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Study Identifies Markers for Presurgical Staging System in Cholangiocarcinoma


A study from Japan identifies markers for a presurgical staging system in intrahepatic cholangiocarcinoma, with results on par with an existing postsurgical staging system.

Intrahepatic cholangiocarcinoma (ICC), or bile duct cancer that occurs within the liver, remains difficult to treat with 5-year survival rates of less than 10% if diagnosed after the localized stage. Surgery remains the only possibility for a cure, but even this option presents challenges.

Clinicians have lacked non-invasive biomarkers to predict ICC prognosis before surgery. Available staging has been based on Liver Cancer Study Group of Japan system, which rely on postoperative findings. Today, however, with some clinical trials examining neoadjuvant treatment for ICC before surgical, presurgical biomarkers that could guide treatment are desired.

A recent paper in Cancers discusses development of a presurgical staging system, called PRE-Stage, developed principally by Hisashi Kosakaand colleagues at Kansai Medical University, Hirakata, Japan. The investigators examined several different indices that evaluate a patient’s nutrition, immunity, and inflammatory status, and then combined these results with categorizations of the ICC tumor location to create a predictive model.

This retrospective analysis used clinical and histopathologic data form 227 consecutive patients treated for ICC following hepatectomy at 5 hospitals in the Kansai, Japan, region from January 2009 to December 2020. The average age of patients was 72, and 69% were male. Investigators had a number of data points available, including a measure of indocyanine green (ICG), which is a dye that binds to membranes of necrotic cells and can be used as a biomarker.

First, investigators looked at available indices, which included neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP)-to-albumin ratio (CAR), and CRP–albumin–lymphocyte (CALLY) index. Each index, taken alone, is “inadequate to use for treatment making and life panning of the patients,” they wrote.

Each of these indices was evaluated base on their ability to predict disease-free survival (DSS) and disease-free survival (DFS). In this analysis, NLR, PNI, and PLR “did not demonstrate significant prognostic value.” The CALLY index offered the best predictive value, followed by CAR.

The team hypothesized that a prognostic model that combined results from the CALLY index, the central tumor location, and whether CA19-9 levels were greater than 40.05 U/mL, as all were more predictive for DFS than other factors, such as age, years with hepatitis, and ICG < 9.65%.

The PRE-Stage was then developed using the 3 prognostic factors, and investigators reported it was able to significantly predict DSS and DFS when patients were stratified into 4 stages, with those at higher stages having a worse prognosis.

“When DSS was stratified by the PRE-Stage, the median DSS of patients with PRE-Stage 4 was 13.9 months,” they wrote. Because the median survival time of patients with unresectable ICC treated with gemcitabine plus cisplatin was 11.7 months in a key trial, “the surgical indications should be carefully determined for patients with PRE-Stage 4.”

And, when DFS was stratified using PRE-Stage, most patients with either PRE-Stage 3 or 4 had their cancer return within a year (median DFS of PRE-Stage 3 vs 4 was 10.3 months vs 7.4 months).

“Such patients with poor prognoses may be candidates for neoadjuvant chemotherapy in future clinical trials, whereas few retrospective studies have evaluated neoadjuvant chemotherapy for patients with locally advanced ICC,” the investigators wrote.

In addition, the PRE-Stage produced similar hazard ratios (HRs) to the Liver Cancer Study Group of Japan (LCSGJ). The HRs for DSS for PRE-Stage and the LCSGJ were 1.923 and 1.985, respectively, both with P < .05.

“The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the LCSGJ stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making,” they concluded.


Kosaka H, Ueno M, Komeda K, et al. The impact of a preoperative staging system on accurate prediction of prognosis in intrahepatic cholangiocarcinoma. Cancers. 2022;14(5):1107. Published February 22, 2022. https://doi.org/10.3390/cancers14051107

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