search for




 

Preoperative neutrophil-to-lymphocyte ratio is prognostic for early recurrence after curative intrahepatic cholangiocarcinoma resection
Ann Hepatobiliary Pancreat Surg 2023 May;27(2):158-65
Published online May 31, 2023;  https://doi.org/10.14701/ahbps.22-114
Copyright © 2023 The Korean Association of Hepato-Biliary-Pancreatic Surgery.

Woo Jin Choi1,2,7, Fiorella Murillo Perez6, Annabel Gravely6, Tommy Ivanics2,3,4, Marco P. A. W. Claasen2,5, Liza Abraham1, Phillipe Abreu2, Robin Visser2, Steven Gallinger1,2, Bettina E. Hansen6,7, Gonzalo Sapisochin1,2

1Department of Surgery, University of Toronto, Toronto, ON, Canada,
2HPB Surgical Oncology, University Health Network, Toronto, ON, Canada,
3Department of Surgery, Henry Ford Hospital, Detroit, MI, United States,
4Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden,
5Division of HPB & Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands,
6Toronto Center for Liver Disease, University Health Network, Toronto, ON, Canada,
7Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Correspondence to: Gonzalo Sapisochin, MD, PhD, MSc
Department of Surgery, University of Toronto, 585 University Avenue, Toronto, ON M5G 2N2, Canada
Tel: +1-416-340-4800 (ext. 5169), Fax: +1-416-340-3237,
E-mail: Gonzalo.sapisochin@uhn.ca
ORCID: https://orcid.org/0000-0001-9527-8723
Received November 14, 2022; Revised December 16, 2022; Accepted December 27, 2022.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Backgrounds/Aims: Within two years of surgery, 70% of resected intrahepatic cholangiocarcinoma (iCCA) recur. Better biomarkers are needed to identify those at risk of “early recurrence” (ER). In this study, we defined ER and investigated whether preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic-inflammatory index were prognostic of both overall relapse and ER after curative hepatectomy for iCCA.
Methods: A retrospective cohort of patients who underwent curative-intent hepatectomy for iCCA between 2005 and 2017 were created. The cut-off timepoint for the ER of iCCA was estimated using a piecewise linear regression model. Univariable analyses of recurrence were conducted for the overall, early, and late recurrence periods. For the early and late recurrence periods, multivariable Cox regression with time-varying regression coefficient analysis was used.
Results: A total of 113 patients were included in this study. ER was defined as recurrence within 12 months of a curative resection. Among the included patients, 38.1% experienced ER. In the univariable model, a higher preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence overall and in the first 12 months after curative surgery. In the multivariable model, a higher NLR was associated with a higher recurrence rate overall and in the ER period (≤ 12 months), but not in the late recurrence period.
Conclusions: Preoperative NLR was prognostic of both overall recurrence and ER after curative iCCA resection. NLR is easily obtained before and after surgery and should be integrated into ER prediction tools to guide preoperative treatments and intensify postoperative follow-up.
Keywords : Cholangiocarcinoma; Hepatectomy; Recurrence; Liver
INTRODUCTION

The incidence of intrahepatic cholangiocarcinoma (iCCA) appears to be increasing worldwide [1-6]. However, the 5-year overall survival rate is as low as 10%, and this dismal survival rate is partly explained by the 70% recurrence rate of iCCA after curative-intent surgery [7-10]. In fact, most recurrences occur relatively early, with 25% occurring within six months and approximately 50% within two years after surgery [11].

The present research addresses the fact that early recurrence (ER) can happen anywhere from 12 to 24 months after curative-intent surgery for iCCA [12-14]. There is a need to better identify patients at high risk for ER who might benefit from additional treatment strategies such as neoadjuvant chemotherapy or intensified postoperative follow-up [11,15]. Several observational studies have identified risk factors for ER after iCCA resection, such as older age, race, cirrhosis, larger tumor size on imaging, high CA19-9, hepatitis B, a high number of tumor lesions, and suspicious lymph nodes [11-14]. Preoperative neutrophil-to-lymphocyte ratio (NLR) is associated with ER in hepatocellular carcinoma (HCC) and hilar cholangiocarcinoma, but this has not been studied in the context of iCCA ER [16,17]. Systemic inflammatory biomarkers such as NLR, platelet-to-lymphocyte ratio (PLR), and the systemic-inflammatory index (SII) are theorized to enhance the tumor growth environment, lymph node metastasis, and subsequently, disease recurrence [18]. In support of this theory, NLR and SII have been shown to be associated with worse recurrence-free survival (RFS) after iCCA resection, with the endpoint being death or recurrence [19-26]. However, whether these systemic inflammatory biomarkers are prognostic of recurrence in the ER period is unknown. Detection of systemic inflammatory biomarkers has several advantages, as it is inexpensive, non-invasive, and readily available before surgery to be incorporated into iCCA recurrence risk stratification tools [27-33].

