Preoperative C-reactive protein-to-albumin ratio as a prognostic factor in biliary tract cancer: A systematic review and meta-analysis

Background:

The preoperative C-reactive protein-to-albumin ratio is a novel inflammation-based prognostic marker in various cancers. However, its prognostic role in biliary tract cancer is unknown. We conducted a systematic review and meta-analysis to evaluate the prognostic value of preoperative C-reactive protein-to-albumin ratio in biliary tract cancer.

Methods:

A systematic search of the literature for studies evaluating the prognostic value of C-reactive protein-to-albumin ratio in patients undergoing surgery for biliary tract cancer was conducted, and a random effects meta-analysis of overall survival and recurrence-free survival was performed.

Results:

Nine studies with 1292 participants were included. The preoperative C-reactive protein-to-albumin ratio negatively correlated with overall survival (hazard ratio, 2.44 [95% confidence interval: 1.98–2.90]; P < .001) and recurrence-free survival (hazard ratio, 2.73 [95% confidence interval: 2.01–3.70]; P < .001). Subgroup analysis showed that an elevated preoperative C-reactive protein-to-albumin ratio predicted poor overall survival, regardless of the cutoff value, sample size, histological type, and treatment.

Conclusion:

An elevated preoperative C-reactive protein-to-albumin ratio is significantly associated with poor prognosis in patients undergoing surgery for biliary tract cancer. The C-reactive protein-to-albumin ratio may be an independent prognostic biomarker for overall survival and recurrence-free survival in patients undergoing surgery for biliary tract cancer.

1. Introduction

Biliary tract cancer (BTC), which includes bile duct cancer, gallbladder cancer, and ampullary carcinoma, is a rare but lethal malignancy.^[1] The incidence of BTC has increased in recent decades.^[1] In Japan, BTC is the 6th leading cause of cancer-related deaths; > 180,000 people die from BTC each year.^[2]

Radical resection is the only curative treatment for BTC. However, the high recurrence rate is a major concern.^[3] BTC is usually diagnosed at an advanced stage when most patients are not eligible for radical resection. Despite advances in surgical techniques and adjuvant therapy, the prognosis of BTC remains poor.^[4,5] Preoperative prognostic markers for BTC may allow better risk-benefit assessment before surgery and permit patient stratification for more individualized treatment.^[6] Therefore, it is important to identify novel predictive biomarkers.

There is increasing evidence that the systemic inflammatory response plays an important role in the progression of various cancers.^[7] Several inflammatory markers, such as platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio, have been used as prognostic markers in various cancers. ^[8,9] These preoperative markers are relatively easy and inexpensive to quantify in blood. Quantification of inflammatory markers has been refined with the use of a selective combination of C-reactive protein and albumin.

The C-reactive protein-to-albumin ratio (CAR) has been reported as a novel inflammation-based prognostic marker in various cancers, including esophageal cancer, hepatocellular carcinoma, and colorectal cancer. ^[10–12] However, its prognostic role in BTC is unknown. We conducted a systematic review and meta-analysis to evaluate the prognostic value of preoperative CAR in patients undergoing surgery for BTC.

2. Materials and methods

2.1. Ethical issues

This systematic review does not require ethical approval or informed consent because there was no direct contact with individual patients, and only previously published data were included in the review.

2.2. Design and search strategy

A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.^[13] PubMed, Cochrane Central, ProQuest, and Google Scholar were systematically searched for studies evaluating the prognostic value of CAR in patients undergoing surgery for BTC up to June 1, 2022. The search terms were: (“C-reactive protein-to-albumin ratio” OR “CAR”) AND (“biliary tract cancer” OR “biliary cancer” OR “bile duct cancer” OR “gallbladder cancer” OR “gallbladder carcinoma” OR “ampulla of Vater cancer” OR “ampullary cancer” OR “cholangiocarcinoma”). Publication language was restricted to English. The references of eligible studies and relevant systematic reviews and meta-analyses were manually retrieved.

2.3. Eligibility criteria

The inclusion criteria were: Pathologically confirmed BTC; Preoperative CAR measured by a blood test; Studies evaluating the prognostic value of CAR for overall survival (OS); A clear cutoff value for CAR; and Studies with sufficient data to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The exclusion criteria were: Reviews, Letters, Case Reports, and Conference Abstracts without original data; Studies with insufficient data for analysis; Overlapping or duplicate data; and non-English studies.

2.4. Data extraction and quality assessment

Two reviewers (MU and MI) independently reviewed all eligible studies and extracted data. Disagreements were resolved by discussion with coauthors. The following data were obtained using Data Abstraction Forms: First author’s name, year of publication, study design, country, recruitment period, sample size, age, sex, histological types, CAR cutoff value, cutoff determination method, treatment, survival analysis, HRs and 95% CIs for OS, and clinicopathological features.

