Correlation between serum total bilirubin and survival in advanced cancer with obstructive jaundice after percutaneous biliary drainage

Abstract

Purpose

The main purpose of our study was to evaluate the impact of a decreased proportion of total serum bilirubin after percutaneous transhepatic biliary drainage (PTBD) on survival and to identify prognostic factors associated with survival in patients with malignant obstruction jaundice (MOJ).

Methods

From July 2010 to February 2021, 269 patients with MOJ were included. Survival time and prognostic factors were analyzed by Kaplan–Meier curves and the Cox model. The cut-off value of a decrease in the proportion of total serum bilirubin level that predicted patient mortality was determined by receiver operating characteristic (ROC) curves.

Results

The overall median survival time after PTBD was 135 days (min13-max1276 days-95% IC:117–153). The overall survival (OS) improved from 95 days to 243 days when the procedure achieved functional success. Multivariate analysis demonstrated that functionally successful drainage and post-drainage treatment were independent positive prognostic factors, but the total bilirubin after drainage and tumor size were independent negative predictive values. The cut-off value of the proportional decrease in the total serum bilirubin level for predicting the clinical prognosis was 0.44.

Conclusions

Palliative care after drainage can prolong patient survival and improve their quality of life. A decreased proportion of total serum bilirubin after PTBD could be used to predict the survival prognosis in patients.

Introduction

Malignant obstructive jaundice (MOJ), a common complication of advanced malignant tumors of the hepatobiliary and peripancreatic region, is caused by local invasion of the extrahepatic biliary tree or less commonly the intrahepatic bile duct(s) [1, 2, 3]. Less common causes include compression by lymph node metastases from other tumors such as lung cancer and lymphoma [4, 5]. The site of obstruction is usually in the extrahepatic biliary tree and most commonly either at the hilum or in the distal common bile duct or periampullary region. Obstructive jaundice markedly affects the quality of life of patients, causing a loss of appetite, very symptomatic pruritus, steatorrhea, and even cachexia. Persistent or advanced biliary obstruction causes liver dysfunction and even biliary cirrhosis, which ultimately makes it too risky or even impossible to perform surgical treatment and chemotherapy. Thus, the extent and duration of MOJ is considered a risk factor for poor prognosis [2, 6].

Achieving effective and durable biliary decompression is the mainstay of treatment for MOJ. The procedures used include placement if an endobiliary drainage catheter via endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic biliary drainage (PTBD), and endoscopic, ultrasound-guided biliary drainage (EUS-BD). Clinically successful drainage with a decrease in serum and bilirubin have been shown to have a significant impact on patient prognosis and survival [2, 7]. The primary objective of this study was to screen for independent risk factors for survival in patients with MOJ. Our secondary objective was to assess whether the extent of changes in serum bilirubin could be used to predict both eventual survival as well as the success of follow-up treatment on survival.

Materials And Methods

Patient selection

From July 2010 to February 2021, we reviewed retrospectively the outcomes of 269 patients with MOJ treated by PTBD (90 male and 179 female). This study was approved by the Institutional Review Board and all patients signed informed consent.

The inclusion criteria were as follows: 1. History of malignant neoplasm; 2. biliary dilation diagnosed by computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), or color Doppler ultrasonography; and 3. laboratory evaluation showing increased serum levels of total and direct bilirubin.

The exclusion criteria were as follows: 1. Patients with severe coagulation dysfunction; 2. patients with multiple organ failure and unable to undergo surgery; 3. patients with severe infection; and 4. patients lacking procedural information.

The collected variables included patient characteristics and history, laboratory data, pathologic type, complications, follow-up treatment, and overall survival.

Follow up

All patients (100%) were followed from the procedure until the time of death or the end of the study period (February 2021). Follow-up data included patient survival, laboratory data 2 weeks after the procedure, and all follow-up treatment.

Definitions

Technical success: Successful placement of a drainage catheter or stent in a biliary stricture.

