Association between primary tumor resection and survival in metastatic intrahepatic cholangiocarcinoma: a retrospective cohort study based on the SEER database

Introduction

Intrahepatic cholangiocarcinoma (ICC) originates from the epithelial lining of the surrounding intrahepatic bile duct epithelium and is associated with poor prognosis and high mortality rate (1,2). As the symptoms are not obvious, early ICC are mostly diagnosed during physical examination. However, the majority of patients present with distant metastasis at the time of diagnosis. Carbohydrate antigen 19-9 (CA19-9) serves as a diagnostic and prognostic biomarker, while nodal involvement and distant disease significantly reduce overall survival (OS), underscoring the need for comprehensive staging (3-6). According to the latest three versions of the Tumor, Node, Metastasis (TNM) staging system established by the American Joint Committee on Cancer (AJCC), ICC patients with distant metastasis are classified as terminal stage, regardless of T and N staging (7-9). Most patients die from various tumor-related complications caused by primary tumor progression. Systemic chemotherapy remains the main treatment of late-stage ICC, but the benefits of survival are limited (10).

Hepatectomy is the standard treatment for early-stage ICC in pursuit of removing all tumors completely (11,12). Only a small proportion of patients have the opportunity to undergo radical surgery, and even fewer patients can really achieve a cure. Prolonging survival time is the main treatment goal for advanced patients. The controversy surrounding M1-stage ICC centers on conflicting guidelines, while National Comprehensive Cancer Network (NCCN)/European Society for Medical Oncology (ESMO) classify distant metastasis as a surgical contraindication (4,13,14), emerging evidence suggests oligometastatic subsets may derive survival benefits from aggressive resection (15,16). Recent advances in technology and perioperative management have pushed the boundaries of surgical indications for ICC (17,18), and it is also true that some patients with metastases undergo primary tumor resection for various reasons. However, studies on whether this intervention actually prolongs survival are limited.

Therefore, it is meaningful to evaluate the survival benefit of surgery for ICC patients with distant metastasis through large sample screening and retrospective analysis. We present this article in accordance with the TRIPOD reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-859/rc).

Methods

Patients

Data of newly diagnosed ICC patients from 2004 to 2020 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. This database is the largest publicly available program sponsored by the National Cancer Institute and includes 18 cancer registries and 26% of the United States population. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

ICC cases were identified using the International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3, World Health Organization (WHO) 2008], with code 8160/3 corresponding to cholangiocarcinoma. Major inclusion criteria were patients with ICC confirmed distant metastasis (M1) at diagnosis, irrespective of TNM staging system version (AJCC 6th–8th editions). The definition of M1 was harmonized across staging systems by adhering to the uniform criterion of “distant organ metastasis”, as consistently defined in all editions of the AJCC TNM staging manual. Patients were divided into two groups according to whether they underwent primary site surgery. Exclusion criteria included patients who were (I) diagnosed by autopsy only; (II) not recommended for surgical treatment; and (III) with other malignant tumors. A total of 256 patients were included in the final analysis.

The data in the SEER registry is anonymous. We got access to the SEER data before the project started. This study complied with the tenets of the Declaration of Helsinki.

Data collection

Clinicopathological features and major treatment data were included, and the survival status mainly included cancer-specific survival (CSS) and OS. OS was defined as the time from diagnosis until death regardless of cause or to the latest follow-up time; CSS was defined as the time calculated from the date of diagnosis to the date of ICC-related death or the latest follow-up time. Data extraction included patient demographics, year of diagnosis, TNM staging (AJCC 6th), tumor size, histological grade, radiotherapy record, chemotherapy recode, and surgery of primary site record.

Statistical analysis

Chi-squared test and Fisher’s exact test were used to compare the clinicopathological and demographic data between the two groups. We undertook multiple imputation method to fill in the missing values to maximize data use. To conquer selection bias and minimize differences, the paired patients with similar basic conditions were selected by the propensity score matching (PSM) analysis between surgery and non-surgery patients. All items listed in the baseline characteristics are included in the propensity score calculation. The PSM analysis was conducted using SPSS, with nearest-neighbor method, 1:1 matching ratio, and a caliper size of 0.02.

Survival curves of subgroups were drawn using the Kaplan-Meier method. Vertical lines show censored patients. Differences in survival were calculated by the log-rank test, and hazard ratio (HR) with 95% confidence interval (CI) was described. Multivariable analyses with the Cox proportional hazards model were used to evaluate the simultaneous effects of demographics, clinical variables, and therapeutic methods on survival. Univariate variables with P≤0.20 and clinically significant factors were included in the Cox regression model for multivariate survival analysis [forward: likelihood ratio (LR) method].

Statistical analysis was conducted using SPSS 26.0 (IBM Corp., Armonk, NY, USA); Empower (R); and R statistical software (version 3.6.1; http://www.r-project.org/). Survival curves were depicted using GraphPad Prism version 8.0 (GraphPad-Prism Software Inc., San Diego, CA, USA). All statistical tests were two-sided, and P<0.05 was considered to indicate statistical significance.