Quality was assessed using the Newcastle-Ottawa Scale, which ranges from 0 to 9, based on selection, comparability, and outcome, with a score of ≥ 6 indicating high quality.^[14]

2.5. Statistical analysis

The meta-analysis was performed using Review Manager (version 5.4; The Nordic Cochrane Center, The Cochrane Collaboration, Denmark). The source of heterogeneity was investigated by subgroup analysis. Pooled risk ratios and 95% CIs were calculated using a random effects model in the presence of significant heterogeneity (chi-square P < .05; I² ≥ 50%). Funnel plots were used to evaluate potential publication bias.

3. Results

3.1. Literature retrieval

A flow diagram of the literature selection process is shown in Figure 1. The initial literature search identified 116 records, of which 18 duplicates were removed. After Title and Abstract screening, 82 records were discarded. Sixteen full-text articles were examined, and 9 (n = 1292 participants) ^[15–23] were included in the meta-analysis. Seven records were excluded because they did not report the necessary data (n = 5) or because they were Conference Abstracts (n = 2).

Figure 1.

Flow diagram of study selection.

3.2. Study characteristics

The baseline characteristics are shown in Table 1. The sample size of the included studies ranged from 53 to 271 participants. All studies were retrospective studies published between 2019 and 2022. Six studies were conducted in Japan,^[17–22] 1 in China,^[15] 1 in Korea,^[16] and 1 in Turkey.^[23] All studies had a Newcastle-Ottawa Scale score ≥ 6, indicating high quality.

Table 1.

Characteristics of the studies included in the meta-analysis.

Author (yr)	Country	Sample size	Age (yr)	Study design	Treatment	Histological type	Stage	Cut off value	Survival data	NOS score
Bao et al (2021)[15]	China	144	63	Retrospective	Surgery	GBC	Mixed	0.069	OS	6
Matsumoto et al (2020)[19]	Japan	72	66	Retrospective	Surgery	ICC	Mixed	0.020	OS/RFS	7
Utsumi et al (2020)[20]	Japan	53	73	Retrospective	Surgery	GBC	Mixed	0.070	OS/RFS	6
Yasukawa et al (2020)[21]	Japan	271	70	Retrospective	Surgery	Ecca	Mixed	0.031	OS/RFS	7
Demir et al (2020)[23]	Turkey	178	65	Retrospective	Chemotherapy	BTC	Mixed	0.660	OS	7
Ito et al (2020)[22]	Japan	82	65	Retrospective	Surgery	ICC	Mixed	0.089	OS/RFS	6
Kano et al (2020)[18]	Japan	88	68	Retrospective	Surgery	ICC	Mixed	0.033	OS/RFS	7
Song et al (2021)[16]	Korea	235	70	Retrospective	Surgery	eBDC	Mixed	0.180	OS/RFS	7
Asakura et al (2022)[17]	Japan	169	75	Retrospective	Surgery	eCCA	Mixed	0.230	OS	7

BTC = biliary tract cancer, eBDA = extrahepatic bile duct cancer, eCCA = extrahepatic cholangiocarcinoma, GBC = gallbladder cancer, ICC = intrahepatic cholangiocarcinoma, NOS = Newcastle-Ottawa Scale, OS = overall survival, RFS = recurrence-free survival.

3.3. CAR and OS

All 9 studies involving 1292 participants reported data on preoperative CAR and OS in BTC. A higher CAR was associated with shorter OS (HR, 2.44 [95% CI: 1.98–2.90]; P < .001). No heterogeneity was observed (P = .42; I² = 2%) (Fig. 2). Subgroup analysis showed that an elevated preoperative CAR predicted poor OS, regardless of the cutoff value, sample size, histological type, and treatment (all P < .05) (Table 2). These results indicate that the CAR is a stable prognostic marker for OS in patients undergoing surgery for BTC.

Figure 2.

Forest plot of the association between C-reactive protein-to-albumin ratio and overall survival. SE = standard error, CI = confidence interval.

Table 2.

Subgroup analysis of overall survival.

Subgroup factor	Studies (n)	Patients (n)	HR (95% CI)	P value	Heterogeneity
					I2 (%)	P value
OS	9	1292	2.44 (1.98–2.99)	<.001	2	.42
Sample size
< 100	4	295	3.26 (2.05–5.21)	<.001	0	.62
≥ 100	5	997	2.28 (1.80–2.90)	<.001	11	.34
Histological type
GBC	2	197	3.71 (1.28–10.73)	.02	43	.19
ICC	3	242	3.00 (1.85–4.88)	<.001	0	.85
eCCA	2	440	1.85 (1.36–2.52)	<.001	0	.93
eBDA	1	235	2.43 (1.35–4.38)	.03	–	–
BTC	1	178	3.44 (2.05–5.77)	<.001	–	–
Treatment
Surgery	8	1114	2.28 (1.83–2.85)	<.001	0	.53
Chemotherapy	1	178	3.44 (2.05–5.77)	<.001	–	–
CAR cut off value
< 0.070	4	575	2.07 (1.60–2.67)	<.001	0	.79
≥ 0.070	5	717	3.19 (2.29–4.43)	<.001	0	.50

BTC = biliary tract cancer, CAR = C-reactive protein-to-albumin ratio, CI = confidence interval, eBDA = extrahepatic bile duct cancer, eCCA = extrahepatic cholangiocarcinoma, GBC = gallbladder cancer, HR = hazard ratio, ICC = intrahepatic cholangiocarcinoma, OS = overall survival.