Functional success: According to previous study [3], total serum bilirubin level decreased to a normal level or to less than half of the value before PTBD.

Postoperative bleeding: A decrease in hemoglobin of > 2 g/dl after surgery and/or symptoms of hematemesis or melena.

Biliary tract infection: Postoperative fever > 38°C or leukocytosis > 10*10⁵/L.

Overall survival: The time from the start of PTBD to patient’s death or the end of follow-up.

Complications

Common adverse reactions were based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.3 [8]. Complications were classified as major and minor in accordance with the reporting standards of the Society of Interventional Radiology [9].

Statistical Analysis

Statistical analysis was performed using SPSS v22.0 (IBM Corp, Armonk, NY). Continuous variables are presented as mean ± standard deviation (normal distribution) or median and interquartile range (IQR) as appropriate by distribution, and categorical variables are described by frequency and percentage. Quantitative data with a normal distribution were analyzed using the t-test; otherwise, they were analyzed by Mann–Whitney U-test. Categorical variables were analyzed by the chi-square test or Mann–Whitney U-test. Prognostic factors were analyzed by the Cox model, and survival time was calculated using Kaplan–Meier curves and the Log rank tests. For all analyses, p-values < 0.05 were considered statistically significant. The proportional decrease in total serum bilirubin level was calculated as: 1 – total serum bilirubin after PTBD/total serum bilirubin before PTBD. To predict the survival rate, the cut-off value for this proportional decrease in serum bilirubin was determined using receiver operating characteristic (ROC) curves and analysis of the area under the ROC curve (AUC).

Results

The clinical characteristics of the patients are summarized in Table 1. Patients with MOJ (n = 269) included 179 women and 90 men. The median age of the patients was 58 years (range: 26–90). The sites of the primary neoplasm were liver cancer (n = 44, 16.4%), cholangiocarcinoma (n = 74, 27.5%), gastric and duodenal periampullary ampulla malignancies (n = 68, 25.3%), pancreatic cancer (n = 14, 5.2%), and colon cancer (n = 54, 20.1%). The mean diameter of the primary neoplasm was 5.2 ± 0.2 cm. Eighty-nine patients underwent resection of the primary neoplasm. The location of MOJ was the hepatic hilar area in 161 patients and the common bile duct in 108. A total of 109 patients underwent anti-neoplastic treatment after bile duct drainage, including 92 patients who received systemic chemotherapy and 17 patients who received local minimally invasive interventional therapy for metastatic or primary tumor. The technical success rate was achieved in 260 patients (96.7%), among whom 8 underwent PTBD after failure of ERCP and 6 underwent ERCP after failure of PTBD. Concerning the functional success, the total serum bilirubin decreased by > 50% in 136 patients (50.6%). Unfortunately, due to less detailed stent implantation records and the small number of stent-related cases in the past, we did not analyze stent-related factors.

Table 1

Characteristics of the 269 patients with MOJ who previously underwent PTBD
Variables	Total (n = 269)
Age (years)	58 ± 12 (range: 26–90)
Sex
Male	90 (34%)
Female	179 (67%)
Primary tumor
Hepatocellular	44 (16)
Cholangiocarcinoma	74 (28)
Gastric	68 (25)
The pancreas	14 (5)
Colorectal	54 (20)
Others	15 (6)
Diameter (cm)	5.2 ± 0.2
Previous surgery (primary)
No	180 (67)
Yes	89 (33)
Cause of obstruction
Invasion	48 (8)
Compression	221 (82)
Site of biliary stenosis
Hilum	161(60)
Common bile duct	108 (40)
Post-drainage treatment
Yes	109 (41)
No	160 (60)
Technical success	260 (97)
Functional success	136 (51`)
WBC (cells × 103 /µL)	7.60 ± 3.23
Hemoglobin (g/L)	110.7 ± 18.7
Complications
Cholangitis	77 (29)
Hemorrhage	3 (1)
Note: Continuous variables are expressed as mean ± standard error. Categorical variables are expressed as n (%). PTBD: Percutaneous transhepatic biliary drainage, WBC: White blood cell.

