|Year : 2020 | Volume
| Issue : 2 | Page : 230-237
Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma: A cohort study
Zhaowei Sun1, Yujie Feng1, Hao Liu2, Fangzhen Shen3, Jinming Xiao4, Xiaoliang Kang5, Yongrong Zhao6, Huazhi Xiao7, Wei Zhao1, Xiao Hu1, Jinliang Li1, Haoyue Ma1, Guanghua Cao1, Na Su8, Bingyuan Zhang1
1 Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
2 Department of Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, China
3 Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
4 Department of Hematology, The Affiliated Hospital of Weifang Medical College, Weifang, China
5 Department of Vascular Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
6 Department of Internal Medicine, Qingdao West Coast New District Second People's Hospital, Qingdao, China
7 Department of Pediatrics, Rongcheng Maternal and Child Care Service Centre, Rongcheng, China
8 Department of Medical Imaging, Shandong Cancer Hospital and Institute, Jinan, China
|Date of Submission||22-Aug-2019|
|Date of Decision||03-Nov-2019|
|Date of Acceptance||15-Nov-2019|
|Date of Web Publication||28-May-2020|
Department of Hepatobiliary Surgery, Affiliated Hospital of Qingdao University, Jiangsu 16, 26000 Qingdao
Department of Hepatobiliary Surgery, Affiliated Hospital of Qingdao University, Jiangsu 16, 26000 Qingdao
Source of Support: None, Conflict of Interest: None
Context: Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA).
Aims: This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA.
Settings and Design: We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013.
Materials and Methods: Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group.
Statistical Analysis Used: The Kaplan–Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model.
Results: There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival.
Conclusions: Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA.
Keywords: Curative effects, hilar cholangiocarcinoma, influence factor, prognostic
|How to cite this article:|
Sun Z, Feng Y, Liu H, Shen F, Xiao J, Kang X, Zhao Y, Xiao H, Zhao W, Hu X, Li J, Ma H, Cao G, Su N, Zhang B. Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma: A cohort study. J Can Res Ther 2020;16:230-7
|How to cite this URL:|
Sun Z, Feng Y, Liu H, Shen F, Xiao J, Kang X, Zhao Y, Xiao H, Zhao W, Hu X, Li J, Ma H, Cao G, Su N, Zhang B. Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma: A cohort study. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:230-7. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/230/285194
FNx01Zhaowei Sun and Yujie Feng contributed equally to this work
| > Introduction|| |
Hilar cholangiocarcinoma (HCCA), also called Klatskin tumor, is a tumor involving the common hepatic duct, the left and right hepatic ducts, and the confluence part of the biliary duct. It has been estimated that the 5-year survival rate after an R0 resection of the HCCA ranges from 10% to 40%. Due to its special position, low resection rate and low 5-year survival rate, HCCA is a very challenging problem for clinicians.,,
Radical resection can extend the survival of patients with HCCA, leading to a 5-year survival rate of 20%–40%,, but most patients are not eligible for radical resection at diagnosis because of a higher tumor location or distant metastasis. Rather, these patients undergo nonradical resection, endoscopic retrograde biliary drainage (ERBD), or percutaneous transhepatic cholangiography and drainage (PTCD). There is still a dispute as to the effects of these methods on survival in patients with HCCA. Moreover, the prognostic factors affecting survival in patients with HCCA are also in dispute. Therefore, we performed a retrospective analysis using the clinical data of 354 patients with HCCA treated at our hospital from January 1, 2003, to December 31, 2013, and analyzed the effects on survival of different treatment methods for HCCA, and the controllable-independent hazards influencing the patient prognosis.
| > Materials and Methods|| |
The research protocol was reviewed and approved by our Research Ethics Committee and performed in accordance with the Declaration of Helsinki. All participants or their guardians gave written consent for the use of their serum samples and medical information in scientific research.
We retrospectively collected the clinical data of 354 patients with HCCA treated at our hospital from January 1, 2003, to December 31, 2013. Two hundred and twenty-seven patients were male and 127 were female, with an average age of 64 years at diagnosis. The average hospital stay was 15 days. Patients with a medical history of underlying internal disease had an average hospital stay of 44 days, those with a history of drinking an average of 41 days, and those with a history of heavy smoking an average of 70 days; the diagnostic criteria used for drinking and heavy smoking were previously described. We also collected the laboratory results of patients before the treatment [Table 1].
All patients who underwent surgery had a confirmed diagnosis of HCCA using a combination of medical history, symptoms, physical signs, preoperative imaging data, intra-operative exploration results, and postoperative pathologic findings (with the data of postoperative pathologic findings available for 203 cases). Patients receiving only biliary drainage procedures received a comprehensive diagnosis using medical history, physical signs, pretreatment imaging data, ultrasonic examination, laboratory examination, and interventional and endoscopic examination, as previously described., We excluded the following patients: (a) patients with HCCA along with other malignant tumors; (b) patients receiving only exploratory laparotomy and tissue biopsy; and (c) patients in the biliary drainage-only group who experienced tumor recurrence after the operation and received jaundice-reducing treatment.
