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Impact of Baseline Cholinesterase in Patients with Primary Liver Tumors Undergoing Radioembolization: Impact on Outcome

  • Franziska Galiè
  • K. J. Paprottka
  • M. Ingrisch
  • A. Todica
  • H. Ilhan
  • M. Michl
  • T. Geith
  • M. Fabritius
  • E. De Toni
  • P. M. Paprottka
Imaging
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Abstract

The purpose of our study was to determine cutoff values for baseline cholinesterase (CHE) and bilirubin levels prognostic for outcome after radioembolization (RE) in patients with primary liver tumors. In this retrospective single-center study, a threshold for baseline levels of CHE and bilirubin was determined based on overall survival (OS) of patients with refractory primary liver tumors who underwent RE. Between-group differences based on the dichotomized cohort were assessed with the log-rank test. We analyzed N = 92 patients (median age 66.6 years (60.6–73.6 interquartile range), 79% male) with primary liver tumors (57 with hepatocellular carcinoma and 35 with intrahepatic cholangiocarcinoma) who were treated with RE. The median baseline level for bilirubin was 0.7 mg/dl (0.5–1.1 IQR) and for CHE 5.10 kU/l (3.64–6.56), respectively. Median OS in all patients was 429 days (307–550). Cutoff values of baseline bilirubin at 1.6 mg/dl and for CHE at 5 kU/l effectively allowed to differentiate survival groups. In patients with baseline bilirubin ≤ 1.6 mg/dl, OS was significantly higher than in those with bilirubin (> 1.6 mg/dl, P < 0.001). Patients with a baseline CHE of > 5 kU/l showed a significantly longer OS than those with CHE ≤ 5 kU/l, P < 0.001). We suggest that baseline CHE and bilirubin levels have prognostic impact on survival in patients with primary liver tumors after RE. Cutoff values of baseline liver parameters as determined in our study (bilirubin 1.6 mg/dl and CHE 5 kU/l) may help to better select patients eligible for RE.

Keywords

Brachytherapy Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Bilirubin Cholinesterase 

Abbreviations

ICC

Intrahepatic cholangiocarcinoma

CHE

Cholinesterase

EHD

Extrahepatic disease

ECOG

Eastern Cooperative Oncology Group

HCC

Hepatocellular carcinoma

OS

Overall survival

RE

Radioembolization

90Y

Yttrium-90

Introduction

In the last decade, radioembolization (RE) became established as a reasonable treatment option in patients with treatment-refractory malignant primary and secondary liver tumors [1, 2, 3, 4, 5, 6].

From a clinical point of view, selection of patients who are likely to benefit from RE is critical. Pre-therapeutic parameters were identified to guide patient selection and include a good Eastern Cooperative Oncology Group (ECOG) performance status [7], good liver reserve [7, 8], and low-to-moderate extrahepatic disease [1, 8]. The prognostic impact of several serum liver parameters such as bilirubin [8, 9], albumin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase on overall survival (OS) was also described [9, 10].

In addition to well-established parameters, we recently identified not only baseline bilirubin, but also baseline cholinesterase (CHE) as another important serum parameter of liver function prognostic for OS after radioembolization [8, 11]. There have also been prior studies that identified CHE as a prognostic marker for patients scheduled for liver surgery [11, 12, 13, 14] or other liver-directed therapies such as radiotherapy [15]. CHE serves as an important biomarker representative for synthetic liver function especially in cirrhotic liver patients [12, 13]. As liver cirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC) [14, 15, 16], impairment of liver function represents a substantial issue in selection of the best treatment options in those patients. Thus, baseline CHE level may provide helpful information on the impairment of liver function to guide further treatment decision. This may also be true for the second most common primary liver tumor, the intrahepatic cholangiocarcinoma (ICC), which may—among other contributing factors—also be associated with liver cirrhosis [17, 18, 19]. Based on their underlying liver disease, HCC and ICC patients may be more vulnerable to post-treatment liver toxicity after RE. However, the relevance of pre-therapeutic CHE levels for patient selection for RE has not been studied in detail yet.

Purpose

Therefore, we aimed to establish cutoff values for baseline bilirubin and baseline CHE levels in order to contribute to the identification of primary liver tumor patients eligible for RE. The present study was based on the results that both parameters showed prognostic impact on OS in HCC/ICC patients undergoing RE.