Therefore, we aimed to identify patients with high iCCA ER risk by considering systemic inflammatory biomarkers before surgery, as this may determine the need for additional treatments such as neoadjuvant chemotherapy, which is the subject of great debate [8]. The objectives of this study were to (1) Define the optimal cut-off timepoint for early vs. late recurrence after curative iCCA resection; (2) Determine if preoperative NLR, PLR, and/or SII are associated with ER after curative iCCA resection.

MATERIALS AND METHODS

Study design and population

A retrospective, observational cohort study was conducted in a large tertiary academic hospital, University Health Network (UHN), Toronto, Ontario, Canada. All patients aged 18 years and older who underwent elective surgery with a histological diagnosis of iCCA between October 2005 and October 2017 were identified. The electronic patient record system of UHN was used to collect all data. The last date of follow-up was in March 2019, allowing up to 1.5 years of follow-up from the latest surgery date. Patients histologically diagnosed with hilar cholangiocarcinoma, distal cholangiocarcinoma, or HCC were excluded. Patients who received neoadjuvant chemotherapy, had an R1 positive margin status at final pathology, were infected, had ongoing steroid use, or had chronic hematological disease were excluded from the study. Patients with stage R1 were excluded because this study aimed to study recurrence in patients who underwent curative resection. Postoperatively, the clinic follow-up was scheduled with computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis, every 3 months for the first two years, followed by every 6 months for an additional 2 years and annual clinic visits thereafter. The UHN Research Ethics Board approved the study protocol (approval no. 18-5233).

Outcome

The primary outcome was ER of the iCCA. Both loco-regional and distant recurrence of iCCA were coded as recurrence. The date of recurrence was quantified in the following order of priority: (1) date of biopsy confirming recurrence (2) date of radiologic imaging (ultrasound, CT, MRI) when a recurring lesion was found (3) the date of clinical notes reporting recurrence. The time-to-recurrence was calculated by the number of days between the date of surgery and the date of recurrence. The ER time point was derived from this cohort.

Independent factors

The association between preoperative NLR, PLR, and SII with iCCA recurrence was examined in both continuous and categorical classifications. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. PLR was calculated by dividing the absolute platelet count by the absolute lymphocyte count. SII was calculated by multiplying the absolute neutrophil count by the platelet count and dividing by the absolute lymphocyte count. Absolute neutrophil, platelet, and lymphocyte counts were collected from a complete blood count (CBC). If multiple CBC levels were measured, the preoperative CBC measured closest to the time of surgery was used. Subjects without a CBC measurement within six months of surgery were excluded.

Covariates

Based on clinical significance and the literature review, the following covariates were chosen: age (continuous), sex (binary), carbohydrate antigen 19-9 (CA19-9, continuous) at diagnosis, major (3 or more segments) vs. minor hepatectomy, number of tumors based on preoperative imaging, largest tumor diameter based on preoperative imaging (continuous), and receipt of adjuvant systemic chemotherapy (binary). The following covariates were measured from the final surgical pathology report: cirrhosis (binary), largest tumor diameter in centimeters (continuous), number of tumors (continuous), microvascular invasion (binary), macrovascular invasion (binary), tumor differentiation (well, moderate, poor differentiation), tumor growth pattern (intraductal, periductal-infiltrating, mass-forming, and mixed types) and N stage (N0, N1, Nx).

Statistical analysis

To estimate the cut-off time point for separating early and late recurrence of iCCA, we constructed a piecewise linear regression model from the overall time-to-recurrence plot using the R ‘segmented’ package version 1.3-4. The intersection of these two fitted linear regression lines was used as an estimate for ER. A landmark analysis was performed at this chosen 12-month time interval, dividing the univariable analysis to estimate early and late recurrence risks. For the first landmark period (≤ 12 months) or ER analysis, time zero was set as the date of surgery, and patients were censored at the date of death, when they were lost to follow-up, or at 12 months if the patient was alive with no recurrence. For the second landmark period (> 12 months) or late recurrence analysis, time zero was set at 12 months, and the remainder of patients were censored on the date of death and lost to follow-up. A univariable Cox regression model was used and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). To create the multivariable model, covariates with p values of less than 0.20 were kept until there were no more degrees of freedom. Multivariable Cox regression analysis was conducted for all-time recurrence. NLR was defined using two time-varying regression coefficients or regression parameters to estimate the effect of NLR before and after 12 months (landmark time) for violating the proportional hazards assumption. NLR, PLR, and SII were also classified as binary variables (high vs. low) based on the cut-off selected using maximally selected rank statistics by the ‘maxstat’ R package [34,35]. Statistical significance was thus defined as a probability of 0.05 α, and two-sided tests were conducted throughout. Only one variable, CA19-9, had a value greater than 20% (61.1% were missing due to chart review restrictions). CA19-9 was excluded from the primary analysis due to a large amount of missing data. Sensitivity analyses were performed, including patients with CA19-9 values, and incorporating NLR as a continuous variable. All analyses were performed using the IBM SPSS Statistics software v27 and R version 4.0.5 [36].