Changes in laboratory data before and after biliary drainage are reported (Table 2). The average preoperative serum total bilirubin level was 248 ± 130 µmol/L, which decreased to 158 ± 134 µmol/L after PTBD. The laboratory evaluation of liver function (including serum total bilirubin, direct bilirubin, AST, ALT) decreased significantly after PTBD compared to before (paired-sample t-test, p < 0.05). The albumin-bilirubin (ALBI) grade was also improved after surgery (p = 0.002), imparting both clinical and statistical significance. Complications after biliary drainage included mainly bleeding and fever. Post-drainage bleeding occurred in three patients, and stopped after giving fresh frozen plasma or correcting the coagulopathy. Seventy-seven patients developed postoperative fever or an increased proportion of the total leukocyte count. After 3–5 days of antibiotic treatment, the body temperature and level of leukocytes returned to normal. The patients whose cause of death was unrelated to the drainage procedure were excluded from data for major complications.

Table 2

Changes in laboratory data before vs. after biliary drainage (using the paired-sample t-test)
	Before biliary drainage	After biliary drainage	P-value
ALT (U/L)	129 ± 180	67 ± 57	< 0.001
AST (U/L)	124 ± 92	85 ± 148	< 0.001
Direct bilirubin (µmol/L)	204 ± 105	131 ± 108	< 0.001
Total bilirubin (µmol/L)	248 ± 130	158 ± 134	< 0.001
ALB (g/L)	35.65 ± 11.1	36.8 ± 7.1	0.859
ALBI score	−1.50	−1.70	0.002
Note: Data are presented as the mean ± standard deviation. ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ALB: albumin, ALBI: albumin-bilirubin.
P-values < 0.05 were considered statistically significant.

Overall survival (OS)

The median OS after PTBD was 135 days (min 13-max 1276 days-95% IC:117–153). The 3 and 6month survival rates were 68.0% and 38.7%, respectively, and the survival time was improved when the procedure was functionally successful. Kaplan–Meier curves and Log rank tests showed that the OS rates after biliary drainage in the non-functional success group (n = 119) were markedly inferior to those (n = 150) in the functional success group (95 days vs. 243 days; p < 0.001; Fig. 1). The functionally successful group were divided into two groups with follow-up treatment (n = 92) and no follow-up treatment (n = 58). The overall median survival was 356 days (95% CI, 312–399) in the group with follow treatment, in which the patients were treated with chemotherapy, transarterial chemoembolization (TACE), or radiofrequency ablation, and was considerably greater than that of the group with no follow-up treatment group (100 days, 95% CI: 82–117; p < 0.001; Fig. 2). Furthermore, the cut-off value of the proportional decrease in total serum bilirubin level for predicting the clinical prognosis after biliary drainage was 0.44. Discrimination power in predicting 6-month mortality was moderately good, with an AUC of 0.768 (95% CI, 0.71–0.82) (Fig. 3), and sensitivity and specificity of 87.5% and 65.5%, respectively. Accordingly, patients with a proportional decrease in total serum bilirubin level of > 0.444 after biliary drainage had better clinical outcomes.

Univariate analysis (Table 3) showed that a hemoglobin < 90 g/L (moderate anemia or less), abnormally increased liver dysfunctional data (total bilirubin, direct bilirubin, AST), larger tumors, and an ALBI grade > − 1.39 were poor prognosis factors. Functionally successful drainage and the ability to undergo post-drainage treatment improved survival. Multivariate analysis demonstrated that success of biliary drainage and post-drainage treatment were independent positive prognostic factors, but post-TBIL and tumor size were independent negative prognostic factors.