Methods and Materials

Ethical Considerations

The study was approved by the institutional review board of [BLINDED], and all subjects signed an informed consent form.

Patients

In this retrospective single-center study, we analyzed a subsample of patients with primary liver tumors (HCC and ICC) from a previously described cohort with primary or secondary liver tumors who underwent RE [8]. Eligibility criteria were patients with primary liver tumor (HCC or ICC) who underwent RE with bilirubin and CHE measurements available at baseline.

Patients and Tumor Characteristics

The following baseline parameters were collected 1 day before the first RE procedure: demographic data (age, gender), tumor burden, extrahepatic disease status (EHD), and absolute bilirubin and CHE level.

Radioembolization

For RE, Yttrium-90 (90Y), a pure beta emitter, was used. It has a mean tissue penetration of 2.5 mm and decays to stable 90Zirconium with an average energy of 0.94 MeV (half-life 2.67 days) and with a maximum range of 11 mm in soft tissue. After injection into the blood stream, the radioactive microspheres follow a predominantly tumor-related vascular distribution, allowing high doses to be reached within the tumor while mainly sparing normal liver parenchyma. Only 90Y resin microspheres (SIR-Spheres; Sirtex, Lane Cove, Australia) at a standard dose of 1.5–2 GBq (with approximately 35 million microspheres with 50 Bq activity each) were used in this study.

Follow-Up

Radiological assessment of tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [20] was performed 3 months after the procedure. Patients were followed-up until death or end of study period.

Statistical Analysis

Descriptive statistics are provided as frequencies and percentages for categorical variables. For continuous variables, medians and interquartile ranges (IQR) are reported. Cutoff values were determined for each, baseline bilirubin and CHE, according to the cutoff finder described in [21]: For every possible cutoff value supported by our dataset, survival data were dichotomized and hazard ratios along with 95% confidence intervals in univariate Cox regression models were calculated.

For survival analysis, Kaplan-Meier plots were generated. Differences between groups were tested using the log-rank test. The level of statistical significance was set at α = 0.05. The statistical software package SPSS was used for descriptive statistics and survival analysis (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). The statistical software package R version 3.3.2 (www.R-project.org) was used to determine the cutoff values and to create the corresponding graphs.

Results

Patients

Out of the complete sample of 389 patients who underwent RE at our institution between March 2009 and December 2012, we identified 92 patients with primary liver tumors who fulfilled the eligibility criteria (see Fig. 1). Table 1 provides an overview of patients and tumor characteristics. Median age was 66.6 years (60.6–73.6) and more male (79%) than female patients (21%) were treated. The majority of the patients had HCC (N = 57 (62%)), compared to 38% with ICC (N = 35). Most patients showed a hepatic tumor burden of less than 25% at baseline. In about half of the patients (55%), extrahepatic disease was present at the time of RE.
Fig. 1

Flowchart patient selection. CHE cholinesterase, HCC hepatocellular carcinoma, ICC intrahepatic cholangiocarcinoma, [BLINDED], RE radioembolization

Table 1

Patients and tumor characteristics

 

Total

HCC patients

ICC patients

N (%)

92

57 (62%)

35 (38%)

Age in years

66.6 (60.6–73.6)

66.5 (62.2–74.6)

67.3 (56.7–73.1)

Male

73 (79%)

50 (88%)

23 (66%)

Tumor burden

 < 25%

46 (51%)

27 (48%)

19 (54%)

 25–50%

32 (35%)

18 (32%)

14 (40%)

 > 50%

13 (14%)

11 (20%)

2 (6%)

Extrahepatic disease

51 (55%)

30 (53%)

21 (60%)

Tumor response

86*

54

32

Partial response

19 (22%)

11 (19%)

8 (25%)

Stable disease

40 (47%)

25 (44%)

15 (47%)

Progressive disease

27 (31%)

18 (32%)

9 (28%)

Bilirubin in mg/dl at baseline (reference range < 1.2)

0.7 (0.5–1.1)

0.9 (0.7–1.2)

0.6 (0.5–0.8)

CHE in kU/l at baseline

(reference range > 4.6)