Results

Characteristics of enrolled patients

A total of 256 ICC patients with distant metastasis registered to the SEER database were included from 2004 to 2020. Of these, 169 (66%) patients underwent primary tumor surgery, while the remaining 87 (34%) patients did not. Comparison of clinicopathological features between the surgery and non-surgery groups is shown in Table 1. Male patients represented 44.4% (n=75) and 50.6% (n=44) in the surgery and non-surgery groups, respectively. Patients in the surgery group were younger (χ²=9.294, P=0.002) and more patients received chemotherapy (χ²=29.229, P<0.001) than those in the non-surgery group. There were also differences in T stage (χ²=34.441, P<0.001), tumor size (χ²=48.216, P<0.001), and tissue differentiation group (χ²=45.159, P<0.001). There was no significant difference with respect to sex, ethnicity, year of surgery, and N stage.

Multiple interpolation and PSM

To minimize bias and reduce the impact of missing data on statistical analysis, multiple interpolation was performed on the missing data in both groups, followed by PSM to balance the above variables. After a 1:1 matching, 68 pairs of patients were selected. The comparative analysis of the basic data of the two groups of patients after screening is shown in Table 2. The difference of clinicopathological features was significantly reduced, which could be used for further analysis. There was still a difference between AJCC T2 and T3, which have been merged in the latest AJCC staging; hence, this difference could be ignored.

The impact of surgery on prognosis

The Kaplan-Meier curves showed that the total mortality and cancer-specific mortality in the surgery group were lower than those in the non-surgery group after PSM. The median OS time of the surgery group and non-surgery group were 8 vs. 4 months (HR =0.591, 95% CI: 0.402–0.869, P=0.002); CSS time showed similar results for 11 and 7 months (HR =0.638, 95% CI: 0.412–0.988, P=0.03), respectively. For the non-surgery group, the rate of 1- and 3-year OS was 20.1% and 3%, while that of the 1- and 3-year CSS was 24.5% and 8.2%, respectively. The corresponding values in the surgery group were 36.8% and 13.8%, and 42.4% and 20.3% respectively, which were significantly higher than those of the non-surgery group (Figure 1A,1B).

Figure 1 Kaplan-Meier curves of ICC patients with distant metastases for surgical and non-surgical treatments of OS and CSS after (A,B) and before (C,D) PSM. CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; ICC, intrahepatic cholangiocarcinoma; OS, overall survival; PSM, propensity score matching.

The survival analysis of patients prior to PSM demonstrated that surgical intervention significantly improved both OS and CSS. For OS, the median survival time was 14 months in the surgery group compared to 5.5 months in the non-surgery group (HR =0.457, 95% CI: 0.322–0.647, P<0.001). For CSS, the median survival time was 18 months in the surgery group versus 7 months in the non-surgery group (HR =0.389, 95% CI: 0.279–0.543, P<0.001). These findings were consistent with the aforementioned results (Figure 1C,1D).

Factors affecting the survival of ICC patients with metastasis

All factors were included in the univariate regression analysis. Surgery and chemotherapy were identified as beneficial factors for OS. In addition to these elements, N1 stage was also a risk factor for CSS (P=0.04). Furthermore, we included the above factors and the factors that may be statistically (P≤0.2) or clinically significant (age, T stage, tumor differentiation, radiotherapy) into the multivariate regression model. In multivariate analysis, absence of chemotherapy and surgery were risk factors for OS and CSS, while the benefits of radiotherapy were not statistically significant (Tables 3,4). The patients before PSM were analyzed by univariate and multivariate analysis, and the results were similar. Furthermore, independent risk factors also include poorly differentiated tumor for OS and poorly differentiated tumor together with T classification for CSS (Tables S1,S2).

Effect of chemotherapy plus surgery on survival time

As chemotherapy is an independent factor affecting patient prognosis, we further explored the effect of surgery plus chemotherapy on patients. Patients before PSM were divided into a chemotherapy plus surgery group and a palliative treatment group, and the OS and CSS of the two groups were compared (Figure 2A,2B). The cumulative survival curve showed that chemotherapy plus surgery provided significant OS and CSS benefits. The respective median durations of OS and CSS in the former group were 18 and 23 months, and 3 and 5 months in the latter.

Figure 2 Kaplan-Meier curves of ICC patients with distant metastases for chemotherapy plus surgery group and palliative treatment group of OS (A) and CSS (B) before PSM. CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; ICC, intrahepatic cholangiocarcinoma; OS, overall survival; PSM, propensity score matching.

Discussion

In this study, we retrospectively analyzed the clinical data of ICC patients with distant metastasis from 2004 to 2020 obtained from the SEER database. After PSM and multiple interpolation, primary site surgery provided better survival benefit. Patients may have a better prognosis after a combination of chemotherapy and surgical treatment.