RESULTS

Study population

A total of 129 charts were reviewed. Patients with neoadjuvant chemotherapy (n = 7), R1 margin status (n = 7) and hematological disease (n = 2) were excluded. After exclusions, 113 patients were included in the final cohort, and the patient characteristics are presented in Table 1. The median age was 63.2 years (IQR 55.1–72.7 years). Sixty-six (58.4%) patients were male, and 15 (13.3%) patients had cirrhosis. The median tumor size on the most recent preoperative imaging was 5.0 cm (IQR 3.7–7.0 cm). Twenty-six (23.0%) subjects received adjuvant systemic chemotherapy. Sixty-one percent of CA19-9 values were missing due to chart review restrictions of any measures outside our institution. The median follow-up after surgery was 2.03 years (IQR 0.95–4.91 years).

Table 1 . Patient characteristics

VariableAll patients (n = 113)
Age (yr)63.2 (55.1–72.7)
Sex
Male66 (58.4)
Female47 (41.6)
Cirrhosis15 (13.3)
NLR2.6 (1.9–3.8)
PLR136.0 (101.5–167.5)
SII586.0 (380.7–810.0)
CA19-9 at diagnosis (U/mL)27.0 (13.0–54.0)
Operation type
Major Hepatectomy97 (85.8)
Minor Hepatectomy16 (14.2)
Tumor size on imaging (cm)5.0 (3.7–7.0)
Tumor size on pathology (cm)5.6 (4.0–7.3)
Number of tumors on imaging1.3 ± 0.8
Number of tumors on pathology1.3 ± 0.8
Tumor differentiation
Well24 (21.2)
Moderate55 (48.7)
Poor31 (27.4)
Tumor growth pattern
Intraductal6 (5.3)
Periductal infiltrating9 (8.0)
Mass forming96 (85.0)
Mixed type2 (1.8)
Microvascular invasion54 (47.8)
Macrovascular invasion44 (38.9)
N stage on pathology
N037 (32.7)
N113 (11.5)
Nx63 (55.8)
Adjuvant systemic therapy26 (23.0)

Values are presented as median (interquartile range), number (%), or mean ± standard deviation.

CA19-9, carbohydrate antigen 19-9; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic inflammatory index.



Recurrence outcome

The overall recurrence rate was 52.2% (59 patients), and the median time-to-recurrence was 18.6 months. The optimal cut-off time point for differentiating early and late recurrence after resection was estimated to be 12 months (y = 3.52x – 3.45 and y = 0.073x + 44.8, x = 14 months, rounded to 12 months cut-off to match the published literature, Fig. 1). Forty-three (38.1%) patients experienced ER, and 16 (14.2%) patients experienced late (> 12 months) recurrence. The absolute recurrence rate measured five years after surgery was 51.3%. Among those who relapsed during ER, liver-only relapse occurred in 13 patients (30.2%).

Fig 1. Piecewise linear regression model to estimate the cut-off time point for differentiating early versus late recurrence of iCCA. Each line's function was y = 3.52x – 3.45 and y = 0.073x + 44.8, with an intersect at x = 14 months. This cut-off was rounded to 12 months to match those published in the literature.

Early vs. late recurrence analysis

The results of the univariable analyses are summarized in Table 2. The high vs. low NLR, PLR, and SII cut-off values were estimated as 4.3, 80.0, 795.0, respectively. High preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence in both the overall and first 12 months after curative surgery (HR 3.04 [95% CI 1.46–6.34]; p = 0.003) and (HR 3.42 [95% CI 1.61–7.23]; p = 0.001), respectively. High preoperative PLR (> 80) was only associated with an increased risk of recurrence overall but not in the early or late recurrence period. High preoperative SII was not associated with the increased risk of recurrence in any time periods. Sex, underlying cirrhosis, tumor size on imaging, microvascular invasion, poor tumor differentiation on pathology, and pathological N1 stage were significantly associated with ER. The number of tumors on pathology (HR 2.35 [95% CI 1.35–4.09]; p = 0.002) and microvascular invasion (HR 6.94 [95% CI 2.23–21.63]; p = 0.001] were significantly associated with late recurrence. The tumor size on pathology and the number of tumors on imaging were removed (HRs closer to 1) due to collinearity with the tumor size on imaging and the number of tumors on pathology, respectively.