5.10

(3.64–6.56)

4.08

(3.27–5.35)

6.46

(5.40–7.65)

Data are presented as medians (interquartile range) and frequencies (percent)

CHE cholinesterase, ICC intrahepatic cholangiocarcinoma, HCC hepatocellular carcinoma, RE radioembolization

*Missing data on tumor response for N = 6 patients

Most patients received either one lobe treatment in a single session (N = 36, 39% with right lobar treatment (30%) or left lobar treatment (including selective lobe 4 treatment) (9%)) or whole-liver treatment in a single session (N = 17, 19%). The remaining 39 patients (42%) underwent at least two treatment sessions (either as whole-liver or partial lobar or selective treatments). The median applied dose was higher in ICC patients (1.368 GBq (0.895–1.892)) than in HCC patients (0.969 GBq (0.662–1.297)). Almost half of the patients (47%) showed a stable disease in the radiological assessment according to RECIST.

Bilirubin and CHE Levels

The median bilirubin at baseline was within normal range with 0.7 mg/dl (0.5–1.1 interquartile range, see Table 1). It was slightly higher in HCC patients (0.9 mg/dl) than in ICC patients (0.6 mg/dl). The median CHE at baseline in the whole cohort was 5.10 kU/l (3.64–6.56) and above normal limits (4.62 kU/l). However, patients with HCC showed a median baseline CHE level below normal limits (4.08 kU/l (3.27–5.35)), while median CHE levels in ICC patients were much higher at baseline (6.46 kU/l (5.40–7.65)).

Survival Analysis

Among all patients who underwent RE and were included in the subsequent analysis, median OS was 429 days (95% confidence interval, 307–550). Table 2 summarizes the number of events and median overall survival (OS) with the 95% confidence interval in several subgroups. When comparing OS between tumor types, HCC and ICC patients showed comparable survival times (443 days versus 429 days; chi-square 0.041, P = 0.840; see Fig. 2). Thus, subsequent analyses were performed for the whole subsample of primary liver tumor patients.
Table 2

Median overall survival by type of primary liver tumor, baseline bilirubin, and CHE cutoff values

 

Total

N

Events

N

Median overall survival in days (95% CI)

P value

Overall

92

48

429 (307–550)

 

 HCC

57

27

443 (260–626)

 

 ICC

35

21

429 (272–586)

0.840

Baseline bilirubin

 ≤ 1.6 mg/dl

86

44

443 (305–581)

 

 > 1.6 mg/dl

6

4

114 (0–279)

< 0.001

Baseline CHE

 (1) Low cutoff

  < 2 kU/l

4

2

234 (2 events only)

 

  ≥ 2 kU/l

88

46

443 (304–581)

< 0.001

 (1) High cutoff

  ≤ 5 kU/l

43

23

318 (209–427)

 

  > 5 kU/l

49

25

429 (307–551)

 

ICC intrahepatic cholangiocarcinoma, CHE cholinesterase, HCC hepatocellular carcinoma, CI confidence interval

Fig. 2

Kaplan-Meier plot by type of primary liver tumor. HCC hepatocellular carcinoma, ICC intrahepatic cholangiocarcinoma

Identification of Cutoff Values for Bilirubin and CHE

Using the cutoff finder, we identified thresholds for pre-therapeutic baseline levels of bilirubin and CHE derived from our sample of primary liver tumor patients who underwent RE. Baseline bilirubin split at 1.5 or 1.6 mg/dl was associated with a significantly increased hazard ratio. As there was no difference between the hazard ratios of 1.5 and 1.6 mg/dl, the threshold was set at 1.6 mg/dl allowing the selection of as many patients as possible who are likely to benefit from RE (see Fig. 3a). Using the bilirubin threshold of 1.6 mg/dl, OS differed significantly between patients with baseline bilirubin ≤ 1.6 mg/dl (443 days (305–581)) compared to those with > 1.6 mg/dl (114 days (0–279 days), chi-square 15.750 P < 0.001) (see Fig. 4a). Concerning CHE, we found that a dichotomization of the cohort based on baseline CHE levels at any point within the range between 2 and 5 kU/l allowed to effectively differentiate survival groups (see Fig. 3b). The lower limit of this range lies at CHE = 2 kU/l. Survival analysis confirmed that patients with baseline CHE levels > 5 kU/l show significantly longer OS (429 days (307–551)) compared to patients with baseline CHE levels of ≤ 5 kU/l (318 days (209–427); chi-square 15.750, P < 0.001) (see Fig. 4b).
Fig. 3

