Introduction
Cholangiocarcinoma (CCA) is the second most widespread malignant tumor after hepatocellular carcinoma (HCC) [
1], and it is an extremely deadly tumor that develops from the bile duct epithelium. The anatomical division of CCA include intrahepatic cholangiocarcinoma (ICCA) and extrahepatic cholangiocarcinoma (ECCA) with the latter accounting for roughly 70–90% and the former for merely 10–20% of all CAA, respectively [
2]. Nevertheless, the majority of patients were discovered at an advanced stage and missed the optimal opportunity to be treated [
3] owing to the poor clinical presentation [
4], the lack of evidence of identifiable biochemical indications, and the high level of aggressiveness. Hence, the prognosis for ECCA is often poor [
5,
6], with a 5-year survival rate of 11–31% [
7]. The sole curative approach for ECCA is surgery and about one-third of patients are candidates for surgery.
Additionally, much advanced ECCA patients have a combination of several comorbidities, such as hypertension, diabetes, and heart disease, and the mortality from these diseases increases with age [
8‐
10]. Therefore, these risk factors need to be taken into account when assessing prognosis, however, the presence of competing risks has not been taken into account in previous studies, biasing the conclusions obtained [
11,
12]. Hence, competing risk factors should be included in the analysis when assessing the prognosis more accurately.
The prognosis of patients with ECCA is frequently assessed through the American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) [
13] approach, although this system solely assesses tumor features without taking other clinical features into account such as gender, age, and adjuvant therapy. It is not effective in predicting the overall prognosis of ECCA patients, therefore, a more comprehensive and effective staging system is warranted to predict the prognosis of patients with advanced ECCA. Nowadays, it is common practice to forecast the prognosis of a wide range of diseases utilizing clinically based nomograms, which incorporate all risk variables into a thorough analysis [
14‐
17]. In addition to making clinical forecasts and better individualized treatment plans, it is more intuitive and can aid physicians.
According to the 7th AJCC-TNM stage used in this investigation, we classified the patients with stage IIIA to IVB as having advanced ECCA. The competing risk factors were assessed, and appropriate nomograms were developed based on data screened from the Surveillance, Epidemiology, and End Results (SEER) database to investigate the overall survival (OS) and cancer-specific survival (CSS) of patients with advanced ECCA.
Discussion
ECCA, as a rare epithelial malignancy, has been increasing in mortality and morbidity in recent years [
21]. Previous studies of ECCA patients have shown that age, stage, surgery, and chemotherapy were associated with overall survival [
22]. However, there are no studies evaluating prognostic events in patients with advanced ECCA and the competing risk factors were not analyzed. Consequently, we employed CSS in addition to OS, which does not account for competing risk factors, to assess factors that affect patient prognosis, removing the impact of competing causes of mortality. And the nomograms with excellent discrimination and calibration were constructed to predict OS and CSS in patients with advanced ECCA in this study for the first time. Furthermore, higher AUC values and C-indexes in patients with advanced ECCA both confirmed the superior discrimination of the nomograms compared with the 7th AJCC stage. By the time of follow-up, we found a 3-year cumulative mortality rate of 78.0 and 15.0% for CSS and non-cancer-specific mortality, respectively, indicating a large competitive relationship between them. Generally, a higher age is the main reason for a competitive relationship [
23]. However, in the present study, increasing age was not significantly associated with OS in patients with advanced ECCA and was more irrelevant in CSS. This is contrary to the conclusions obtained from previous studies [
24], may be related to the low overall survival rate of ECCA and the study population of advanced patients. Therefore, age may be temporarily excluded as a consideration when assessing whether patients with advanced ECCA have a favorable prognosis. Gender was a predictive factor in univariate analysis in the current study (OS:
P = 0.018, CSS:
P = 0.017), but it had no statistically significant impact with regard to any of the multifactorial variables (OS:
P = 0.141, CSS:
P = 0.126). However, investigations on other cancers revealed that gender was an independent prognostic factor and that males’ survival times were much shorter than females’. Both the study of Yu et al. study on elderly colonized patients [
25] and the study of Wang et al. study on SCLC patients came to the same conclusions [
26].