Table 3

Results of univariate and multivariate analysis to identify independent prognostic factors for overall survival (using Cox regression model) after biliary drainage
Variables	HR	95% IC	P	HR	95% IC	P
Sex (female)	1.14	0.88–1.47	0.318
Age	1.00	0.99–1.01	0.746
Site of primary neoplasm (Hepatocellular)			0.053
Previous surgery (primary)	1.179	0.913–1.523	0.207
Infection (YES)	1.258	0.964–1.642	0.091
HGB (< 90 g/L)	1.947	1.341–2.828	0.001
Pre-ALT (U/L)	1.000	0.999–1.001	0.386
Pre-AST (U/L)	1.000	0.999–1.001	0.848
Albumin (g/L)	0.988	0.973–1.004	0.132
Pre-DBIL(µmol/L)	1.001	1.000–1.003	0.022
Pre-TBIL(µmol/L)	1.001	1.000–1.002	0.016
Ratio of pre-ALBI			0.006
≤ −1.39
> −1.39	1.411	1.104–1.802
Post-ALT (U/L)	1.001	0.999–1.003	0.35
Post-AST (U/L)	1.003	1.002–1.004	0.001
Post-DBIL(µmol/L)	1.005	1.003–1.006	0.001
Post-TBIL(µmol/L)	1.004	1.003–1.004	0.001	1.001	1.000-1.003	0.018
Ratio of Post-ALBI			0.001
≤ -1.39
> -1.39	2.035	1.575–2.630
Diameter (cm)	1.073	1.030–1.118	0.001	1.072	1.026–1.120	0.002
Obstruction level
Hilar	0.87	0.68–1.11	0.27
Common bile duct
Functional success			0.001	0.683	0.484–0.963	0.030
No
Yes	0.293	0.224–0.382
Follow-up treatment			0.001	0.044	0.025–0.077	0.001
No
Yes	0.034	0.020–0.059
Note: HR: Hazard ratio, CI: Confidence interval. Pre-DBIL: Direct bilirubin before biliary drainage, Pre-TBIL: Total bilirubin before biliary drainage, Post-DBIL: Direct bilirubin after biliary drainage, Post-TBIL: Total bilirubin after biliary drainage.

Discussion

MOJ often occurs in the advanced stage of locally invasive, malignant neoplasms, which directly invade or compress the biliary tree either by the primary tumor or via nodal metastases. The resultant obstructive jaundice further leads to the failure of liver function. The aim of our study was to investigate the prognostic factors of MOJ and the effect of drainage and follow-up treatment on survival time. Our results demonstrated: 1). The median OS in the functionally successful group was statistically significantly greater than in the non-functionally successful group (243 vs 95 days); 2). the median survival time of the group able to undergo follow-up treatment group was also greater than the no follow-up treatment group (356 vs 100 days); 3). anemia, increased serum bilirubin before and persistently after PTBD tumor size, and ALBI grade were poor prognostic factors; and 4. patients with a proportional decrease in total serum bilirubin level after drainage of > 44.4% had a better clinical prognosis. The ROC curve and AUC showed the predictive ability of a proportional decreased in total serum bilirubin. Indeed, an AUC of 0.768 could predict mortality in 77% of patients with MOJ.

In our study, while the technical success rate was 96.7%, which was similar to some previous findings, the clinical success rate of only 50.6% as defined by a decrease to normal or a > 50% decrease was less than that observed in the study of Zhang et al (76.5%) [10]. In the Zhang study, however, clinical success was defined as a 20% decrease in serum bilirubin, which was considerably less than our definition (50%). Moreover, our relatively lower clinical success rate may be explained by the baseline bilirubin levels in our patients which were relatively greater and in our study more patients had advanced cancer, most of whom had hilar invasion, which leads to a high failure rate of biliary drainage.

Univariate statistical analysis revealed the significant variables responsible for poor survival, including anemia, poor liver function, and tumor-related factors. The ALBI grade was statistically significant, with a higher grade being indicative of a worse prognosis. In another study of patients with hepatocellular cancer, the Child–Pugh class was included and showed that Child–Pugh C liver function was a factor affecting survival [3]; however, there was no comparison of the effect of two liver function classifications on survival time in obstructive jaundice. In our study, multivariate statistics showed that after biliary drainage, the resultant total bilirubin was an independent prognostic factor for poor survival despite the pre-drainage serum bilirubin levels were generally not associated with clinical success similar to the findings of a previous study [10].