Table 2 . Univariable Cox regression with the overall and landmark method analysis of factors associated with early (≤ 12 month) vs. late (> 12 month) iCCA recurrence

VariableOverall recurrence periodEarly recurrence periodLate recurrence period



HR (95% CI)pHR (95% CI)pHR (95% CI)p
Age (per unit increase) (yr)1.01 (0.97–1.01)0.441.00 (0.97–1.02)0.870.97 (0.93–1.02)0.20
Sex (ref.: male)1.69 (0.98–2.90)0.062.08 (1.07–4.07)0.031.03 (0.39–2.76)0.95
Cirrhosis (ref.: no)2.53 (1.29–4.97)0.012.65 (1.30–5.44)0.011.75 (0.23–13.97)0.58
Major hepatectomy (ref.: no)2.47 (0.98–6.2)0.062.10 (0.75–5.87)0.163.98 (0.52–30.3)0.18
NLR > 4.3 (ref.: ≤ 4.3)3.04 (1.46–6.34)0.0033.42 (1.61–7.23)0.0011.31e-08 (0–inf)0.99
PLR > 80 (ref.: ≤ 80)0.44 (0.23–0.86)0.020.57 (0.26–1.24)0.160.14 (0.04–0.53)0.003
SII > 795 (ref.: ≤ 795)1.46 (0.83–2.54)0.191.61 (0.85–3.05)0.141.08 (0.35–3.38)0.89
Tumor size (imaging; per unit increase)1.21 (1.10–1.35)< 0.0011.25 (1.11–1.40)< 0.0011.08 (0.85–1.38)0.54
Number of tumors (pathology; per unit increase)1.38 (1.09–1.75)0.011.28 (0.96–1.69)0.092.35 (1.35–4.09)0.002
Microvascular invasion (ref.: no)2.85 (1.66–4.88)< 0.0012.07 (1.12–3.82)0.026.94 (2.23–21.63)0.001
Macrovascular invasion (ref.: no)0.91 (0.53–1.56)0.721.05 (0.56–1.94)0.890.58 (0.19–1.83)0.36
Tumor differentiation (ref.: well)
Moderate1.71 (0.83–3.51)0.142.61 (1.0–6.81)0.050.68 (0.19–2.38)0.55
Poor2.60 (1.20–5.61)0.023.00 (1.07–8.43)0.042.52 (0.76–8.36)0.13
Tumor growth pattern (ref.: Intraductal)
Periductal infiltrating0.83 (0.14–4.99)0.840.31 (0.03–3.42)0.341.00 (0.22–4.5)0.99
Mass forming1.73 (0.42–7.14)0.451.31 (0.32–5.42)0.714.72e07 (0–inf)0.99
Mixed type3.46 (0.48–24.7)0.221.53 (0.14–16.9)0.736.68 (0.81–54.8)0.08
N stage (ref.: N0)
N13.65 (1.67–7.92)0.0014.86 (1.97–12.03)0.0011.99 (0.24–16.2)0.52
Nx1.10 (0.61–1.99)0.761.60 (0.74–3.45)0.230.52 (0.19–1.45)0.21
Adjuvant systemic therapy (ref.: no)1.44 (0.83–2.51)0.201.24 (0.63–2.41)0.533.98 (0.52–30.3)0.18

iCCA, intrahepatic cholangiocarcinoma; HR, hazard ratio; CI, confidence interval; ref., reference; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic inflammatory index; inf, infinity.



Multivariable Cox regression was conducted on all time-recurrence outcomes (Table 3). Effect estimates of preoperative NLR during the ER and late recurrence periods were adjusted for underlying cirrhosis, tumor size on imaging, microvascular invasion, and pathologic N stage. High preoperative NLR was significantly associated with a higher overall recurrence rate (HR 2.85 [95% CI 1.21–6.71]; p = 0.02). High preoperative NLR was associated with higher recurrence rate in the first 12 months after curative surgery (HR 5.16 [95% CI 1.59–16.8]; p = 0.006), but not after 12 months (HR 2.00 [95% CI 0.69–5.84]; p = 0.20). Underlying cirrhosis, tumor size on imaging, microvascular invasion, and pathologic N1 stage were associated with higher all-time iCCA recurrence (Table 4).

Table 3 . Multivariable Cox regression analysis for all-time iCCA recurrence

VariableHR (95% CI)p
Cirrhosis (ref.: no)3.42 (1.45–8.09)0.005
NLR > 4.3 (ref.: ≤ 4.3)2.85 (1.21–6.71)0.02
Tumor size (imaging, per unit increase)1.21 (1.07–1.37)0.003
Number of tumors (pathology, per unit)0.93 (0.70–1.23)0.60
Microvascular invasion (ref.: no)2.72 (1.50–4.94)0.001
N stage (ref.: N0)
N13.73 (1.64–8.50)0.002
Nx1.37 (0.74–2.52)0.30

iCCA, intrahepatic cholangiocarcinoma; CI, confidence interval; HR, hazard ratio; ref., reference; NLR, neutrophil-to-lymphocyte ratio.