The survival of patients suffering from advanced ECCA is related to other predictors, such as the T stage and M stage, in the nomograms to predict OS as well as CSS. However, in both OS and CSS, the univariate analysis revealed that the N stage and TNM stage were the independent predictive indicators and not in the multifactorial analysis. This may be due to the small number of lymph node metastases in the current study, particularly N2, and the brief follow-up observation period. In addition, tumor grade, an inherent characteristic, was taken into account when assessing survival in patients with advanced ECCA. This study determined that grade was connected to both OS and CSS and was a distinct risk factor for patients who had advanced ECCA, which is consistent with other prior related studies. As according to Khan et al., patients with higher grades were more likely to have shorter survival time [
22] and in other studies the same conclusion has been presented [
27]. Additionally, this study included diagnostic techniques in the observed variables, but due to variations in subgroups, sample sizes, and study periods, there was no significant link with the prognosis of patients with advanced ECCA.
Radical surgical resection is the only way to treat bile duct cancer [
28], achieving a negative margin R0 can dramatically improve patient survival. It has been indicated that lymph node status is one of the major prognostic factors after R0 resection for cholangiocarcinoma [
29,
30], so local lymph node dissection with a clear scope of lymphatic resection is important to improve the overall survival rate of patients [
31]. For patients who cannot be operated on or who need further care following surgery, adjuvant therapy is aslo crucial. Capecitabine is currently considered a conventional adjuvant chemotherapy agent [
6], and fluorouracil and gemcitabine are also frequently used [
32]. In this study, it was shown that patients can have a good prognosis after treatment with surgery or chemotherapy. The result is in line with the prior finding, as Greenberg et al. suggested that patients with ECCA had been demonstrated to experience significant prognostic advantages from adjuvant chemotherapy [
33]. However, the present study obtained results contrary to previous studies that showed radiotherapy did not provide any benefit to patients with advanced ECCA. Although Razumilava et al. showed that a strong association between radiotherapy and the prognosis of ECCA patients [
34]. And radiotherapy can support surgical treatment to assist patients experience larger advantages, according to Wang et al. [
35].
AJCC staging is widely used to determine a patient’s prognosis for cancer with the disadvantage of not taking age, disease grading, and adjuvant therapy into account [
7]. In this study using an extensive database, we carried out a risk assessment analysis and created nomograms to forecast the influencing factors impacting OS and CSS of patients with advanced ECCA for the first time. The nomogram facilitates the development of individualized treatment regimens by physicians, offers more precise prognostic predictions, and has been applied to the evaluation of a variety of malignancies such as colorectal cancer,osteosarcoma and lung cancer [
36‐
38]. Prognostic nomogram establishment was carried out in ECCA patients by Fang et al. showed that nomograms are more predictive for patient survival than AJCC staging [
23]. As in our study, in comparison to the 7th AJCC stage, the produced nomograms displayed higher time-dependent C-indexes and AUC values, demonstrating their modified discriminative ability to predict OS and CSS. It was also observed that the actual survival rate had a high agreement with the predicted raw survival rate of the nomograms based on the calibration plots, demonstrating the reliability of the nomograms. Moreover, the DCA results showed that the nomograms had more predictive power for survival compared to the AJCC stage and the results of IDI and NRI also supported the view that nomograms were reliable and accurate.
We divided the patients into groups with high and low risk in accordance with the general nomogram scores before doing the Kaplan-Meier survival analysis. According to the score information, patients in the group with a high risk showed considerably worse OS and CSS survival rates compared with those in the group with a low risk. In this study, to get a result that can be broadly applied in the current investigation, we used a substantial sample size. It can assist physicians in the treatment process to stratify risk according to the nomograms, to better assess the predictive characteristics of patients, and to take more aggressive treatment measures for high-risk patients, while overtreating low-risk patients can be avoided. In the future, receiving more specialized, personalized medical care will be possible.
One of the limitations of the study is that the normal clinical findings of CA19–9, CEA, and degree of vascular invasion were not collected in the SEER database, making it unable to assess these variables. The accuracy of determining the prognosis of patients with ECCA has been reported to be improved by including CA19–9 in the AJCC staging [
39]. In addition, because this study was retrospective and did not obtain information on any specific surgery. It is not yet clear in analyzing the relationship between surgical modality and prognosis, and further research is needed. Meanwhile this study’s accuracy aslo needs to be further improved and a bigger sample size was required for the external validation examination in the future.
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