Our study and several others have demonstrated that successful drainage of obstructive jaundice followed by the ability to provide local therapy, such as TACE, chemotherapy, radiotherapy, or radiofrequency or systemic chemotherapy significantly prolongs survival time and improves the quality of life of patients [2, 11, 12, 13]. The results of our multivariate analysis showed that functional clinical success and post-drainage treatment were independent factors of better survival and improved patient outcomes in these patients with advanced tumors. The overall median survival time in our study was 135 days, which was slightly greater than the intervals of 79–104 days reported in previous studies [2, 11, 13], but OS varies with the patient population studied. What is important is that the median survival time of 243 days in the patients with a functionally successful drainage was significantly greater than in the non-successful group (95 d). In the functionally successful group, patients who received chemotherapy, radiofrequency ablation, or TACE had a greater survival rate than those in the group with no follow-up treatment. Although other studies of patients with colorectal cancer [14] have not shown a relationship between biliary drainage and survival, such differing results might be related to different prognostic factors and patient characteristics. However, our study demonstrated that survival was closely associated with functionally successful drainage and follow-up treatment. However, different results might be generated in different studies due to different prognostic factors and patient characteristics. We maintain that the proportional decrease in post drainage total serum bilirubin level is an important prognostic factor, because the ROC curve and AUC showed its predictive ability.

As in multiple other studies, common complications of biliary drainage include cholangitis, hemorrhage, pancreatitis, pleural injury, biliary-heart reflex, and displacement of the biliary drainage tube after PTBD. Among them, infection and hemorrhage are the main causes of PTBD-related death. In our study, although postoperative infection occurred in 28% of patients, after antibiotic treatment, body temperature and leukocytes returned to normal. No patient died due to infection, and the 30-day mortality rate was 5%, compared to 2–19.8% in previous studies [15.16].

Our study has several limitations that warrant discussion. First, this study was retrospective and included multiple different sites of the primary neoplasm, with the resultant expected heterogeneity in the response to treatment. Second, no subgroup analysis of stenting alone was performed due to the small number of stent-related cases. Third, we only evaluated the outcomes of PTBD patients and did not compare those patients who underwent the somewhat less invasive means of internal biliary drainage like ERCP/endoprosthesis. Fourth, because clinical symptoms such as itching, weakness, nausea, and nutritional status were excluded from our study, we did not analyze the patients’ quality of life. Fifth, no data on general PS were analyzed in this study, which may lead to selection bias between groups. This imbalance of clinical background may have influenced the difference in survival between patients who received successful drainage and those whose PTBD and post-drainage further treatment was unsuccessful. Therefore, randomized controlled trials are needed to support our findings, and possibly focused on specific patient groups like hepatic cancer, cholangiocarcinoma, periampullary and pancreatic cancers, and metastases from colon cancer.

In conclusion, PTBD can be used successfully in selected patients with MOJ to prolong the survival time of patients. Indeed, palliative care after biliary drainage can prolong patients’ survival and improve their quality of life. The proportional decrease in total serum bilirubin level of > 44.4% can be used to expect a greater survival advantage in patients with MOJ.

Declarations

Ethics Approval and Consent to Participate

This retrospective study was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center and all patients signed informed consent. All methods were carried out in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Funding

This study has received funding by National Natural Science Foundation (fund No: 81871467 to Fujun Zhang)

Authors' contributions

Fujun Zhang conceived the project idea. Pan Hu1and Xu He collected the data, Data analysis was performed by Wenliang Zhu and Huanqing Guo. Wenliang Zhu and Huanqing Guo drafted the manuscript. Fujun Zhang reviewed, commented on and approved on the final manuscript.

Acknowledgements

We thank the patients enrolled in this study.

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