As shown in [Figure 1], there were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group. Patients who received surgical treatment underwent preoperative examinations by hepatobiliary surgeons at our hospital which included enhanced computed tomography and magnetic resonance imaging. Radical resection was defined as pathologically negative surgical margins by the naked eye (R0 resection). Liver resection was also performed according to the Bismuth–Corlette classification during the operation in certain patients (n = 110). Nonradical resection was defined as positive microscopic resection margins (R1 resection; 52 cases) or positive macroscopic resection margins (R2 resection; 41 cases).
|Figure 1: Management algorithm for 354 patients with hilar cholangiocarcinoma. ERBD = Endoscopic retrograde biliary drainage, PTCD = Percutaneous transhepatic cholangiography and drainage, R1 = Resection, microscopically nonradical resection, R2 = Resection, macroscopically nonradical resection. *Eleven patients were lost to follow-up, ten patients underwent preoperative PTCD, and two patients underwent endoscopic nasobiliary drainage,#three patients were lost to follow-up, six patients underwent surgery and PTCD, and two patients underwent endoscopic nasobiliary drainage, #one patient was lost to follow-up, and eight patients underwent preoperative PTCD, • ten patients were lost to follow-up, ♦ and 17 patients were lost to follow-up|
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ERBD treatment encompassed endoscopic bile duct examination, Oddi endoscopic sphincterotomy, and ERBD. The biliary stents were generally plastic, and the average number of stents inserted was 2. PTCD treatment includes simple PTCD and placing the trestle into the bile duct after the PTCD. The average number of PTCD drainage tubes was 2.
Follow-up mainly consisted of telephone calls and clinical visits, with letters and household registration queries as necessary. For thefirst 2 years, patients were followed every 3 and 6 months thereafter. The last follow-up was on October 1, 2015. Survival was defined as the date of initial treatment to the date of death or last follow-up.
All data were managed with Microsoft Excel software (Microsoft Corp., Redmond, WA USA) and subjected to statistical analysis using IBM SPSS Statistics software (version 20.0; IBM Corp., Armonk, NY, USA). The effects of different treatment methods on survival were calculated by log-rank inspection and using a Kaplan–Meier curve. t-test and U-test were adopted for continuous variables, and a Chi-squared test or Fisher's exact test was used for categorical variables. Cox proportional hazards regression models were constructed for multiple factor analysis. Missing values were discarded, with no replacement value. All analyses were subject to two-sided tests with the inspection standard of α = 0.05, and P < 0.05 was deemed as having statistical significance.
| > Results|| |
There were 354 patients with HCCA included in the study, and 42 were lost to follow-up, with a follow-up rate of 88.1%. Two hundred and three patients underwent operative treatment, of whom 110 underwent radical resection (R0 resection group), and 93 underwent nonradical resection (nonradical resection group; R1 resection: 52 patients and R2 resection: 41 patients). The median survival of the R0 resection group was 21.7 months (1.0–71.0 months), and the 1-, 2-, and 3-year survival rates were 70.7%, 49.5%, and 31.3%, respectively. The median survival of the nonradical resection group was 13.6 months (2.0–45.4 months), and the 1-, 2-, and 3-year survival rates were 62.9%, 24.7%, and 9.0%, respectively. There were 151 patients in the biliary drainage-only group; this group had a median survival of 8.7 months (4.0–28.0 months) and the 1-, 2-, and 3-year survival rates of 34.7%, 4.0%, and 0%, respectively. The median survival time among the three groups was significantly different [P < 0.001 for each; [Figure 2]. The median survival time between patients undergoing nonradical resection and those undergoing biliary drainage were also significantly different (P < 0.001). There was no significant difference detected in the survival time between patients undergoing R1 resection and R2 resection or between patients receiving ERBD treatment and PTCD treatment [14.0 vs. 13.0 months; P = 0.367 and 9.0 vs. 8.7 months; P = 0.89, respectively; [Figure 3].
|Figure 2: Kaplan–Meier survival estimates of patients in the three treatment groups. The difference in median survival between the three treatment groups was statistically significant (P < 0.001)|
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|Figure 3: Kaplan–Meier survival estimates of patients in the five treatment groups|
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Univariate analysis showed that the treatment method, albumin (ALB), prealbumin, total bilirubin (TBIL), triglycerides (TGs), tumor diameter, postoperative pathological T-stage (pT-stage), lymph node metastasis, distant metastasis, and Bismuth–Corlette type were significantly associated with survival [Table 2]. These were included in the multivariate Cox proportional hazards regression model, the treatment method (hazard ratio [HR]: 1.88; 95% confidence interval [CI]: 1.21–2.91), ALB (HR: 0.65; 95% CI: 0.45–0.94), TBIL (HR: 1.63; 95% CI: 1.02–2.59), pT-stage (HR: 1.43; 95% CI: 1.19–1.72), and distant metastasis (HR: 2.29; 95% CI: 1.15–4.52) were retained as independent prognostic factors [Table 3].
| > Discussion|| |
In this study, we examined the effects on survival and prognostic factors of different treatment methods for HCCA and found that a radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of these patients.
