported that the median RFS was 11 months in patients with major pathologic response versus 14 months in those with minor pathologic response (P = .7), and the OS was 44 months in patients with major pathologic response versus 75 months in those with minor pathologic response (P = .9).

“Pathologic response was not associated with median recurrence-free survival, nor was it associated with overall survival,” said Dr Rocha. “Even the 2 patients who had a pathologic complete response had an early disease recurrence and limited survival. Therefore, pathologic response to neoadjuvant chemotherapy was not associated with improved survival after resection,” he emphasized.

“Future studies should focus on objective biomarkers of response to neoadjuvant chemotherapy that can perhaps better prognosticate survival than standard pathological tumor evaluation,” Dr Rocha concluded.

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Use of Robotic versus Open Surgery in Patients with CCA Shows Similar Outcomes

Aliya Ansari, BS, Ohio State University Comprehensive Cancer Center, Columbus, presented the results of “Short- and Long-Term Outcomes Following Robotic and Open Resection for Cholangiocarcinoma: A National Cohort Study.”

Curative-intent surgical resection with porta hepatis lymphadenectomy provides the best chance for long-term survival for patients with cholangiocarcinoma (CCA), according to Ms Ansari. She noted that although a robotic approach has been increasingly adopted by surgeons at high-volume centers, its impact on perioperative and long-term outcomes remains largely unknown.

Ms Ansari and colleagues used the National Cancer Database to select patients with stage I to stage III CCA who underwent resection between 2004 and 2017. They investigated the association between surgical approach (open or robotic) and any short- and long-term surgical and oncologic outcomes, including lymph node yield, surgical margins, length of stay, 30-day readmission rate, 90-day mortality, and overall survival.

Of the 1876 patients with CCA, as many as 96.5% (N = 1810) underwent an open procedure; only 3.5% (N = 66) of the patients had a robotic-assisted resection.

Although patients who underwent robotic-assisted resection had a shorter hospital stay, no difference was seen in the rates of 30-day readmission or 90-day mortality between the 2 groups, Ms Ansari explained.

“Demographic information revealed that patients who underwent a robotic resection tended to be older compared to patients who had open surgery,” said Dr Rocha. “However, there was no other difference in variables, including gender, race, insurance status, hospital volume, or comorbidities.”

There was also no difference in the tumor size or disease stage between the groups, and the rate of regional lymph node resection was similar. The incidence of non–margin-negative resection was also similar between the groups. Patients who underwent robotic resection had a shorter hospital stay (6 days) than patients who had open resection (9 days), said Dr Rocha, but no difference was seen in the 30-day readmission rates or the 90-day mortality rate between the groups.

“This study demonstrated very similar outcomes in patients undergoing robotic-assisted or open surgery, but there still seems to be a decrease in adoption of robotic surgery for this disease,” said Dr Rocha. “Therefore, future studies should focus on a patient-centered approach in determining the best surgical option for resection of this disease,” he concluded.

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FGFR2 Fusion Associated with Improved Survival in Patients with Resected CCA

EeeLN Buckarma, MD, of the Mayo Clinic in Rochester, MN, presented the results of a study conducted at the Mayo Clinic and titled “Cholangiocarcinoma with an FGFR2 Phenotype: Outcomes in Patients Following Surgical Resection.”

This retrospective study included 150 patients with cholangiocarcinoma (CCA) whose tumor was resected between 2008 and 2014. Of the 150 patients, 95 had intrahepatic CCA; among these 95 patients, 12 (13%) had an FGFR2 fusion. Given the time of the study, none of those patients received an FGFR-targeted therapy, Dr Rocha said.

Molecular profiling studies have shown that the different CCA subtypes, as defined by anatomical location (ie, intrahepatic, extrahepatic, perihilar, or distal) have varying mutational profiles, with FGFR2 fusions more frequently observed in intrahepatic CCA than the other subtypes, Dr Buckarma said.

The 5-year overall survival (OS) was 83% in patients with FGFR2 fusion compared with 32% in patients without FGFR2 fusion (P = .009). The 10-year OS was 46% in patients with FGFR2 fusion versus 22% in those without (P = .04). The 5- and 10-year disease-free survival rates were also increased in patients with FGFR2 fusion (68% vs 33%, P = .04; and 68% vs 25%, P = .02; respectively).