Table 4 . Multivariable Cox regression analysis for all-time iCCA recurrence with the NLR effect in early (≤ 12 month) vs. late recurrence (> 12 month) periods

VariableHR (95% CI)p
Cirrhosis (ref.: no)3.58 (1.51–8.52)0.004
NLR > 4.3 (ref.: ≤ 4.3)a)
Effect estimate for early recurrence period5.16 (1.59–16.8)0.006
Effect estimate for late recurrence period2.00 (0.69–5.84)0.20
Tumor size (imaging, per unit increase)1.22 (1.08–1.37)0.001
Number of tumors (pathology, per unit)0.92 (0.70–1.23)0.58
Microvascular invasion (ref.: no)2.46 (1.34–4.52)0.004
N stage (ref.: N0)
N14.22 (1.80–9.89)< 0.001
Nx1.41 (0.76–2.59)0.27

iCCA, intrahepatic cholangiocarcinoma; HR, hazard ratio; CI, confidence interval; ref., reference; NLR, neutrophil-to-lymphocyte ratio.

a)NLR was defined using two time-varying regression coefficients or regression parameters to estimate the effect of NLR before and after the landmark time of 12 months for violating the proportional hazard assumption.



Sensitivity analysis

The analysis was repeated, keeping the CA19-9 variable with 61.1% missing values and the conclusion of the results did not change. The analysis was also repeated using a continuous NLR variable. The continuous NLR was associated with an increased risk of recurrence in the first 12 months after curative surgery (HR 1.39 [95% CI 1.12–1.71]; p = 0.002) but not in the overall period (HR 1.21 [95% CI 0.9–1.54]; p = 0.10).

DISCUSSION

In this study, ER was defined as recurrence occurring within 12 months after curative hepatectomy for iCCA. Forty-three (38.1%) patients experienced ER. A high preoperative NLR was significantly associated with a higher risk of ER, while high PLR and SII were not. In the adjusted analysis, high preoperative NLR was significantly associated with a higher recurrence rate in the first 12 months after curative surgery. This study is the first to examine the prognostic performance of systemic inflammatory biomarkers for pure recurrence events during the early iCCA recurrence period.

Based on current evidence, the ER of iCCA is defined as recurrence within 12 to 24 months after curative-intent surgery [12,14,37]. One study defined “very early recurrence” as recurrence within 6 months after curative-intent iCCA resection [11]. Although our 38% ER rate is lower than their 50% ER rate, our results corroborate the 12-month ER definition reported by Wang et al. [14]. Our results are further supported by some authors who advocate a 12-month ER definition in the field of HCC compared to the traditional 24 months ER definition [38,39]. External validation of this 12-month ER definition will be needed to correctly select patients who might be harboring aggressive type of iCCA that leads to ER and worse survival [40]. Our study specifically analyzed patients who achieved R0 or negative margin resections, and 70.0% of ER occurred in extrahepatic locations, suggesting that microscopic systemic disease might have been present around the time of surgery and thereafter [41]. The association between high preoperative NLR and higher recurrence rate in the first 12 months suggests that high preoperative NLR status may reflect a higher tumor burden with an increased risk of harboring microscopic systemic disease. These highlight the need for new treatment and surveillance strategies for patients at risk of ER and suggest that we consider providing neoadjuvant or adjuvant systemic treatments [41].

Systemic inflammatory biomarkers such as NLR have been used to augment risk stratification tools for iCCA survival. However, to our knowledge, there are no studies examining NLR in the context of 12-month ER after iCCA resection [27,30]. Instead, many studies have selected RFS as the primary endpoint, which is a composite outcome of both recurrence and death [19-26]. For example, worse RFS was reported in patients with a NLR greater than 2.49 after iCCA resection [20,21]. In contrast, two studies reported that preoperative NLR was not associated with worse RFS after iCCA resections [13,26]. To keep the statistical analysis reflective of our objectives, our study used only recurrence as the primary endpoint and censored death. Furthermore, to demonstrate that the proportional hazards assumptions of NLR were not met after adjusting for other covariates, we kept the early and late effects of NLR in one combined model.