Of the 354 patients with HCCA in this study, 203 underwent resection, with an R0 resection rate of 54.2% (110/203) lower than the 76.7% reported by Guglielmi et al. However, they examined only 62 cases in that study. Operative resection was superior to biliary drainage procedures alone in terms of median survival (P < 0.001), and radical resection was superior to other treatment methods in terms of median survival and 1-, 2-, and 3-year survival rates (P < 0.001), as it has been reported in other studies.,, Subgroup analysis of the nonradical resection group showed that the survival of patients receiving R1 and R2 resections with differing TG levels (P = 0.043), patients with lymph node metastasis (P = 0.003), and patients with distant metastasis (P < 0.001) were significantly different. However, in no other subgroups could significant differences in survival be detected, and overall, the patients in these two groups showed no significant difference in survival (P = 0.367), which is similar to the results of Matull et al., but different from those of other studies., For patients who cannot undergo radical resection, using intra-operative frozen margin examination will not expand the resection range significantly and will reduce the influence of the operative wound on the prognosis. However, relevant standards must be further developed for the pathological examination of operative margins.,
Nonradical resection still showed the improvement in survival over biliary drainage procedures alone (13.6 vs. 8.7 months; P < 0.001). The effect of nonradical lump resection on the improvement of biliary obstruction is superior to that of biliary drainage-only and further prevents tumor invasion. However, patients with HCCA receiving nonradical resection may have poor performance with advanced tumor stage, and thus, deaths and other complications caused by operative wound emergencies cannot be ignored. One patient who underwent R0 resection in our study died due to multi-organ dysfunction syndrome on the postoperative day 29, and one patient who underwent R1 resection died due to septic shock on the postoperative day 62. For patients with HCCA receiving biliary drainage-only, treatment with ERBD and PTCD had no statistically significant effect on survival (P = 0.897). Other than TBIL (P = 0.002) and carbohydrate antigen 19-9 (P = 0.008), there were no significant factors related to survival detected in the two groups [Table 4]. In our hospital, after analyzing survival and complications, we administer jaundice-reducing treatment to patients with HCCA, which could have resulted in the patients that received ERBD and PTCD having no difference in survival.
|Table 4: Endoscopic retrograde biliary drainage group and percutaneous transhepatic cholangiography and drainage group pretreatment demographics and tumor characteristics|
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We found that the treatment method, ALB, TBIL, pT-stage, and distant metastasis were significant independent factors influencing the prognosis [Table 3]. ALB reflects the fasting serum ALB levels of the patient before receiving nutritional therapy in our hospital and can reflect the nutritional status of the patient. Previous studies have shown that malnutrition is related to poor prognosis in other malignant tumors.,, The nutritional status of the whole body can be assessed by many methods although ALB is a superior index to many of these options., As the tumor invades the surrounding nerves and blood vessels, patients with HCCA are caused pain and other discomforts, which can result in the patient reducing their food intake, and if an infection of the biliary tract occurs, energy consumption will increase, which further aggravates malnutrition. When ALB is low and the nutritional status is poor, patients are less capable of undergoing more taxing treatment methods, such as surgery. The nutritional indexes status of the patient (e.g., ALB) before receiving treatment will also influence the selection of treatment methods. We found that patients with HCCA with an ALB level ≥35 g/L had superior survival to those with an ALB level <35 g/L (P < 0.001). Clinically, we have improved the prognosis of patients with HCCA by intravenous administration of ALB, which relieves edema. Clinicians should consider improving the nutritional status of the patient, thus further improving prognosis.
TBIL was an independent prognostic factor for HCCA (HR: 1.620; 95% CI: 1.020–2.573). An increase in the bilirubin level can damage multiple organs, so preoperative reduction in the bilirubin level can improve the prognosis.,, However, at present, there are still disputes as to at what level a preoperative jaundice-reducing treatment can be safely performed.,, Japanese scholars suggest that, for patients with HCCA with jaundice, jaundice-reducing treatment should be performed before resection, but this point of view is too absolute. We found that when patients were stratified by high and low TBIL (4 mg/dL), there was a significant difference in survival (P = 0.006), and most of our patients did not undergo preoperative jaundice-reducing treatment (162/188). These data reflect the influence of TBIL on HCCA.
The treatment of patients with HCCA in our center, mainly focuses on hepatobiliary surgery. However, our study also found that for patients with HCCA treated in other departments, some patients having early Bismuth–Corlette staging, and no distant metastasis on enhanced computed tomography or magnetic resonance imaging examinations underwent nonoperative treatment. At present, HCCA has multiple treatment options, and each method has different effects, and thus, our study highlights the value of multidisciplinary treatment in the comprehensive management of HCCA patients to improve the prognosis.
| > Conclusion|| |
The early diagnosis of HCCA and radical surgery are important to prolong survival. ALB, TBIL, pT-stage, and distant metastasis are independent prognostic factors for HCCA. Improving the level of preoperative ALB and decreasing that of preoperative TBIL are conducive to improving the prognosis of patients with HCCA, but this requires confirmation in a prospective, multicenter, randomized controlled study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]