Determination of cutoff values. This figure shows the determination of a baseline bilirubin and b baseline cholinesterase (CHE) (x-axis) cutoff values based on the hazard ratios of survival (y-axis). Dots indicate the hazard ratio for the respective threshold value; lines indicate the 95% confidence interval. The red dots indicate that there is no statistical significant difference in the hazard ratios for the corresponding values. The green dots indicate that a dichotomization of the cohort at any point within this range was able to effectively differentiate survival groups (P < 0.05)

Fig. 4

Overall survival based on cutoff values. Kaplan-Meier survival curves for hepatocellular carcinoma and intrahepatic cholangiocarcinoma patients below and above the suggested threshold for a baseline bilirubin threshold at 1.6 mg/dl and b baseline cholinesterase at 5 kU/l.

Discussion

In this study, we determined the following thresholds of baseline bilirubin and CHE for patients with primary liver tumors undergoing RE: bilirubin = 1.6 mg/dl (SI units, 27.36 μmol/l) and CHE = 5 kU/l. By establishing thresholds for these two baseline parameters, we aimed to provide easy assessable and safety-orientated cutoff levels for prognostic serum biomarkers that can assist in patient selection for RE.

RE has been shown to be a safe and effective treatment option in unresectable HCC [22, 23, 24, 25, 26, 27] as well as ICC [3, 28]. The rising incidence of HCC, which is the most common type of primary liver cancer and the second cause of death due to malignancy [29], might augment the importance of RE in the near future. ICC is the second most common primary liver cancer and its incidence is also increasing within the recent years [30]. Taking the growing number of patients with HCC and ICC into consideration, the development of evidence-based decision aids that guide patient selection is crucial.

It is a common understanding that RE requires a sufficient liver reserve and an adequate liver tolerance. Therefore, laboratory inclusion criteria are normal synthetic liver function (often determined by albumin > 2.8 or 3.0 g/dl) and normal total bilirubin (< 2.0 mg/dl) [28, 31, 32]. A well-established and widely used threshold of baseline bilirubin at 2.0 mg/dl to select patients eligible for RE was described in the literature [31, 32]. Although the reason behind this recommendation is to ensure sufficient liver reserve function, a rationale for using exactly 2.0 mg/dl as the cutoff has never been explicitly stated in the literature. While some studies on RE in HCC patients used this 2.0 mg/dl threshold [4], other authors reported slightly stricter inclusion criteria with bilirubin (< 1.75 mg/dl) [10]. Elsewhere, even less strict inclusion criteria with bilirubin < 3.0 mg/dl were suggested [33]. Presumably, in all studies, the baseline bilirubin level was a criterion for patient selection with the rationale to ensure preserved liver function to some extent.

In our cohort, we observed a significant survival difference when using the suggested baseline bilirubin threshold at 1.6 mg/dl. This finding, however, needs to be interpreted with regard to the retrospective study design and the characteristics of our study cohort. Following the currently established baseline bilirubin level of 2.0 mg/dl as an inclusion criterion for patients undergoing RE, only N = 3 patients had higher levels with a maximum of 2.3 mg/dl. These patients underwent RE following the explicit request by the referring physician and the patient in the absence of other therapeutic options. Our results provide first evidence that primary liver tumor patients with bilirubin levels above 1.6 mg/dl live significantly shorter after RE which may be an important additional information when selecting patients for RE. However, before translating this finding into practice, it needs to be confirmed in future studies.

While elevated bilirubin levels indicate impaired hepatic bilirubin clearance [34], CHE is a marker for the synthetic function of the liver [35]. In addition, CHE is considered to be an excellent marker in liver cirrhosis [12] and may therefore be crucial for pre-therapeutic evaluations of liver function especially in primary liver tumor patients and underlying liver cirrhosis. Up to date, only few studies take CHE levels into consideration, namely either as an inclusion criterion (baseline CHE levels within normal limits) [3] or for monitoring liver function after RE [36].