Whether or not systemic inflammatory biomarkers should be analyzed as continuous variables is debatable, as some evidence suggests that these marker levels may be patient-specific rather than a universal fixed value to categorize as high or low [42]. Nevertheless, we decided to categorize it based on a cut-off value for easier interpretation by clinicians. In our sensitivity analysis using a continuous NLR value, the significance of NLR was retained in the ER period, but not in the overall period. This implies that the preoperative inflammatory effects of NLR have a stronger association with recurrence in the first 12 months after surgery. One possible explanation for our findings is that neutrophilia is a sign of inflammation caused by cancer, while lymphocytopenia is a sign of decline in a patient-specific adaptive immune response [42]. Only one other group studied NLR in the pure context of ER and showed that NLR was not associated with ER. However, their definition of ER was set at 24-months, and the analysis of NLR was not adjusted for potential confounders [12]. Our findings demonstrate that preoperative NLR can provide prognostic information for patients undergoing iCCA surgery.

Currently published iCCA ER risk factors are either postoperative factors reported with tumor pathology (pathologic tumor stage, grade, multifocality, lymph node metastasis), or preoperative factors that are difficult to measure accurately (i.e., cirrhosis, CA19-9) [9,43-46]. NLR is easily obtained by non-invasive blood tests, is inexpensive, and is routinely collected before surgery [32]. This makes NLR an attractive biomarker to be implemented in recurrence risk stratification tools designed to guide preoperative treatment decisions and intensify postoperative follow-up [11].

Several strengths and limitations of this study should be noted. In terms of strengths, our study adds a new prognostic factor to the literature in the context of ER. Rather than using the combined effect of both recurrence and death to measure RFS, a Cox regression with a time-varying regression coefficient model was used to focus only on the recurrence effect. However, this study is limited by its single-center and retrospective nature and may be subject to confounding bias from unmeasured confounders. The small sample size may have attenuated the association between NLR level and ER observed in this study. Many CA19-9 tumor markers were measured outside our institution and external chart reviews were restricted by our Research Ethics Board. However, a sensitivity analysis conducted, including 38.9% of CA19-9 values, showed no difference in the conclusion of our results. Routine lymphadenectomy for iCCA resections was recently implemented at our institution following the introduction of the 8th edition of the American Joint Committee on Cancer (AJCC) guidelines in 2017 [47].

In conclusion, we identified that ER can be defined within 12-months after hepatectomy for iCCA. High preoperative NLR was associated with a higher recurrence rate in the first 12 months after curative surgery, but not after 12 months. Because preoperative NLR is easily obtainable by non-invasive tests, this information can be incorporated into existing ER risk prediction tools to help guide preoperative therapies and to intensify postoperative follow-up.

FUNDING

Woo Jin Choi has been supported by the Canadian Institutes of Health Research (CIHR) (FRN: 181365, 2022) for his PhD studies.

CONFLICT OF INTEREST

Gonzalo Sapisochin: Consulting: Astra-Zeneca, Roche, Novartis, Evidera and Integra. Financial compensation for talks: Roche, Astra-Zeneca, Chiesi, and Integra. Research grant: Roche. Other authors do not have any conflicts of interest to declare.

AUTHOR CONTRIBUTIONS

Conceptualization: All authors. Data curation: WJC, AG, LA, PA. Methodology: WJC, FMP, TI, MPAWC, BEH, GS. Visualization: WJC. Writing - original draft: WJC. Writing - review & editing: All authors.

