Prognosis Of Intrahepatic Cholangiocarcinoma: Fudan Score System Based On Clinical Features To Evaluate Staging And Outcome. And Benefit Of Radiotherapy For 90 Patients With Resected Intrahepatic Cholangiocarcinoma And Concurrent Lymph Node Metastases

BackgroundIntrahepatic cholangiocarcinoma (ICC) by definition originates from the second(segmental) or the proximal branch of the bile duct, it is the second most common primary liver malignancy after hepatocellular carcinoma. In the past three decades, the incidence of ICC and its mortality rates have increased worldwide.Surgery is currently the most effective treatment for ICC. This disease typically has a lack of symptoms until late in its course, therefore a fair number of patients have unresectable tumors at diagnosis with a poor median survival. Majority reported that prognosis of the resectable ICC patients was still poor. Intrahepatic failure, bile duct obstruction, lymph node(LN) and distant metastasis are leading causes of death in patients with ICC.At present, ICC has captured more and more attention of clinical research, clinicians constantly try to explore new treatment modalities, search new markers, identify prognostic factors. Radiotherapy was found to be an important treatment for ICC. We had reported that radiotherapy seemed to improve the prognosis of patients with unresectable ICC, whereas the small number of cases. Analysis of the Surveillance, Epidemiology, and End Results(SEER) database also showed that radiation therapy was benefit for improving survival, but that was a retrospective analysis with subjective selectivity of treatment.Despite the increasing studies on ICC, ICC is staged using a tumor-node-metastasis (TNM) classification of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) liver cancer staging system, which is based on data from patients affected by hepatocellular carcinoma(HCC). It is not sufficiently accurate for ICC as these two diseases have different pathogenesis and biological characteristics. In clinical, patients with unresectalbe ICC are more common in department of radiation oncology. Well, which variables are the progonostic factors of these patients and which treatment mordality is appropriate? There remains poor studies. Given this background, a need remains for a reliably predictive staging system that could be applied to unresectable cases and, preoperatively, to resectable cases. This is also the first part of the thesis.Lymph node metastasis is a major cause of poor prognosis for surgical ICC. Lymph node dissection is not adovated, then whether postoperative radiotherapy for the macroscopic LN could improve local control and the prognosis? This is the second part of the thesis.Part 1. Prognosis of intrahepatic cholangiocarcinoma:Fudan score system based on clinical features to evaluate staging and outcome.Objective To identify clinical risk factors and establish a prediction scoring system for intrahepatic cholangiocarcinoma (ICC).Methods From January 1998 to July 2008, ICC patients who underwent surgical resection in our hospital had been reviewed. We collected their pathologic and clinical data, including the tumor size, tumor number, tumor edge, portal vein invasion, TNM stage, serum alpha-fetoprotein (AFP), serum carcino embryonic antigen (CEA),serum carbohydrate antigen 19-9 (CA19-9),HBsAg, serum level of albumin, TB, ALT, AST, GGT and ALP and so on. Those patients who had tumors confirmed by surgical histological examination and had complete clinical and radiographic data, including tumor information and laboratory value, were included as the training set and follow-up. Retrospective univariate and multivariate survival analyses were conducted for 344 ICC patients with hepatectomy in a institution. A simple clinical scoring system was developed based on the independent predictors to evaluate the staging and prognosis. The prognostic validity of the Fudan score system was internally assessed by bootstrap methods. We also collected the non-surgical ICC patients initially treated in our hospital in the same period, and screen out the external validation group with the same included and the excluded criteria. The prognostic accuracy of the Fudan score system was assessed on this cohort of unresected patients. PASW Statistics18.0 was used for statistic analysis.Results In the training set, serum alkaline phosphatase (ALP) level, carbohydrate antigen 19-9 (CA19-9) level, tumor boundary type, tumor size and number of intrahepatic tumors (P<0.05) were independent predictive factors of survival of ICC both in univariate and multivariate analyses, which were incorporated into a proposed scoring system(Fudan score) to predict stage and prognosis. Patients were categorized into four subsets according to the total score with 5-year overall survival rate of 48.6%,25.6%,10.3% and 0% for low, intermediate, high and extremely high risk group, respectively. The discriminatory ability of the Tokyo score was internally validated by bootstrap methods, differences in 1,3 and 5 year survival rates were significant and The lower confidence limit of difference between each pair of two contiguous risk groups was greater than zero with small span, indicating that Fudan score system was therefore shown to be highly robust in estimating prognosis in distinct groups.The good predictive ability of the Fudan score was also validated in the unreseceted validation set, with 1-year overall survival rate of 100%,62.5%,22.9% and 4.4% for low, intermediate, high and extremely high risk group, respectively.Compared with the AJCC staging system, Fudan score system showed a better discriminative ability.Conclusion The Fudan score system is a simple system based on clinical factors which provides good prediction of prognosis for patients with ICC both resected and unrescetable.Part 2. Benefit of Radiotherapy for 90 Patients with Resected Intrahepatic Cholangiocarcinoma and Concurrent Lymph Node Metastases.Purpose To evaluate the role of radiotherapy for patients with resected intrahepatic cholangiocarcinoma with concurrent macroscopic abdominal lymph node metastases.Methods We identified 90 patients with resected intrahepatic cholangiocarcinoma and concurrent regional lymph node metastases treated between 1999 and 2008, thereinto 24 patients received local limited external beam radiotherapy (classiWed as the radiotherapy group) with a median total dose of 50 Gy (range 34-60 Gy) in fractions of 2 Gy five times a week. The remaining 66 patients did not receive external beam radiotherapy (classiWed as the nonradiotherapy group). We studied survival and tumor response to radiotherapy, demonstrated by symptoms and results of imaging, by Kaplan-Meier method and Cox analysis.Results After radiotherapy, lymph nodes showed partial response in nine patients (37.5%) and complete response in nine patients (37.5%). The pain had been completely relieved in the five symptomatic patients without the use of analgesics.Median survival was 19.1 months in the radiotherapy group and 9.5 months in the non-radiotherapy group (P=0.011). Survival at 1,2,5-year were 68.8%,23.8% and 11.9% in the radiotherapy group versus 43.2%,12.1% and 1.5% in the nonradiotherapy group. The survival between the two groups was significantly different.The results of univariate analyses of survival showed that age, tumor number, preoperative level of CA19-9 and radiotherapy was predictive factors, primary tumors in the caudate lobe also had a worse prognosis. Multivariate analysis showed that increasing age, multiple intrahepatic primary tumors, higher level of CA19-9, and non-radiotherapy group were related to a poorer prognosis.During follow-up, one patient had locoregional lymph node relapse in the radiation field 5 months after completing radiotherapy. In five patients, lymph node metastases recurred outside of the radiation fields within 3 years after completing radiotherapy. The most common cause of death was intrahepatic recurrence, and death resulting from lymph node-related complications was similar between the two groups.Gastrointestinal side effects and fatigue were main side effects during and after radiotherapy.Conclusions External beam radiotherapy seems to improve the prognosis of patients with resected intrahepatic cholangiocarcinoma and concurrent macroscopic lymph node metastases, by prolonging survival and reducing the regional lymph node. These results suggest that it may be appropriate to consider either adjuvant or palliative radiation in patients with intrahepatic cholangiocarcinoma and lymph node metastases.