We found that baseline CHE is a sensitive prognostic marker for survival in primary liver tumor patients who underwent RE at our institution. According to our analysis, the possible baseline CHE thresholds identified were 2 and 5 kU/l. Taking into account that in our cohort, only N = 2 patients had a baseline CHE < 2 kU/l, our data provide a limited basis to establish this lower threshold. The limited patient number with a baseline CHE below 2 kU/l is due to the fact that patients at our institutions were usually not considered for RE in case of strongly impaired liver function as, e.g., indicated by very low CHE levels.

Therefore, we suggest determining the CHE baseline threshold at 5 kU/l. By determining this cutoff value at 5 kU/l—which is slightly higher than the normal limit (4.62 kU/l)—we have evenly distributed groups in our dataset (see Table 2). While the median OS among those with CHE levels below 5 kU/l was 111 days shorter than among those with levels about the suggested threshold (median OS, 318 vs. 429 days), this difference was much smaller than that for the median OS between survival groups for the bilirubin cutoff value with 329 days.

It is also important to note that while the higher cutoff value for baseline CHE at 5 kU/l lies within normal limits (> 4.62 kU/l), while a baseline bilirubin of > 1.6 mg/dl is already indicative of significant liver function impairment. Therefore, CHE may serve as a more sensitive marker of liver function than bilirubin. However, one might also argue that using a threshold that is even slightly above the lower limit of the normal range may be too strict, especially in cirrhotic patients who are very likely to show reduced synthetic liver function. Thus, further studies, preferably in a prospective and multi-centric setting, are needed to confirm a clinically meaningful cutoff value for baseline CHE.

Our study should be interpreted in context of the retrospective, single-center study design and the moderate sample size. Although our results may be able to aid in clinical decision-making and patient selection for RE, they need to be confirmed in future studies.

Although both, HCC and ICC, are primary liver malignancies, these entities differ as ICC mainly occurs in the non-cirrhotic liver [37]. It may therefore be interesting to further investigate whether the suggested cutoff values can be validated also in larger cohorts of HCC and ICC patients undergoing RE.

Furthermore, our results cannot be generalized as selection criteria for all patients who were evaluated for treatment using RE as differences between primary and secondary liver malignancies need to be considered. As bilirubin and CHE are likely to be affected more in primary than in metastatic liver disease and treatment approaches and patient selection should be tailored to the corresponding group [32]. However, as CHE has previously been identified as an independent pre-therapeutic factor to predict OS in a mixed group of patients [8, 11], it would also be interesting to investigate CHE levels in metastatic liver disease to evaluate whether diagnosis-specific cutoff values can be established for other malignancies, i.e., metastatic colorectal cancer.

Despite the importance of the two liver function parameters bilirubin and CHE that have been the focus of this study, other parameters also need to be considered. For example, one study reported a cutoff value for the neutrophil-to-lymphocyte ratio in HCC patients who underwent RE [38]. Albumin as another parameter of synthetic liver function has also been shown to predict prognosis in ICC [39]. However, albumin is considered to be a negative acute-phase protein [40] and may therefore be—especially in an inflammatory situation—a less specific marker of synthetic liver function than CHE.

Based on our analyses, we suggest the proposed cutoff values for CHE and bilirubin as they effectively split survival groups of patients with primary liver tumors undergoing RE. The thresholds derived from our cohort were determined at 1.6 mg/dl for baseline bilirubin and at 5 U/l for baseline CHE. Baseline levels of bilirubin and CHE may therefore be useful to stratify patients eligible for RE and provide important guidance in the decision-making process when weighing potential treatment options.

Notes

Funding

This study did not receive any additional funding.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

This article does not contain any studies with animals performed by any of the authors.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of RadiologyUniversity Hospital Munich (LMU)MunichGermany
  2. 2.Department of Nuclear MedicineUniversity Hospital Munich (LMU)MunichGermany
  3. 3.Department of Medicine III, Hematology and OncologyUniversity Hospital, LMU MunichMunichGermany
  4. 4.Institute of Diagnostic and Interventional RadiologyTechnical University of Munich (TUM)MunichGermany
  5. 5.Department of HepatologyUniversity Hospital, LMU MunichMunichGermany

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