3.4. CAR and recurrence-free survival (RFS)

Six studies involving 801 patients reported data on preoperative CAR and RFS in BTC. A higher CAR was associated with shorter RFS (HR, 2.73 [95% CI: 2.01–3.70]; P < .001). No heterogeneity was observed (P = .82; I² = 0%) (Fig. 3).

Figure 3.

Forest plot of the association between C-reactive protein-to-albumin ratio and recurrence-free survival. SE = standard error, CI = confidence interval.

3.5. Publication bias

The shapes of the funnel plots revealed no obvious asymmetry (see Figure S1, Supplemental Digital Content, http://links.lww.com/MD/I901, which presents funnel plots of publication bias), suggesting that there was no obvious publication bias.

4. Discussion

To our knowledge, this is the first systematic review to evaluate the prognostic value of preoperative CAR in BTC. We combined the outcomes of 1292 participants from 9 individual studies, indicating that an elevated preoperative CAR is associated with poor prognosis (OS and RFS) without heterogeneity. Therefore, we hypothesized that preoperative CAR should be a potential prognostic biomarker in patients with BTC.

The association between inflammation and cancer is based on the observations that tumors often arise at sites of chronic inflammation, and that inflammatory cells are present in biopsied tumor samples.^[24] Clinical and laboratory studies have indicated that inflammation is closely related to cancer progression and metastasis, and an inflammatory tumor microenvironment has recently been proposed as the 7th hallmark of cancer.^[25–27] Therefore, inflammatory markers may predict the prognosis of various cancers, including BTC. Elevated serum C-reactive protein levels reflect a nonspecific inflammatory response to tumor necrosis or local tissue damage and cause a favorable environment for the establishment and growth of distant metastases.^[28] In an experimental study, it has been shown that serum C-reactive protein inhibits cancer cell apoptosis.^[29]

Hypoalbuminemia, a marker of malnutrition and cachexia, is frequently observed in patients with advanced cancer. Serum albumin is also involved in the systemic inflammatory response. Reduced albumin levels are associated with poor long-term survival in patients with various cancers including BTC.^[30]

Preoperative CAR may reflect the systemic inflammatory response and progressive nutritional decline, resulting in poor survival. Perioperative nutritional support is recommended to improve the nutritional status of patients with hepatobiliary-pancreatic carcinoma, because of the high prevalence of malnutrition.^[31] Preoperative immunonutrition has been reported to suppress the perioperative inflammatory response.^[32] Further investigation to evaluate the relationship between immunonutrition and this inflammatory-based prognostic score is important to improve the management of patients with BTC.

This study has several limitations. First, the number of included studies and participants was too small to achieve sufficient statistical power. Second, the CAR cutoff value varied between studies, which may have contributed to the heterogeneity. Third, the majority of studies were retrospective studies from Asia. So it should be careful to apply to Western populations. Fourth, most studies showed positive results. Publication bias may have occurred because positive results are preferentially published over negative results. However, the funnel plots showed no obvious publication bias. More studies with negative results are needed to validate our findings.

5. Conclusion

We showed that an elevated preoperative CAR is significantly associated with poor prognosis in patients undergoing surgery for BTC. The CAR could be a convenient and economical prognostic biomarker of BTC in clinical practice, which could facilitate individual therapeutic approaches and inform the perioperative management of patients with BTC.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Author contributions

Conceptualization: Masaru Inagaki.

Data curation: Masashi Utsumi, Koji Kitada, Naoyuki Tokunaga, Midori Kondo, Kosuke Yunoki, Ryosuke Hamano.

Formal analysis: Masashi Utsumi.

Investigation: Koji Kitada, Naoyuki Tokunaga, Midori Kondo, Kosuke Yunoki, Yuya Sakurai, Ryosuke Hamano, Hideaki Miyasou.

Supervision: Yuya Sakurai.

Validation: Naoyuki Tokunaga.

Writing – original draft: Masashi Utsumi.

Writing – review & editing: Masaru Inagaki, Ryosuke Hamano, Hideaki Miyasou, Yousuke Tsunemitsu, Shinya Otsuka.