Largest Registry Study of Cholangiocarcinoma Discusses Challenges of Late Diagnosis

A registry study of more than 2200 European patients with cholangiocarcinoma finds that late diagnosis presents multiple treatment challenges, and the prognosis remains “dismal” in most cases.

The study, published today on World Cholangiocarcinoma Day, comes from a 10-year effort of the European Network for the Study of Cholangiocarcinoma (ENSCCA), which drew data from treatment centers in Austria, France, Germany, Italy, Lithuania, the Netherlands, Norway, Poland, Romania, Spain, and the United Kingdom. Data were gathered from 2010 through 2019. There were more men than women in the study (males 56.4%), and the median age was 66.

Although cholangiocarcinoma, or bile duct cancer, is still relatively rare, it is becoming more common as obesity and other lifestyle risk factors—notably alcohol use—increase worldwide. The registry study highlighted the links between lifestyle factors and rising cholangiocarcinoma incidence and called for greater efforts by primary care physicians in sounding the arm to prevent cancer.

At diagnosis, 35.7% of the patients had a body mass index (BMI) of 25 to 30 kg/m2, classifying them as overweight, and 19.4% had a BMI above 30 kg/m2, classifying them as obese. Other comorbidities included: 22.5% with diabetes, 39.9% with arterial hypertension; 15% were obese and had diabetes.

The study served to delineate subtypes of cholangiocarcinoma (CCA), which are delineated by where the tumor is located. Of the 2234 patients, 1243 had intrahepatic (iCCA), 592 had perihilar (pCCA), and 399 had distal (dCCA) disease. More than half the patients in the study already had either locally advanced disease (29.4%) or metastatic disease (28.4%) at the time of diagnosis.

According to a statement from the investigators, the Clinical ENSCCA Registry was the network’s first initiative to do the following:

• describe the natural course of CCA in Europe and potential risk factors;
• improve the current classification system;
• investigate early and non-invasive accurate tumor biomarkers for diagnosis;
• estimate prognosis; compare the effectiveness of therapies; and select patients for clinical trials.

“CCA is a rare cancer, but its incidence is increasing worldwide, and we need to stop treating it as an orphan disease,” explained lead investigator Jesus M. Banales, PhD, professor Ikerbasque at Biodonostia, University of Navarra and CIBERehd, Spain.

“Although CCA constitutes a major challenge for clinicians, scientists, national health systems and society, there is a lack of coordinated multidisciplinary pan-European studies," he said. "We, therefore, used the ENSCCA registry to gather vital information.”

A diagnosis of iCCA was associated with being overweight/obese and with chronic liver diseases, including cirrhosis and viral hepatitis—and these patients had the worst outcomes. A diagnosis of pCCA was associated with primary sclerosing cholangitis, an inflammation of the bile ducts; and dCCA was associated with choleodocholithiasis, or bile duct stones or gallstones.

Those who were able to undergo resection (50.3%) had the best outcomes, especially if the surgery resulted in a negative resection margin, meaning there was no residual disease in the margins. In these cases, median overall survival (mOS) was 45.1 months. By contrast, in cases where there was margin involvement after surgery, the mOS was 24.7 months; if there was lymph node invasion, the mOS was 23.3 months.

Among patients with unresectable disease, the prognosis was much worse: the mOS was 10.6 months for those receiving palliative therapies, typically chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%).

The authors highlighted the differences in clinical presentation in the various forms of CCA. “This study suggests that perihilar and distal tumors are detected earlier than intrahepatic lesions, mainly because they usually cause obstructive jaundice at an early stage,” they wrote, noting that the iCCA tumors presented in a “mass-forming growth pattern,” while tumors in the other 2 subtypes were often flat.

The authors note that “hepatic dissemination of iCCA is not formally considered metastasis,” based on current guidelines, but that these patients have worse prognosis whether the lymph nodes are involved, suggesting the need for a new code in the guidelines.

Also, the study found that biomarkers serum CEA and CA19-9 are “increasingly elevated as the disease progresses, supporting previous reports in which preoperative elevation of serum CA19-9 appears as a predictor of nodal invasion.” Thus, the authors write, future clinical trials could be designed around using these biomarkers to identify patients for more detailed staging and stratification.

Finally, the study found that nonalcoholic fatty liver disease (NAFLD) could be a major risk factor for CCA, either alone or in association with obesity. In this study, 12.6% of those with iCCAs “arose on a cirrhotic background,” linked to viral infection, alcohol consumption, or NAFLD.

“Our study including more than 2200 patients with CCA from 11 European countries provides a comprehensive analysis of diagnostic, prognostic and therapeutic aspects of the complex CCA landscape, showing that CCA is still diagnosed at an advanced stage, a significant proportion of patients fail to receive any cancer-specific therapy, and therefore, the prognosis is dismal,” the authors concluded.

“Accordingly, the promotion of awareness campaigns and education programs aimed to prevent lifestyle-related risk factors and the implementation of surveillance for early detection of CCA in high-risk populations are urgently required in order to decrease cancer-related mortality.”

Reference

Sanchez LI, Lamarca A, La Casta A, et al. Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry. J Hepatol. Published online February 12, 2022. https://doi.org/10.1016/j.jhep.2021.12.010