Most pCCA are diagnosed at an advanced stage [26]. Therefore, individualized survival evaluation via easily accessible measures for patients is of importance. In the current study, five independent determinants were screened through univariate and multivariate Cox proportional hazard regression analysis, namely as age, surgery, chemotherapy, radiation and summary stage. We developed the nomogram with these five factors to predict 1-, 2-, and 3-year OS probabilities of pCCA, which allows physicians to predict their patients’ prognosis in an easy-to-implement way. It’s in agreements between the nomogram-predicted OS and the observed OS as evidenced by C-indies of 0.703 and 0.718 in both training and validation sets respectively. We had an additional interpretation that the calibration for 3-year OS was slightly reduced when externally validated, whereas the discrimination was outstanding. Tumor characteristics, management strategies and the differences within patients may be responsible for the suboptimal calibration in validation set. In addition, survival curves of distinct risk groups manifested the significantly statistical difference, indicating the feasibility of the constructed monograph.
As our results indicated, age was significantly correlated with OS rates, with older age corresponding to shorter OS, which was in accordance with the published studies [27, 28]. To obtain the most significant difference between age groups, optimal cut-off values derived from X-tile analysis were applied to both the training and validation cohort. It’s recognized that patients with older age have worse surgery or other treatment tolerance and other comorbidities that overall survival might be negatively affected. However, Koerkamp et al [29] revealed that age was not a significant factor to predict disease-specific survival (DSS). We speculated that deaths from some other competing risks like cardiovascular events may partially explain the result. Interestingly, in the nomogram presented by Chen et al [30], age was also related to the OS, whereas age at 55 years old indicated the lowest OS rate, with the OS rate conversely increasing within the age between 55 to 85. The underlying reason for the contradiction remained unclear.
SEER summary stage is a basic method of determining how far a cancer has extended from its point of origin, mainly comprising local, regional, and distant stage. What’s more, the regional stage consists of three detailed classifications, including direct extension only, lymph nodes involved only, both direct extension and lymph node involvement. The present study detected the prognostic value of summary stage in association with OS probabilities, which was similar to the results published by Qi et al [28]. Compared to the cases at regional and distant stage, only tumors at the localized stage had better prognosis.
With regards to the treatments, other two treatment modalities of chemotherapy and radiation also demonstrated significant correlation with survival outcome besides surgery. Surgery with curative intent can prolong the median OS of patients from 8 months to 40 months [31]. Nevertheless, only a confined portion of patients met the eligibility for surgical treatment, with the addition of high recurrence rate after the resection, so options like chemotherapy or radiation should be considered in these cases for adjuvant or palliative treatment. Controversy also exists in the correlation between chemotherapy or radiation and OS. Chen et al [30] proposed that chemotherapy and radiotherapy was not related to the OS, while they were both independent prognostic factors in our study, thus integrated in the nomogram. In reference of a randomized trial [32], adjuvant capecitabine chemotherapy should be given to patients with the resected cholangiocarcinoma for 6 months duration [33], with a dose of 1,250 mg/m2 twice a day in every 3-week cycle. In addition, several evidences disclosed that there were potential benefits of chemotherapy treatment in both preoperative and postoperative Klatskin tumors [34–36]. The regimen of gemcitabine and cisplatin was recommended for inoperable or postoperative pCCA patients [4, 37], but detailed chemotherapy regimen information were unavailable in SEER database. Patients with extrahepatic cholangiocarcinoma may be offered chemoradiation therapy, which was administered with a dose of 45 Gy to regional lymphatics and 54 to 59.4 Gy to the tumor bed [38, 39]. With respect to the radiotherapy for perihilar cholangiocarcinoma, Leng et al [40] argued that adjuvant radiotherapy was of no association with survival improvement for resected pCCA groups. A retrospective study [41] of SEER dataset also concluded that radiation modality had no therapeutic benefits for pCCA. But in the light of some reviews [42, 43], external beam and endoluminal radiation therapy was an option for unresectable hilar cholangiocarcinoma. In general, although the efficacy of radiotherapy for pCCA was still in dispute, it was fit into our final model on multivariate analysis. Methods of radiation mainly comprised the beam radiation, radioactive implants (including brachytherapy), and combination of beam with implants or isotopes. Additionally, appropriate dosing, timing and radioactive source were needed for further investigation.
There have been several prognostic models for pCCA reported, including a point scoring system and three nomograms [28–30, 44]. As specified in several previous studies, lymph node counts and lymph node metastasis were often identified as independent predictors for pCCA [45, 46]. For instance, lymph node ratio (LNR) was often utilized to develop the nomogram for biliary tract system diseases [47, 48]. While in our study, LNR is hard to formulate due to the missing data, and AJCC N stage failed to enter into the final model with statistical insignificance. Compared to the scoring system, the current study confirmed the prognostic roles of age and chemoradiation in patients with pCCA, and the proposed nomogram could work for a scoring system and a visualized prediction approach at the same time. Concerning the nomograms developed for patients with resected pCCA by Koerkamp et al [29] and Chen et al [30], our model did not include portal vein or hepatic artery involvement, tumor pathological differentiation and lymph node status as well as margin status, which might influence the prognosis of the pCCA patients, but SEER summary stage could equivalently reflect these tumor characteristics to a great extent. Moreover, we have encompassed the chemotherapy and radiation factors rarely mentioned in other studies. With regard to a recently published nomogram with C-index of 0.651, it was only based on 317 patients from the SEER database [28], without consideration of chemotherapy and radiation information. In contrast, our model was based on a large cohort of cases, and has a comparable discrimination and calibration to those relevant models.
Despite the good performance and easy-to-use of our constructed monograph as a prognostic model, some limitations in our study should be noted. For instance, due to the retrospective nature, the nomogram establishment was based on the data from the SEER program that selection bias is a potential concern. Furthermore, some important clinicopathological parameters and widely used tumor biomarkers for pCCA, such as surgical margin status, the information of serum carbohydrate antigen 19 − 9 (CA199), carcinoembryonic antigen (CEA) and vascular encasement were unavailable in SEER database. In addition, many promising options like interventional therapy [49], immunotherapy [50] and targeted treatment [51] are enjoying increasing popularities among pCCA patients, but it is a pity that they have been inaccessible in SEER program until now. As a user-friendly method for prognosis prediction and decision-making, there is difficulty in providing everlastingly excellent prognosis prediction in clinical practice, because not all significant prognostic factors were embodied in this tool.