References
  1. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int 2019;39 Suppl 1:98-107.
    Pubmed CrossRef
  2. Todua F, Gagua R, Maglakelidze M, Maglakelidze D. Cancer incidence and mortality - major patterns in GLOBOCAN 2012, Worldwide and Georgia. Bull Georgian Natl Acad Sci 2015;9:168-173.
  3. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;40:472-477.
    Pubmed CrossRef
  4. Flemming JA, Zhang-Salomons J, Nanji S, Booth CM. Increased incidence but improved median overall survival for biliary tract cancers diagnosed in Ontario from 1994 through 2012: a population-based study. Cancer 2016;122:2534-2543.
    Pubmed CrossRef
  5. Ali H, Tedder B, Waqar SH, Mohamed R, Cate EL, Ali E. Changing incidence and survival of intrahepatic cholangiocarcinoma based on Surveillance, Epidemiology, and End Results Database (2000-2017). Ann Hepatobiliary Pancreat Surg 2022;26:235-243.
    Pubmed KoreaMed CrossRef
  6. Javle M, Lee S, Azad NS, Borad MJ, Kate Kelley R, Sivaraman S, et al. Temporal changes in cholangiocarcinoma incidence and mortality in the United States from 2001 to 2017. Oncologist 2022;27:874-883.
    Pubmed KoreaMed CrossRef
  7. Waseem D, Tushar P. Intrahepatic, perihilar and distal cholangiocarcinoma: management and outcomes. Ann Hepatol 2017;16:133-139.
    Pubmed KoreaMed CrossRef
  8. Scott AJ, Shroff RT. Moving the needle forward with locoregional treatment in unresectable cholangiocarcinoma-the jury is still out. JAMA Oncol 2020;6:29-31.
    Pubmed CrossRef
  9. Hu LS, Zhang XF, Weiss M, Popescu I, Marques HP, Aldrighetti L, et al. Recurrence patterns and timing courses following curative-intent resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2019;26:2549-2557.
    Pubmed CrossRef
  10. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268-1289.
    Pubmed CrossRef
  11. Tsilimigras DI, Sahara K, Wu L, Moris D, Bagante F, Guglielmi A, et al. Very early recurrence after liver resection for intrahepatic cholangiocarcinoma: considering alternative treatment approaches. JAMA Surg 2020;155:823-831.
    Pubmed KoreaMed CrossRef
  12. Yang H, Wang J, Li Z, Yang Y, Yang L, Zhang Y, et al. Risk factors and outcomes of early relapse after curative resection of intrahepatic cholangiocarcinoma. Front Oncol 2019;9:854.
    Pubmed KoreaMed CrossRef
  13. Zhang Y, Shi SM, Yang H, Yang LX, Wang Z, Li XD, et al. Systemic inflammation score predicts survival in patients with intrahepatic cholangiocarcinoma undergoing curative resection. J Cancer 2019;10:494-503.
    Pubmed KoreaMed CrossRef
  14. Wang C, Pang S, Si-Ma H, Yang N, Zhang H, Fu Y, et al. Specific risk factors contributing to early and late recurrences of intrahepatic cholangiocarcinoma after curative resection. World J Surg Oncol 2019;17:2.
    Pubmed KoreaMed CrossRef
  15. Yadav S, Xie H, Bin-Riaz I, Sharma P, Durani U, Goyal G, et al. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: a propensity score matched analysis. Eur J Surg Oncol 2019;45:1432-1438.
    Pubmed CrossRef
  16. Hu HJ, Jin YW, Shrestha A, Ma WJ, Wang JK, Liu F, et al. Predictive factors of early recurrence after R0 resection of hilar cholangiocarcinoma: a single institution experience in China. Cancer Med 2019;8:1567-1575.
    Pubmed KoreaMed CrossRef
  17. Shimoda M, Maruyama T, Suzuki K, Tago T, Nishida K, Shimazaki J, et al. Risk factors for recurrence of hepatocellular carcinoma after curative resection. Surg Gastroenterol Oncol 2018;23:314-319.
    CrossRef
  18. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-444.
    Pubmed CrossRef
  19. Sellers CM, Uhlig J, Ludwig JM, Stein SM, Kim HS. Inflammatory markers in intrahepatic cholangiocarcinoma: effects of advanced liver disease. Cancer Med 2019;8:5916-5929.
    Pubmed KoreaMed CrossRef
  20. Chen Q, Yang LX, Li XD, Yin D, Shi SM, Chen EB, et al. The elevated preoperative neutrophil-to-lymphocyte ratio predicts poor prognosis in intrahepatic cholangiocarcinoma patients undergoing hepatectomy. Tumour Biol 2015;36:5283-5289.
    Pubmed CrossRef
  21. Lin G, Liu Y, Li S, Mao Y, Wang J, Shuang Z, et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget 2016;7:50963-50971.
    Pubmed KoreaMed CrossRef
  22. Ohira M, Yoshizumi T, Yugawa K, Kosai-Fujimoto Y, Inokuchi S, Motomura T, et al. Association of inflammatory biomarkers with long-term outcomes after curative surgery for mass-forming intrahepatic cholangiocarcinoma. Surg Today 2020;50:379-388.
    Pubmed CrossRef
  23. Buettner S, Galjart B, van Vugt JLA, Bagante F, Alexandrescu S, Marques HP, et al. Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma. J Surg Oncol 2017;116:1085-1095.
    Pubmed CrossRef
  24. Tan DW, Fu Y, Su Q, Guan MJ, Kong P, Wang SQ, et al. Prognostic significance of neutrophil to lymphocyte ratio in oncologic outcomes of cholangiocarcinoma: a meta-analysis. Sci Rep 2016;6:33789.