ICC is a highly fatal hepatobiliary tumor with increasing incidence all over the world. There are limited effective treatment modalities for the management of the primary tumor in unresectable ICC (18). Intrahepatic tumor dissemination is the main cause of death in most patients with advanced ICC. Therefore, local surgical treatment may be helpful for patients with good general condition and sufficient remnant liver volume. Traditional guidelines usually do not recommend surgery for the primary lesion in ICC patients with distant metastasis. However, precisely because such surgeries are rarely performed in clinical practice, there is a lack of large-scale evidence-based research on whether these patients can benefit from such operations. This study conducted a detailed retrospective analysis to explore this clinical situation, which suggests that in this patient population, surgery on the primary lesion can still improve patient prognosis (19,20).

The potential reasons for the efficacy of surgical treatment in ICC distant metastasis may include the following aspects. First, some patients are in an oligometastatic state (characterized by a limited number of metastatic lesions with restricted spread), making surgical resection of both the primary tumor and metastatic foci more feasible for achieving local control. Second, advanced ICC patients with distant metastasis often suffer from severe local symptoms induced by the primary tumor (e.g., obstructive jaundice, cholangitis, and duodenal obstruction). These symptoms not only impair quality of life but may also trigger multiple organ failure (e.g., sepsis secondary to cholangitis or liver failure). Surgical resection of the primary tumor can directly alleviate these complications. Third, surgery induces a cytoreductive effect by reducing tumor burden, which enhances the sensitivity to subsequent systemic therapy and thereby improves overall therapeutic outcomes.

A study has confirmed that local regional therapy for these patients with good general condition may reduce local complications and even prolong the survival rate of patients (20). A study has shown that surgery and other adjuvant therapy for patients with cholangiocarcinoma and spinal metastasis can help to prolong the survival duration (21). The authors suggest that surgical treatment may be beneficial for ICC patients with spinal metastasis if the following conditions are met: (I) the primary site is resectable; (II) the metastatic focus is functionally stable; and (III) the overall general health of the patient meets the surgical requirements (21).

For resectable tumors, the survival rate after resection mainly depends on negative surgical margin, no vascular infiltration, well-differentiated tumor grading, no lymph node metastasis, acceptable biliary tract rebuilding options and functional liver residues (22,23), which may also affect the acceptability of surgery for our target population. However, there are only few studies on the relationship between survival time and clinicopathological features in patients with distant metastasis, especially with regard to therapeutic plan. Significant indicators concluded from the multivariate analysis have impaction on OS, included surgery, chemotherapy, tumor differentiation.

Although many literatures have shown that vascular invasion is one of the major indicators affecting the prognosis of ICC. However, due to missing data in the database and lack of clear definition, we did not include this index in our research. Furthermore, tumor number may be a prognostic factor for the early ICC (24). However, as the included ICC patients had accompanying metastasis, the number of metastatic tumors cannot be reflected in the database; hence, we did not include the number of tumors in the analysis.

In early-stage ICC, postoperative chemotherapy is not a routine practice. However, this combination may be beneficial to patients with distant metastasis of ICC, based on our study. As recommended in most guidelines, chemotherapy in these patients provides significant survival benefits, with significant improvements in OS and CSS (25-27). A phase III randomized clinical trial conducted by Valle et al. convicted the effects of chemotherapy on OS in patients with locally advanced or metastatic cholangiocarcinoma (26). So, validation of combination therapy requires further study.

The median survival time of stage IV ICC patients without surgery and chemotherapy in our study was 3 months, which was similar to the previous study (2.5 months) (28), and significantly lesser than that of patients who received both surgery and chemotherapy (18 months). In our study, after trying to eliminate the bias in clinicopathological features between the two groups, surgery at the primary site showed significant survival benefits, both in OS and CSS. Surgery for necessary palliative treatment could likely reduce the occurrence of local-related complications, shrink tumor volume, decrease tumor loading and prolong survival rather than pursue a clinical cure.

Radiotherapy may help relieve pain and reduce cholestasis in patients with unresectable hilar cholangiocarcinoma. However, owing to lack of high-quality clinical studies, data on the survival time of radiotherapy are contradictory, and mostly limited to non-random series (29). In our study, radiotherapy mainly included beam radiation and radioisotopes and did not show a significant survival improvement, but it may also be related to the inclusion of fewer patients.

There are some limitations in this study. First, this is a retrospective study, and there may be some biases that are not reflected in the SEER database when choosing the treatment method. Hence, a large-sample prospective research study is essential. In addition, due to the limitations of the number of cases and data integrity, no further analysis was made on the survival improvement of different chemotherapeutics. Finally, internal and external validation was not performed due to insufficient cases.

Conclusions

In conclusion, our retrospective study found that surgery for primary cholangiocarcinoma with distant metastasis may provide some survival benefits. Surgery combined with chemotherapy may be more effective, but the findings need to be verified by rigorous clinical experiments.

Acknowledgments

We would like to thank all the participants who involved in this study.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-859/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-859/prf

Funding: This study was supported by Natural Science Foundation of Shandong Province (No. ZR2022QH329).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-859/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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