Based on these results, FGFR2 fusion status is an independent prognostic factor for improved survival in patients with CCA who had undergone resection, Dr Buckarma said.

“When compared to patients who tested negative for FGFR2, those with the fusion were found to have a longer 5-year and 10-year overall survival,” said Dr Rocha. “Similarly, the 5- and 10-year disease-free survival was also increased in patients who harbored the FGFR2 mutation,” he added.

“On multivariate Cox regression, FGFR2 fusion status was the strongest independent factor associated with improved overall survival and disease-free survival,” Dr Rocha said.

“Interesting, an FGFR2 fusion was not identified in any perihilar or distal CCA cases,” he said, adding that FGFR2 rearrangement was more likely to be present in younger patients, and in female patients.

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Intraoperative Frozen Section and Revision of Positive Biliary Margins Improve Survival in Perihilar CCA

Routine intraoperative biliary evaluation with revision should be conducted during resection of perihilar cholangiocarcinoma (CCA), according to data from the study “Does Intraoperative Frozen Section and Revision of Margins Lead to Improved Survival in Patients Undergoing Resection of Perihilar Cholangiocarcinoma? A Systematic Review and Meta-Analysis.” Tori Lenet, MD, Resident, Surgeon Scientist Program, Division of General Surgery, University of Ottawa, Canada, presented the study results.

Achieving a margin-negative resection (R0) is the most important prognostic indicator for long-term survival in perihilar CCA but remains a challenge, given the anatomical location of tumors, Dr Lenet explained.

For this meta-analysis, Dr Lenet and colleagues performed a comprehensive search of electronic databases (up to October 2020) for studies that compared patients undergoing resection of perihilar CCA with intraoperative frozen section of the proximal and/or distal bile ducts, including patients who had margin-negative resection (R0), those with an initially positive-margin resection who had been revised to negative margins (R1R0), and those with a persistently positive-margin resection, with or without revision of a positive margin (R1).

The primary outcome of the study was overall survival (OS) and the secondary outcomes included the risk for postoperative complications. The researchers screened 409 studies, of which 10 retrospective observational studies were included in this meta-analysis.

Among the 1955 patients included in the analysis, those undergoing successful revision of a positive proximal and/or distal bile duct margin had a similar OS (P = .56) as those with a primary margin-negative resection, but they had a similar (P = .002) or better OS compared with patients with a final bile duct margin.

“This review supports the practice of 1 routine interoperative biliary margin evaluation during the resection of perihilar CCA and the revision to a negative margin, if technically feasible, should the first margin come back positive,” said Dr Rocha.

Additional resection was not associated with an increase in the rate of postoperative complications, but Dr Lenet noted that postoperative morbidity was inconsistently reported in the studies analyzed.

“These results leave the interpretation of postoperative morbidity for additional studies,” Dr Rocha concluded.

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Liver Transplant plus Neoadjuvant Chemotherapy Improve Survival in Patients with Locally Advanced Intrahepatic CCA

A multimodal treatment approach of transplant plus chemotherapy and radiation offers a survival advantage for patients with liver-limited, locally advanced intrahepatic cholangiocarcinoma (CCA) and may be a viable alternative for unresectable disease, suggested Guergana Panayotova, MD, MHS, General Surgery Resident, New Jersey Medical School, Rutgers University, Newark, NJ.

Dr Panayotova presented the results of a study titled “Surgery and Combined Transplant with Chemotherapy Improve Survival for Patients with Liver Limited and Locally Advanced Intrahepatic Cholangiocarcinoma: A SEER Database Analysis” at the meeting.

The data from this small, single-center series indicate improved survival for patients with intrahepatic CCA who receive neoadjuvant chemotherapy, said Dr Panayotova, but the overall impact of this approach remains unclear. Even less is known about the impact of multimodal therapy on surgery and liver transplant for this disease.

Dr Panayotova and colleagues queried the SEER database for patients diagnosed with intrahepatic CCA between 2004 and 2014 who were candidates for a transplant. They evaluated demographics, tumor characteristics, and survival outcomes, and stratified patients based on treatment modality.

They identified 1621 patients with a diagnosis of liver-limited or locally advanced intrahepatic CCA. Most (55%) patients had T1 disease.