    Pubmed KoreaMed CrossRef
  25. Tsilimigras DI, Moris D, Mehta R, Paredes AZ, Sahara K, Guglielmi A, et al. The systemic immune-inflammation index predicts prognosis in intrahepatic cholangiocarcinoma: an international multi-institutional analysis. HPB (Oxford) 2020;22:1667-1674.
    Pubmed CrossRef
  26. Zhang Z, Zhou Y, Hu K, Huang Y. Investigating effects of preoperative inflammatory biomarkers on predicting survival outcomes of intrahepatic cholangiocarcinoma after curative resection. World J Surg Oncol 2020;18:272.
    Pubmed KoreaMed CrossRef
  27. Yoh T, Seo S, Hatano E, Taura K, Fuji H, Ikeno Y, et al. A novel biomarker-based preoperative prognostic grading system for predicting survival after surgery for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2017;24:1351-1357.
    Pubmed CrossRef
  28. Tsilimigras DI, Hyer JM, Paredes AZ, Diaz A, Moris D, Guglielmi A, et al. A novel classification of intrahepatic cholangiocarcinoma phenotypes using machine learning techniques: an international multi-institutional analysis. Ann Surg Oncol 2020;27:5224-5232.
    Pubmed CrossRef
  29. Sasaki K, Margonis GA, Andreatos N, Bagante F, Weiss M, Barbon C, et al. Preoperative risk score and prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma. J Am Coll Surg 2018;226:393-403.
    Pubmed CrossRef
  30. Tsilimigras DI, Mehta R, Aldrighetti L, Poultsides GA, Maithel SK, Martel G, et al. Development and validation of a laboratory risk score (LabScore) to predict outcomes after resection for intrahepatic cholangiocarcinoma. J Am Coll Surg 2020;230:381-391.e2.
    Pubmed CrossRef
  31. Bartsch F, Hahn F, Müller L, Baumgart J, Hoppe-Lotichius M, Kloeckner R, et al. Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging. Hepatobiliary Pancreat Dis Int 2021;20:262-270.
    Pubmed CrossRef
  32. Choi WJ, Cleghorn MC, Jiang H, Jackson TD, Okrainec A, Quereshy FA. Preoperative neutrophil-to-lymphocyte ratio is a better prognostic serum biomarker than platelet-to-lymphocyte ratio in patients undergoing resection for nonmetastatic colorectal cancer. Ann Surg Oncol 2015;22 Suppl 3:S603-S613.
    Pubmed CrossRef
  33. Kitano Y, Yamashita YI, Yamamura K, Arima K, Kaida T, Miyata T, et al. Effects of preoperative neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios on survival in patients with extrahepatic cholangiocarcinoma. Anticancer Res 2017;37:3229-3237.
    CrossRef
  34. Lausen B, Hothorn T, Bretz F, Schumacher M. Assessment of optimal selected prognostic factors. Biom J 2004;46:364-374.
    CrossRef
  35. Hothorn T, Lausen B. On the exact distribution of maximally selected rank statistics. Comput Stat Data Anal 2003;43:121-137.
    CrossRef
  36. R Core Team. A language and environment for statistical computing [Internet]. Vienna: R Foundation for Statistical Computing 2016 [cited 2022 Dec 16].
  37. Zhang XF, Beal EW, Bagante F, Chakedis J, Weiss M, Popescu I, et al. Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg 2018;105:848-856.
    Pubmed CrossRef
  38. Jung SM, Kim JM, Choi GS, Kwon CHD, Yi NJ, Lee KW, et al. Characteristics of early recurrence after curative liver resection for solitary hepatocellular carcinoma. J Gastrointest Surg 2019;23:304-311.
    Pubmed CrossRef
  39. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200-207.
    Pubmed CrossRef
  40. Sahara K, Tsilimigras DI, Toyoda J, Miyake K, Ethun CG, Maithel SK, et al. Defining the risk of early recurrence following curative-intent resection for distal cholangiocarcinoma. Ann Surg Oncol 2021;28:4205-4213.
    Pubmed CrossRef
  41. Akateh C, Ejaz AM, Pawlik TM, Cloyd JM. Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma. World J Hepatol 2020;12:693-708.
    Pubmed KoreaMed CrossRef
  42. Howard R, Kanetsky PA, Egan KM. Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer. Sci Rep 2019;9:19673.
    Pubmed KoreaMed CrossRef
  43. Park HM, Yun SP, Lee EC, Lee SD, Han SS, Kim SH, et al. Outcomes for patients with recurrent intrahepatic cholangiocarcinoma after surgery. Ann Surg Oncol 2016;23:4392-4400.
    Pubmed CrossRef
  44. Saiura A, Yamamoto J, Kokudo N, Koga R, Seki M, Hiki N, et al. Intrahepatic cholangiocarcinoma: analysis of 44 consecutive resected cases including 5 cases with repeat resections. Am J Surg 2011;201:203-208.
    Pubmed CrossRef
  45. Bartolini I, Risaliti M, Fortuna L, Agostini C, Ringressi MN, Taddei A, et al. Current management of intrahepatic cholangiocarcinoma: from resection to palliative treatments. Radiol Oncol 2020;54:263-271.
    Pubmed KoreaMed CrossRef
  46. Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg 2014;149:565-574.
    Pubmed CrossRef
  47. Zhang XF, Xue F, Dong DH, Weiss M, Popescu I, Marques HP, et al. Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis. Ann Surg 2021;274:e1187-e1195.
    Pubmed CrossRef

 

February 2024, 28 (1)