Tumor size >7 cm and tumor stage >T1 also significantly increased the risk for mortality. Patients with tumor stage >T2 were nearly twice as likely to die compared with those with tumor stage <T1.

“The median survival for patients receiving surgery alone or surgery with medical therapy was 46 months compared with 5 months for those patients who had no treatment and 13 months for those with medical therapy only,” said Dr Rocha.

“Liver transplant alone did improve that median survival to 19 months, with an old 5-year overall survival of 14%, which was statistically similar to the 5-year survival of 27% for surgery alone, and 25% for surgery with medical therapy,” he added.

“Liver transplant plus medical therapy offered the best survival, with a median survival greater than 60 months, and a 62% rate of 5-year survival,” Dr Rocha said.

“Using this database, the authors of this study concluded that liver-limited or locally advanced intrahepatic CCA may be best treated with the combination of chemotherapy, radiation, and liver transplant,” said Dr Rocha. “However, prospective clinical data are needed to further establish the role of liver transplantation, particularly in the context of neoadjuvant therapy, surgical candidacy, and the organ shortage,” he concluded.

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Neoadjuvant Chemotherapy Reduces Margin-Positive Resection in Patients with Intrahepatic Cholangiocarcinoma

Neoadjuvant chemotherapy before surgery in patients with intrahepatic cholangiocarcinoma (CCA) is associated with lower rates of margin-positive resection, resulting in decreased mortality risk, according to the study “Neoadjuvant Chemotherapy Is Associated with Lower Rates of Margin-Positive Resection of Intrahepatic Cholangiocarcinoma.” The results of this study were presented by Rebecca Marcus, MD, Surgical Oncology Fellow, Providence Saint John’s Cancer Institute, Santa Monica, CA.

Neoadjuvant chemotherapy is increasingly being used as an adjunct to surgical resection, but prospective evidence is limited to support its use. Dr Marcus and colleagues compared the utilization rates and associated outcomes of neoadjuvant chemotherapy versus other treatment strategies in patients with intrahepatic CCA.

“Adoption of neoadjuvant chemotherapy for the treatment of intrahepatic CCA has increased at the national level over the past 2 decades. This increase has been associated with a decreased risk of death in the same population,” said Dr Rocha.

Using the National Cancer Database, the researchers identified 2736 patients with stage I to stage III intrahepatic CCA who underwent curative-intent surgery between 2006 and 2016. Patients were stratified by year of diagnosis and treatment regimen, including surgery alone, neoadjuvant therapy followed by surgery, and surgery followed by adjuvant therapy.

“Overall, chemotherapy utilization was quite low, with only 36% of patients receiving chemotherapy as part of their treatment regimens either before or after surgery,” said Dr Rocha, adding that 6% of the patients received neoadjuvant therapy, and 29% received adjuvant therapy.

“The use of adjuvant therapy did not change with time in this cohort, but utilization of neoadjuvant therapy increased from 4.3% to 7.2% after controlling for competing factors,” Dr Rocha noted.

Dr Marcus reported that higher disease stage was predictive of the use of neoadjuvant chemotherapy compared with surgery alone. Higher disease stage and margin-positive resection were also predictive of the use of adjuvant therapy after surgery.

“Patients who had neoadjuvant therapy were more likely to undergo margin-negative resection compared to those who had surgery alone,” said Dr Rocha. “Receipt of chemotherapy either before or after surgery was not associated with the decreased risk of death. However, a margin-positive resection did result in a significantly increased risk of death,” he added.

“Neoadjuvant chemotherapy was more likely to result in margin-negative resection, which again, decreased the risk of death,” said Dr Rocha. “Therefore, we should be focusing on the application of neoadjuvant chemotherapy as a first-line strategy for patients with resectable CCA,” Dr Rocha concluded.

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Related Items

Key Abstracts Presented at the Americas Hepato-Pancreato-Biliary Association (AHPBA) 2021 Annual Meeting
By Flavio G. Rocha, MD, FACS, FSSO
Flavio G. Rocha, MD, FACS, FSSO, from the Knight Cancer Institute, Oregon Health & Science University, provides expert commentary on key abstracts and posters presented at the 2021 annual meeting of the Americas Hepato-Pancreato-Biliary Association. Dr Rocha will highlight new data from 10 presentations on interventional modalities for patients with cholangiocarcinoma.

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